Evidence-Based Reviews

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

While most psychiatric treatments have traditionally consisted of pharmacotherapy with oral medications, a better understanding of the pathophysiology underlying many mental illnesses has led to the recent increased use of treatments that require specialized administration and the creation of a subspecialty called interventional psychiatry. In Part 1 of this 2-part article (“Interventional psychiatry [Part 1]," Current Psychiatry, May 2023, p. 24-35, doi:10.12788/cp.0356), we highlighted parenteral medications used in psychiatry, as well as stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections. In Part 2, we review interventional approaches that involve therapeutic neuromodulation and acupuncture.

Neuromodulation treatments

Neuromodulation—the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation, to specific neurologic sites—is an increasingly common approach to treating a variety of psychiatric conditions. The use of some form of neuromodulation as a medical treatment has a long history (Box^1-6). Modern electric neuromodulation began in the 1930s with electroconvulsive therapy (ECT). The 1960s saw the introduction of deep brain stimulation (DBS), spinal cord stimulation, and later, vagus nerve stimulation (VNS). Target-specific noninvasive brain stimulation became possible with transcranial magnetic stimulation (TMS). These approaches are used for treating major depressive disorder (MDD), obsessive-compulsive disorder (OCD), anxiety disorders, and insomnia. Nearly all these neuromodulatory approaches require clinicians to undergo special training and patients to participate in an invasive procedure. These factors also increase cost. Nonetheless, the high rates of success of some of these approaches have led to relatively rapid and widespread acceptance.

Box

Electroconvulsive therapy

In ECT, electric current is applied to the brain to induce a self-limiting seizure. It is the oldest and best-known interventional psychiatric treatment. ECT can also be considered one of the first treatments specifically developed to address pathophysiologic changes. In 1934, Ladislas J. Meduna, who had observed in neuropathologic studies that microglia were more numerous in patients with epilepsy compared with patients with schizophrenia, injected a patient who had been hospitalized with catatonia for 4 years with camphor, a proconvulsant.⁷ After 5 seizures, the patient began to recover. The therapeutic use of electricity was subsequently developed and optimized in animal models, and first used on human patients in Italy in 1939 and in the United States in 1940.⁸ The link between psychiatric illness and microglia, which was initially observed nearly a century ago, is making a comeback, as excessive micro­glial activation has been demonstrated in animal and human models of depression.⁹

Administering ECT requires specialized equipment, anesthesia, physician training, and nursing observation. ECT also has a negative public image.¹⁰ All of these factors conspire to reduce the availability of ECT. Despite this, approximately 100,000 patients in the United States and >1 million worldwide receive ECT each year.¹⁰ Patients generally require 6 to 12 ECT treatments¹¹ to achieve sufficient response and may require additional maintenance treatments.¹²

Although ECT is used to treat psychiatric illnesses ranging from mood disorders to psychotic disorders and catatonia, it is mainly employed to treat people with severe treatment-resistant depression (TRD).¹³ ECT is associated with significant improvements in depressive symptoms and improvements in quality of life.¹⁴ It is superior to other treatments for TRD, such as ketamine,¹⁵ though a recent study did not show IV ketamine inferiority.¹⁶ ECT is also used to treat other neuropsychiatric disorders, such as Parkinson disease.¹⁷

Clinicians have explored alternate methods of inducing therapeutic seizures. Magnetic seizure therapy (MST) utilizes a modified magnetic stimulation device to deliver a higher energy in such a way to induce a generalized seizure under anesthesia.¹⁸ While patients receiving MST generally experience fewer adverse effects than with ECT, the procedure may be equal to¹⁹ or less effective than ECT.²⁰

Transcranial magnetic stimulation

In neuroimaging research, certain aberrant brain circuits have been implicated in the pathogenesis of depression.²¹ Specifically, anatomical and functional imaging suggests connections in the prefrontal cortex are involved in the depression process. In TMS, a series of magnetic pulses are administered via the scalp to stimulate neurons in areas of the brain associated with MDD. Early case reports on using TMS to stimulate the prefrontal cortex found significant improvement of symptoms in patients with depression.²² These promising results spurred great interest in the procedure. Over time, the dose and duration of stimulation has increased, along with FDA-approved indications. TMS was first FDA-approved for TRD.²³ Although the primary endpoint of the initial clinical trial did not meet criteria for FDA approval, TMS did result in improvement across multiple other measures of depression.²³ After the FDA approved the first TMS device, numerous companies began to produce TMS technology. Most of these companies manufacture devices with the figure-of-eight coil, with 1 company producing the Hesed-coil helmet.²⁴

Continue to: An unintended outcome...

An unintended outcome of the increased interest in TMS has been an increased understanding of brain regions involved in psychiatric illness. TMS was able to bring knowledge of mental health from synapses to circuits.²⁵ Work in this area has further stratified the circuits involved in the manifestation of symptom clusters in depression.²⁶ The exact taxonomy of these brain circuits has not been fully realized, but the default mode, salience, attention, cognitive control, and other circuits have been shown to be involved in specific symptom presentations.^26,27 These circuits can be hyperactive, hypoactive, hyperconnected, or hypoconnected, with the aberrancies compared to normal controls resulting in symptoms of psychiatric illness.²⁸

This enhanced understanding of brain function has led to further research and development of protocols and subsequent FDA approval of TMS for OCD, anxious depression, and smoking cessation.²⁹ In addition, it has allowed for a proliferation of off-label uses for TMS, including (but not limited to) tinnitus, pain, migraines, and various substance use disorders.³⁰ TMS treatment for these conditions involves stimulation of specific anatomical brain regions that are thought to play a role in the pathology of the target disorder. For example, subthreshold stimulation of the motor cortex has shown some utility in managing symptoms of pain disorders and movement disorders,^31,32 the ventromedial prefrontal cortex has been implicated in disorders in the OCD spectrum,³³ stimulation of the frontal poles may help treat substance use disorders,³⁴ and the auditory cortex has been a target for treating tinnitus and auditory hallucinations.³⁵

The location of stimulation for treating depression has evolved. The Talairach-Tournoux coordinate system has been used to determine the location of the dorsolateral prefrontal cortex (DLPFC) in relation to the motor cortex. This was measured to be 5 cm from the motor hotspot and subsequently became “the 5.5 cm rule,” taking skull convexity into account. The treatment paradigm for the Hesed coil also uses a measurement from the motor hotspot. Another commonly used methodology for coil placement involves using the 10 to 20 EEG coordinate system to individualize scalp landmarks. In this method, the F3 location corresponds most accurately to the DLPFC target. More recently, using fMRI-guided navigation for coil placement has been shown to lead to a significant reduction in depressive symptoms.³⁶

For depression, the initial recommended course of treatment is 6 weeks, but most improvement is seen in the first 2 to 3 weeks.¹⁴ Therefore, many clinicians administer an initial course of 3 weeks unless the response is inadequate, in which case a 6-week course is administered. Many patients require ongoing maintenance treatment, which can be weekly or monthly based on response.³⁷

Research to determine the optimal TMS dose for treating neuropsychiatric symptoms is ongoing. Location, intensity of stimulation, and pulse are the components of stimulation. The pulse can be subdivided into frequency, pattern (single pulse, standard, burst), train (numbers of pulse groups), interval between trains, and total number of pulses per session. The Clinical TMS Society has published TMS protocols.³⁸ The standard intensity of stimulation is 120% of the motor threshold (MT), which is defined as the amount of stimulation over the motor cortex required to produce movement in the extensor hallucis longus. Although treatment for depression traditionally utilizes rapid TMS (3,000 pulses delivered per session at a frequency of 10 Hz in 4-second trains), in controlled studies, accelerated protocols such as intermittent theta burst stimulation (iTBS; standard stimulation parameters: triplet 50 Hz bursts at 5 Hz, with an interval of 8 seconds for 600 pulses per session) have shown noninferiority.^36,39 

Recent research has explored fMRI-guided iTBS in an even more accelerated format. The Stanford Neuromodulation Therapy trial involved 1,800 pulses per session for 10 sessions a day for 5 days at 90% MT.³⁶ This treatment paradigm was shown to be more effective than standard protocols and was FDA-approved in 2022. Although this specific iTBS protocol exhibited encouraging results, the need for fMRI for adequate delivery might limit its use.

Continue to: Transcranial direct current stimulation

Therapeutic noninvasive brain stimulation technology is plausible due to the relative lack of adverse effects and ease of administration. In transcranial direct current stimulation (tDCS), a low-intensity, constant electric current is delivered to stimulate the brain via electrodes attached to the scalp. tDCS modulates spontaneous neuronal network activity^40,41 and induces polarization of resting membrane potential at the neuronal level,⁴² though the exact mechanism is yet to be proven. N-methyl-D-aspartate-glutamatergic receptors are involved in inhibitory and facilitatory plasticity induced by tDCS.⁴³

tDCS has been suggested as a treatment for various psychiatric and medical conditions. However, the small sample sizes and experimental design of published studies have limited tDCS from being clinically recommended.³⁰ No recommendation of Level A (definite efficacy) for its use was found for any indication. Level B recommendation (probable efficacy) was proposed for fibromyalgia, MDD episode without drug resistance, and addiction/craving. Level C recommendation (possible efficacy) is proposed for chronic lower limb neuropathic pain secondary to spinal cord lesion. tDCS was found to be probably ineffective as a treatment for tinnitus and drug-resistant MDD.³⁰ Some research has suggested that tDCS targeting the DLPFC is associated with cognitive improvements in healthy individuals as well as those with schizophrenia.⁴⁴ tDCS treatment remains experimental and investigational.

Deep brain stimulation

DBS is a neurosurgical procedure that uses electrical current to directly modulate specific areas of the CNS. In terms of accurate, site-specific anatomical targeting, there can be little doubt of the superiority of DBS. DBS involves the placement of leads into the brain parenchyma. Image guidance techniques are used for accurate placement. DBS is a mainstay for the symptomatic treatment of treatment-resistant movement disorders such as Parkinson disease, essential tremor, and some dystonic disorders. It also has been studied as a potential treatment for chronic pain, cluster headache, Huntington disease, and Tourette syndrome.

For treating depression, researched targets include the subgenual cingulate gyrus (SCG), ventral striatum, nucleus accumbens, inferior thalamic peduncle, medial forebrain bundle, and the red nucleus.⁴⁵ In systematic reviews, improvement of depression is greatest when DBS targets the subgenual cingulate cortex and the medial forebrain bundle.⁴⁶ 

The major limitation of DBS for treating depression is the invasive nature of the procedure. Deep TMS can achieve noninvasive stimulation of the SCG and may be associated with fewer risks, fewer adverse events, and less collateral damage. However, given the evolving concept of abnormal neurologic circuits in depression, as our understanding of circuitry in pathological psychiatric processes increases, DBS may be an attractive option for personalized targeting of symptoms in some patients.

DBS may also be beneficial for severe, treatment-resistant OCD. Electrode implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens, is used⁴⁷; there is little difference in placement as a treatment for OCD vs for movement disorders.⁴⁸

Continue to: A critical review of 23 trials...

A critical review of 23 trials and case reports of DBS as a treatment for OCD demonstrated a 47.7% mean reduction in score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a mean response percentage (minimum 35% Y-BOCS reduction) of 58.2%.⁴⁹ Most patients regained a normal quality of life after DBS.⁴⁹ A more rigorous review of 15 meta-analyses of DBS found that conclusions about its efficacy or comparative effectiveness cannot be drawn.⁵⁰ Because of the nature of neurosurgery, DBS has many potential complications, including cognitive changes, headache, infection, seizures, stroke, and hardware failure.

Vagus nerve stimulation

VNS, in which an implanted device stimulates the left vagus nerve with electrical impulses, was FDA-approved for treating chronic TRD in 2005.⁵¹ It had been approved for treatment-resistant epilepsy in 1997. In patients with epilepsy, VNS was shown to improve mood independent of seizure control.⁵² VNS requires a battery-powered pacemaker device to be implanted under the skin over the anterior chest wall, and a wire tunneled to an electrode is wrapped around the left vagus nerve in the neck.⁵³ The pacemaker is then programmed, monitored, and reprogrammed to optimize response.

VNS is believed to stimulate deep brain nuclei that may play a role in depression.⁵⁴ The onset of improvement is slow (it may take many months) but in carefully selected patients VNS can provide significant control of TRD. In addition to rare surgery-related complications such as a trauma to the vagal nerve and surrounding tissues (vocal cord paralysis, implant site infection, left facial nerve paralysis and Horner syndrome), VNS may cause hoarseness, dyspnea, and cough related to the intensity of the current output.⁵¹ Hypomania and mania were also reported; no suicidal behavior has been associated with VNS.⁵¹

Noninvasive vagus nerve stimulationIn noninvasive vagus nerve stimulation (nVNS) or transcutaneous VNS, an external handheld device is applied to the neck overlying the course of the vagus nerve to deliver a sinusoidal alternating current.⁵⁵ nVNS is currently FDA-approved for treating migraine headaches.^55,56 It has demonstrated actions on neurophysiology⁵⁷ and inflammation in patients with MDD.⁵⁸ Exploratory research has found a small beneficial effect in patients with depression.^59,60 A lack of adequate reproducibility prevents this treatment from being more widely recommended, although attempts to standardize the field are evolving.⁶¹

Cranial electrical stimulation

Cranial electrical stimulation (CES) is an older form of electric stimulation developed in the 1970s. In CES, mild electrical pulses are delivered to the ear lobes bilaterally in an episodic fashion (usually 20 to 60 minutes once or twice daily). While CES can be considered a form of neuromodulation, it is not strictly interventional. Patients self-administer CES. The procedure has minimal effects on improving sleep, anxiety, and mood.^62-66 Potential adverse effects include a tingling sensation in the ear lobes, lightheadedness, and fogginess. A review and meta-analysis of CES for treating addiction by Kirsch⁶⁷ showed a wide range of symptoms responding positively to CES treatment, although this study was not peer-reviewed. Because of the low quality of nearly all research that evaluated CES, this form of electric stimulation cannot be viewed as an accepted treatment for any of its listed indications.

Continue to: Other neuromodulation techniques

In addition to the forms of neuromodulation we have already described, there are many other techniques. Several are promising but not yet ready for clinical use. Table 1 and Table 2 summarize the neuromodulation techniques described in this article as well as several that are under development.

Acupuncture

Acupuncture is a Chinese form of medical treatment that began >3,000 years ago; there are written descriptions of it from >2,000 years ago.⁶⁸ It is based on the belief that there are channels within the body through which the Qi (vital energy or life force) flow, and that inserting fine needles into these channels via the skin can rebalance Qi.⁶⁸ Modern mechanistic hypotheses invoke involvement of inflammatory or pain pathways.⁶⁹ Acupuncture frequently uses electric stimulation (electro-acupuncture) to increase the potency of the procedure. Alternatively, in a related procedure (acupressure), pressure can replace the needle. Accreditation in acupuncture generally requires a master’s degree in traditional Chinese medicine but does not require any specific medical training. Acupuncture training courses for physicians are widely available.

All forms of acupuncture are experimental for a wide variety of mental and medical conditions. A meta-analysis found that most research of the utility of acupuncture for depression suffered from various forms of potential bias and was considered low quality.⁷⁰ Nonetheless, active acupuncture was shown to be minimally superior to placebo acupuncture.⁷⁰ A meta-analysis of acupuncture for preoperative anxiety^71,72 and poststroke insomnia⁷³ reported a similar low study quality. A study of 72 patients with primary insomnia revealed that acupuncture was more effective than sham acupuncture for most sleep measures.⁷⁴

Challenges and complications

Psychiatry is increasingly integrating medical tools in addition to psychological tools. Pharmacology remains a cornerstone of biological psychiatry and this will not soon change. However, nonpharmacologic psychiatric treatments such as therapeutic neuromodulation are rapidly emerging. These and novel methods of medication administration may present a challenge to psychiatrists who do not have access to medical personnel or may have forgotten general medical skills.

Our 2-part article has highlighted several interventional psychiatry tools—old and new—that may interest clinicians and benefit patients. As a rule, such treatments are reserved for the most treatment-resistant, challenging psychiatric patients, those with hard-to-treat chronic conditions, and patients who are not helped by more commonly used treatments. An additional complication is that such treatments are frequently not appropriately researched, vetted, or FDA-approved, and therefore are higher risk. Appropriate clinical judgment is always necessary, and potential benefits must be thoroughly weighed against possible adverse effects.

Bottom Line

Several forms of neuromodulation, including electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, and vagus nerve stimulation, may be beneficial for patients with certain treatment-resistant psychiatric disorders, including major depressive disorder and obsessive-compulsive disorder.

Related Resources

• Janicak PG. What’s new in transcranial magnetic stimulation. Current Psychiatry. 2019;18(3):10-16.
• Sharma MS, Ang-Rabanes M, Selek S, et al. Neuromodulatory options for treatment-resistant depression. Current Psychiatry. 2018;17(3):26-28,33-37.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Deaths of children who are killed by their parents often make the news. Cases of maternal infanticide may be particularly shocking, since women are expected to be selfless nurturers. Yet when a child is murdered, the most common perpetrator is their parent, and mothers and fathers kill at similar rates.¹

As psychiatrists, we may see these cases in the news and worry about the risks of our own patients killing their children. In approximately 500 cases annually, an American parent is arrested for the homicide of their child.² This is not even the entire story, since a large percentage of such cases end in suicide—and no arrest. This article reviews the reasons parents kill their children, and considers common characteristics of these parents, dispelling some myths, before discussing the importance of prevention efforts.

Types of child murder by parents

Child murder by parents is termed filicide. Infanticide has various meanings but often refers to the murder of a child younger than age 1. Approximately 2 dozen nations (but not the United States) have Infanticide Acts that decrease the penalty for mothers who kill their young child.³ Neonaticide refers to murder of the infant at birth or in the first day of life.⁴

Epidemiology and common characteristics

Approximately 15%—or 1 in 7 murders with an arrest—is a filicide.² The younger the child, the greater the risk, but older children are killed as well.² Internationally, fathers and mothers are found to kill at similar rates. For other types of homicide, offenders are overwhelmingly male. This makes child murder by parents the singular type of murder in which women and men perpetrate in equal numbers. Fathers are more likely than mothers to also commit suicide after they kill their children.⁵ The “Cinderella effect” refers to the elevated risk of a stepchild being killed compared to the risk for a biological child.⁶

In the general international population, mothers who commit filicide tend to have multiple stressors and limited resources. They may be socially isolated and may be victims themselves as well as potentially experiencing substance abuse.¹ Some mothers view the child they killed as abnormal.

Less research has been conducted about fathers who kill. Fathers are more likely to also commit partner homicide.^5,7 They are more likely to complete filicide-suicide and use firearms or other violent means.^5,7-9 Fathers may have a history of violence, substance abuse, and/or mental illness.⁷

Neonaticide

Mothers are the most common perpetrator of neonaticide.⁴ It is unusual for a father to be involved in a neonaticide, or for the father and mother to perpetrate the act together. Rates of neonaticide are considered underestimates because of the number of hidden pregnancies, hidden corpses, and the difficulty that forensic pathologists may have in determining whether a baby was born alive or dead.

Continue to: Perpetrators of neonaticide...

Perpetrators of neonaticide tend to be single, relatively young women acting alone. They often live with their parents and are fearful of the repercussions of being pregnant. Pregnancies are often hidden, with no prenatal care. This includes both denial and concealment of pregnancy.⁴ Perpetrators of neonaticide commonly lack a premorbid serious mental illness, though after the homicide they may develop anxiety, depression, posttraumatic stress disorder (PTSD), or adjustment disorder.⁴ (Individuals who unwittingly find a murdered baby’s corpse may also be at risk of PTSD.)

Hidden pregnancies may be due to concealment or denial of pregnancy.^10,11 Concealment of pregnancy involves a woman knowing she is pregnant, but purposely hiding from others. Concealment may occur after a period of denial of pregnancy. Denial of pregnancy has several subtypes: pervasive denial, affective denial, and psychotic denial. In cases of pervasive denial, the existence of the pregnancy and the pregnancy’s emotional significance is outside the woman’s awareness. Alternatively, in affective denial, she is intellectually aware that she is pregnant but makes little emotional or physical preparation. In the rarest form, psychotic denial, a woman with a psychotic disorder such as schizophrenia may intermittently deny her pregnancy. This may be correlated with a history of custody loss.^10,11 Unlike denial of other medical conditions, in cases of denial of pregnancy, there will exist a very specific point in time (delivery) when the reality of the baby confronts the woman. Risks in cases of hidden pregnancies include those from lack of prenatal care and an assisted delivery as well as neonaticide. An FBI study¹² of law enforcement files found most neonaticide offenders were single young women with no criminal or psychological history. A caveat is that in the rare cases in which a woman with psychotic illness commits neonaticide, she may have different characteristics from those generally reported.¹³

Motives

Fathers and mothers have a similar set of motives for killing their child (Table 1^13-15). Motives are critical to understand not only within forensics, but also for prevention. In performing assessments after a filicide, forensic psychiatrists must be mindful of gender bias.^7,16 Resnick¹⁵ initially described 5 motives based on his 1969 review of the world literature. Our work^5,17 has subsequently further explored these motives.

In child homicides from “fatal maltreatment,” the child has often been a chronic victim of abuse or neglect. National American data indicate that approximately 2 per 100,000 children are killed from child maltreatment annually. Of note in conceptualizing prevention, out of the same population of 100,000, there will be 471 referrals to Child Protective Services and 91 substantiated cases.¹⁸ However, only a minority of children who die from maltreatment had previous Child Protective Services involvement. While a child may be killed by fatal maltreatment at any age, one-half are younger than age 1, and three-quarters are younger than age 3.¹⁸ In rare cases, a parent who engages in medical child abuse (including factitious disorder imposed upon another) kills the child. Depending on the location and whether or not the death appeared to be intended, parents who kill because of fatal maltreatment might face charges of various levels of murder or manslaughter.

“Unwanted child” homicides occur when the parent has determined that they do not want to have the child, especially in comparison to another need or want. Unwanted child motive is the most common in neonaticide cases, occurring after a hidden pregnancy.⁴

Continue to: In "partner revenge" cases...

In “partner revenge” cases, parenting disputes, a custody battle, infidelity, or a difficult relationship breakup is often present. The parent wants to make the other parent suffer, and does so by killing their child. A parent may make statements such as “If I can’t have [the child], no one can,” and the child is used as a pawn.

In the final 2 motives—“altruistic” and “acutely psychotic”—mental illness is common. These are the populations we tend to find in samples of filicide-suicide cases where the parent has killed themselves and their child, and those found not guilty by reason of insanity.^5,17 Altruistic filicide has been described as “murder out of love.” How can a parent kill their child out of love? Our research has shown several ways. First, the parent may be severely depressed and suicidal. They may be planning their own suicide, and as a parent who loves their child, they plan to take their child with them in death and not leave them alone in the “cruel world” that they themselves are departing. Or the parent may believe they are killing the child out of love to prevent or relieve the child’s suffering. The psychotic parent may believe that a terrible fate will befall their child, and they are killing them “gently.” For example, the parent may believe the child will be tortured or sex trafficked. Some parents may believe that their child has a devastating disease and think they would be better off dead. (Similar thinking of misguided altruism is seen in some cases of intimate partner homicide among older adults.¹⁹)

Alternatively, in rare cases of acutely psychotic filicide, parents with psychosis kill their child with no comprehensible motive. For example, they may be in a postictal state or may hear a command hallucination from God in the context of their psychosis.¹⁵

Myths vs realities of filicide

Common myths vs the realities of filicide are noted in Table 2. There are issues with believing these myths. For example, if we believe that most parents who kill their child have mental illness, this conflates mental illness and child homicide in our minds as well as the mind of the public. This can lead to further stigmatization of mental illness, and a lack of help-seeking behaviors because parents experiencing psychiatric symptoms may be afraid that if they report their symptoms, their child will be removed by Child Protective Services. However, treated mental illness decreases the risks of child abuse, similar to how treating mental illness decreases risks of other types of violence.^20,21

Focusing on prevention

On a local level, we need to understand these tragedies to better understand prevention. To this end, across the United States, counties have Child Fatality Review teams.²² These teams are a partnership across sectors and disciplines, including professionals from health services, law enforcement, and social services—among others—working together to understand cases and consider preventive strategies and additional services needed within our communities.

Continue to: When conceptualizing prevention...

When conceptualizing prevention of child murder by parents, we can think of primary, secondary, and tertiary prevention. This means we want to encourage healthy families and healthy relationships within the family, as well as screening for risk and targeting interventions for families that have experienced difficulties, as well as for parents who have mental illness or substance use disorders.

Understanding the motive behind an individual committing filicide is also critical so that we do not conflate filicide and mental illness. Conflating these concepts leads to increased stigmatization and less help-seeking behavior.

Table 3^{3,4,7,18,22,23} describes the importance of understanding the motives for child murder by a parent in order to conceptualize appropriate prevention. Prevention efforts for 1 type of child murder will not necessarily help prevent murders that occur due to the other motives. Regarding prevention for fatal maltreatment cases, poor parenting skills, including inappropriate expressions of discipline, anger, and frustration, are common. In some cases, substance abuse is involved or the parent was acutely mentally unwell. Reporting to Child Protective Services can be helpful, but as previously noted, it is difficult to ascertain which cases will lead to a homicide. Recommendations from Child Fatality Review teams also are valuable.

Though many parents have frustrations with their children or thoughts of child harm, the act of filicide is rare, and individual cases may be difficult to predict. Regarding prediction, some mothers who committed filicide saw their psychiatrist within days to weeks before the murders.¹⁷ A small New Zealand study found that psychotic mothers reported no plans for killing their children in advance, whereas depressed mothers had contemplated the killing for days to weeks.²⁴

Several studies have asked mothers about thoughts of harming their child. Among mothers with colicky infants, 70% reported “explicit aggressive thoughts and fantasies” while 26% had “infanticidal thoughts” during a colic episode.²⁵ Another study²⁶ found that among depressed mothers of infants and toddlers, 41% revealed thoughts of harming their child. Women with postpartum depression preferred not to share infanticidal thoughts with their doctor but were more likely to disclose that they were having suicidal thoughts in order to get needed help.²⁷ Psychiatrists need to feel comfortable asking mothers about their coping skills, their suicidal thoughts, and their filicidal thoughts.^14,23,28 Screening and treatment of mental illness is critical. Postpartum psychosis is well-known to pose an elevated risk of filicide and suicide.²³ Obsessive-compulsive disorder may cause a parent to ruminate over ego-dystonic child harm but should be treated and the risk conceptualized very differently than in postpartum psychosis.^23,29 Screening for postpartum depression and appropriate treatment of depression during pregnancy and the postpartum period decrease risk.³⁰

Continue to: Regarding prevention of neonaticide...

Regarding prevention of neonaticide, Safe Haven laws, baby boxes, anonymous birth options, and increased contraceptive information and availability can help decrease the risk of this well-defined type of homicide.⁴ Safe Haven laws originated from Child Fatality Review teams.²⁴ Though each state has its own variation, in general, parents can drop off an unharmed unwanted infant into Safe Havens in their state, which may include hospitals, police stations, or fire stations. In general, the mother remains anonymous and has immunity from prosecution for (safe) abandonment. There are drawbacks, such as lack of information regarding adoption and paternal rights. Safe Haven laws do not prevent all deaths and all unsafe abandonments. Baby boxes and baby hatches are used in various nations, including in Europe, and in some places have been used for centuries. In anonymous birth options, such as in France, a mother is not identified but is able to give birth at a hospital. This can decrease the risk from unattended delivery, but many women with denial of pregnancy report that they did not realize when they were about to give birth.⁴

Bottom Line

Knowledge about the intersection of mental illness and filicide can help in prevention. Parents who experience mental health concerns should be encouraged to obtain needed treatment, which aids prevention. However, many other factors elevate the risk of child murder by parents.

Related Resources

• National Center for Fatality Review and Prevention. https://ncfrp.org/
• Child Welfare Information Gateway. https://www.childwelfare.gov/topics/preventing/overview/federal-agencies/

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶

Amnesia secondary to stroke may be transient or permanent.⁷ Amnesia is present in approximately 1% of all strokes and in approximately 19.3% of posterior cerebral artery strokes.^7,17 Unlike TIA and TGA, ischemic amnesia would present with MRI findings detectable at symptom onset. TGA does reveal MRI findings, particularly punctate lesions in the CA1 area of the hippocampus; however, these lesions are typically much smaller than those found in stroke, and are not detectable until 12 to 48 hours after episode onset.^1,17 MRI findings in ischemic amnesia are typically associated with extrahippocampal lesions.¹⁷ Finally, the presence of vascular risk factors such as hyperlipidemia, smoking, diabetes, and hypertension may also favor a diagnosis of stroke or TIA as opposed to TGA, which is not associated with these risk factors.¹⁸ Though ischemic amnesia and TGA usually can be differentiated based on history and presentation, MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging may be performed to definitively distinguish stroke from TGA.⁷

Transient epileptic amnesia (TEA), a focal form of epilepsy within the temporal lobe, should also be considered in patients who present with acute-onset amnesia. Like TGA, TEA may present with simultaneous anterograde and retrograde amnesia accompanied by repetitive questioning.¹⁹ Amnesia can be the sole symptom of TEA in up to 24% of cases. However, several key features distinguish TEA from TGA. TEA most often presents with other clinical signs of seizures, such as oral automatisms and/or olfactory hallucinations.²⁰ There is also a significant difference in episode length; TEA episodes last an average of 30 to 60 minutes and tend to occur upon wakening, whereas TGA episodes last an average of 4 to 6 hours and do not preferentially occur at any particular time.^1,21 In the interictal period—between seizures—patients with TEA may also experience accelerated long-term forgetting, autobiographical amnesia, and topographical amnesia.^19,20 Finally, a diagnosis of TEA also requires recurrent episodes. Recurrence can happen with TGA, but is less frequent.²¹ Generally, history and presentation can distinguish TEA from TGA. Though there is no formal protocol for TEA workup, Lanzone et al²¹ recommend 24-hour EEG or EEG sleep monitoring in patients who present with amnesia as well as other clinical manifestations of epileptic phenomenon.

Continue to: Toxic and metabolic

Toxic and metabolic etiologies of amnesia include opioid and cocaine use, general anesthetics,²² and hypoglycemia.^7,23 Toxic and metabolic causes of amnesia may mirror TGA in their acute onset as well as anterograde nature. However, these patients will likely present with fluctuating consciousness and/or other neuropsychiatric features, such as pressured speech, delusions, and/or distractability.²³ Obtaining a patient’s medical history, including substance use, medication use, and the presence of diabetes,²⁴ is typically sufficient to rule out toxic and metabolic causes.⁷

Posttraumatic amnesia (PTA) describes transient memory loss that occurs after a traumatic brain injury. Anterograde amnesia is most common, though approximately 20% of patients may also experience retro­grade amnesia pertaining to the events near the date of their injury. Unlike TGA, which typically resolves within 24 hours, the recovery time of amnestic symptoms in PTA ranges from minutes to years.⁷ A distinguishing feature of PTA is the presence of confusion, which often resembles a state of delirium.²⁵ The presentation of PTA can vary immensely with regards to agitation, psychotic symptoms, and the time to resolution of the amnesia. Though TGA can be distinguished from PTA based on a lack of clouding of consciousness, a case of anterograde amnesia warrants inquiry into a potential history of head injuries to rule out a traumatic cause.²⁶

Box 2^1,3,23,27-33 outlines current theories of the etiology and pathogenesis of TGA.

Box 2

Transient global ischemia: Psychiatric features

Several studies have demonstrated psychiatric precipitants, features, and comorbidities associated with TGA. Of the TGA cases associated with precipitating events, 29% to 50% are associated with an emotional stressor.^3,4 Examples of emotional stressors include a quarrel,⁴ the announcement of a birth or suicide, and a nightmare.¹⁵ For Ms. A, learning her daughter worked in the sex industry was an emotional stressor.²

During its acute phase, TGA has been shown to present with mood and anxiety symptoms.³⁴ Moreover, during episodes, patients often demonstrate features of panic attacks, such as dizziness, fainting, choking, palpitations, and paresthesia.^3,35

Continue to: Finally, patients with TGA...

Finally, patients with TGA are more likely to have psychiatric comorbidities than those without the condition. In a study of 25 patients who experienced TGA triggered by a precipitant, Inzitari et al⁴ found a strong association of TGA with phobic personality traits, including agoraphobia and simple phobic attitudes (ie, fear of traveling far from home or the sight of blood). Pantoni et al³⁵ replicated these results in 2005 and found that in comparison to patients with TIA, patients with TGA are more likely to have personal and family histories of psychiatric disease. A 2014 study by Dohring et al³⁶ found that compared to healthy controls, patients with TGA are more likely to have maladaptive coping strategies and stress responses. Patients with TGA tended to exhibit increased feelings of guilt, take more medication, and exhibit more anxiety compared to healthy controls.³⁶

Treatment: Benzodiazepines

There are no published treatment guidelines for TGA. However, in case reports, benzodiazepines (specifically lorazepam³⁷) have been shown to have utility in diagnosing and treating DA. The success of benzodiazepines is attributed to its gamma-aminobutyric acid mechanism, which involves inhibiting activity of the N-methyl-D-aspartate (NMDA) receptor, thereby reversing amnesia.³⁷ The NMDA receptor is also implicated in the stress theory of TGA. Though TGA typically resolves on its own within 24 hours, given the distressing nature of this disorder, benzodiazepines may be a suitable option to hasten memory improvement, particularly in patients with psychiatric risk factors.

However, the benzodiazepine midazolam has been identified as a precipitant of TGA. In a case report, Rinehart et al²² identified flumazenil—a benzodiazepine antagonist used primarily to treat retrograde postoperative amnesia—as an antidote. The potentially paradoxical role of benzodiazepines in both the precipitation and treatment of TGA may relate back to the heterogeneity of the etiologies of TGA. Further research comparing the treatment of TGA in patients with stress-induced TGA vs postoperative TGA is needed to better understand the neurochemical basis of TGA and work toward establishing optimal treatment options for different patient demographics.

A generally favorable prognosis

TGA carries a low risk of recurrence. In studies with 3- to 7-year follow-up periods, the recurrence rates ranged from 1.4% to 23.8%.^23,35,38

Memory impairments may be present for 5 to 6 months following a TGA episode. The severity of these impairments may range from clinically unnoticeable to the patient meeting the criteria for mild cognitive impairment.^23,39 The risk is higher in patients who have had recurrent TGA compared to those patients who have experienced only a single episode.²³

Continue to: TGA does not increase...

TGA does not increase the risk of cerebrovascular events. There is controversy regarding a potentially increased risk for dementia as well as epilepsy, though there is insufficient evidence to support these findings.^23,40

CASE CONTINUED

Five hours after the onset of Ms. A’s symptoms, the treatment team initiates oral lorazepam 1 mg. One hour after taking lorazepam, Ms. A’s anterograde and retrograde amnesia improve. She cannot recall why she was brought to the hospital but does remember the date and location, which she was not able to do on initial presentation. She feels safe, states a clear plan for self-care, and is discharged in the care of her partner. Though Ms. A’s memory improved soon after she received lorazepam, this improvement also could be attributed to the natural course of time, as TGA tends to resolve on its own within 24 hours.

Bottom Line

Transient global amnesia (TGA) is an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. It represents an interesting diagnosis at the intersection of psychiatry and neurology. TGA has many established psychiatric risk factors and features—some of which may resemble conversion disorder—but these may only apply to a particular subset of patients, which reflects the heterogeneity of the condition.

Related Resources

• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part I: pathophysiology and etiology. J Clin Med. 2022;11(12): 3373. doi:10.3390/jcm1112337
• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part II: a clinical road map. J Clin Med. 2022;11(14):3940. doi:10.3390/ jcm11143940

Drug Brand Names

Flumazenil • Romazicon
Lorazepam • Ativan
Midazolam • Versed

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶

Amnesia secondary to stroke may be transient or permanent.⁷ Amnesia is present in approximately 1% of all strokes and in approximately 19.3% of posterior cerebral artery strokes.^7,17 Unlike TIA and TGA, ischemic amnesia would present with MRI findings detectable at symptom onset. TGA does reveal MRI findings, particularly punctate lesions in the CA1 area of the hippocampus; however, these lesions are typically much smaller than those found in stroke, and are not detectable until 12 to 48 hours after episode onset.^1,17 MRI findings in ischemic amnesia are typically associated with extrahippocampal lesions.¹⁷ Finally, the presence of vascular risk factors such as hyperlipidemia, smoking, diabetes, and hypertension may also favor a diagnosis of stroke or TIA as opposed to TGA, which is not associated with these risk factors.¹⁸ Though ischemic amnesia and TGA usually can be differentiated based on history and presentation, MRI with fluid-attenuated inversion recovery and diffusion-weighted imaging may be performed to definitively distinguish stroke from TGA.⁷

Transient epileptic amnesia (TEA), a focal form of epilepsy within the temporal lobe, should also be considered in patients who present with acute-onset amnesia. Like TGA, TEA may present with simultaneous anterograde and retrograde amnesia accompanied by repetitive questioning.¹⁹ Amnesia can be the sole symptom of TEA in up to 24% of cases. However, several key features distinguish TEA from TGA. TEA most often presents with other clinical signs of seizures, such as oral automatisms and/or olfactory hallucinations.²⁰ There is also a significant difference in episode length; TEA episodes last an average of 30 to 60 minutes and tend to occur upon wakening, whereas TGA episodes last an average of 4 to 6 hours and do not preferentially occur at any particular time.^1,21 In the interictal period—between seizures—patients with TEA may also experience accelerated long-term forgetting, autobiographical amnesia, and topographical amnesia.^19,20 Finally, a diagnosis of TEA also requires recurrent episodes. Recurrence can happen with TGA, but is less frequent.²¹ Generally, history and presentation can distinguish TEA from TGA. Though there is no formal protocol for TEA workup, Lanzone et al²¹ recommend 24-hour EEG or EEG sleep monitoring in patients who present with amnesia as well as other clinical manifestations of epileptic phenomenon.

Continue to: Toxic and metabolic

Toxic and metabolic etiologies of amnesia include opioid and cocaine use, general anesthetics,²² and hypoglycemia.^7,23 Toxic and metabolic causes of amnesia may mirror TGA in their acute onset as well as anterograde nature. However, these patients will likely present with fluctuating consciousness and/or other neuropsychiatric features, such as pressured speech, delusions, and/or distractability.²³ Obtaining a patient’s medical history, including substance use, medication use, and the presence of diabetes,²⁴ is typically sufficient to rule out toxic and metabolic causes.⁷

Posttraumatic amnesia (PTA) describes transient memory loss that occurs after a traumatic brain injury. Anterograde amnesia is most common, though approximately 20% of patients may also experience retro­grade amnesia pertaining to the events near the date of their injury. Unlike TGA, which typically resolves within 24 hours, the recovery time of amnestic symptoms in PTA ranges from minutes to years.⁷ A distinguishing feature of PTA is the presence of confusion, which often resembles a state of delirium.²⁵ The presentation of PTA can vary immensely with regards to agitation, psychotic symptoms, and the time to resolution of the amnesia. Though TGA can be distinguished from PTA based on a lack of clouding of consciousness, a case of anterograde amnesia warrants inquiry into a potential history of head injuries to rule out a traumatic cause.²⁶

Box 2^1,3,23,27-33 outlines current theories of the etiology and pathogenesis of TGA.

Box 2

Transient global ischemia: Psychiatric features

Several studies have demonstrated psychiatric precipitants, features, and comorbidities associated with TGA. Of the TGA cases associated with precipitating events, 29% to 50% are associated with an emotional stressor.^3,4 Examples of emotional stressors include a quarrel,⁴ the announcement of a birth or suicide, and a nightmare.¹⁵ For Ms. A, learning her daughter worked in the sex industry was an emotional stressor.²

During its acute phase, TGA has been shown to present with mood and anxiety symptoms.³⁴ Moreover, during episodes, patients often demonstrate features of panic attacks, such as dizziness, fainting, choking, palpitations, and paresthesia.^3,35

Continue to: Finally, patients with TGA...

Finally, patients with TGA are more likely to have psychiatric comorbidities than those without the condition. In a study of 25 patients who experienced TGA triggered by a precipitant, Inzitari et al⁴ found a strong association of TGA with phobic personality traits, including agoraphobia and simple phobic attitudes (ie, fear of traveling far from home or the sight of blood). Pantoni et al³⁵ replicated these results in 2005 and found that in comparison to patients with TIA, patients with TGA are more likely to have personal and family histories of psychiatric disease. A 2014 study by Dohring et al³⁶ found that compared to healthy controls, patients with TGA are more likely to have maladaptive coping strategies and stress responses. Patients with TGA tended to exhibit increased feelings of guilt, take more medication, and exhibit more anxiety compared to healthy controls.³⁶

Treatment: Benzodiazepines

There are no published treatment guidelines for TGA. However, in case reports, benzodiazepines (specifically lorazepam³⁷) have been shown to have utility in diagnosing and treating DA. The success of benzodiazepines is attributed to its gamma-aminobutyric acid mechanism, which involves inhibiting activity of the N-methyl-D-aspartate (NMDA) receptor, thereby reversing amnesia.³⁷ The NMDA receptor is also implicated in the stress theory of TGA. Though TGA typically resolves on its own within 24 hours, given the distressing nature of this disorder, benzodiazepines may be a suitable option to hasten memory improvement, particularly in patients with psychiatric risk factors.

However, the benzodiazepine midazolam has been identified as a precipitant of TGA. In a case report, Rinehart et al²² identified flumazenil—a benzodiazepine antagonist used primarily to treat retrograde postoperative amnesia—as an antidote. The potentially paradoxical role of benzodiazepines in both the precipitation and treatment of TGA may relate back to the heterogeneity of the etiologies of TGA. Further research comparing the treatment of TGA in patients with stress-induced TGA vs postoperative TGA is needed to better understand the neurochemical basis of TGA and work toward establishing optimal treatment options for different patient demographics.

A generally favorable prognosis

TGA carries a low risk of recurrence. In studies with 3- to 7-year follow-up periods, the recurrence rates ranged from 1.4% to 23.8%.^23,35,38

Memory impairments may be present for 5 to 6 months following a TGA episode. The severity of these impairments may range from clinically unnoticeable to the patient meeting the criteria for mild cognitive impairment.^23,39 The risk is higher in patients who have had recurrent TGA compared to those patients who have experienced only a single episode.²³

Continue to: TGA does not increase...

TGA does not increase the risk of cerebrovascular events. There is controversy regarding a potentially increased risk for dementia as well as epilepsy, though there is insufficient evidence to support these findings.^23,40

CASE CONTINUED

Five hours after the onset of Ms. A’s symptoms, the treatment team initiates oral lorazepam 1 mg. One hour after taking lorazepam, Ms. A’s anterograde and retrograde amnesia improve. She cannot recall why she was brought to the hospital but does remember the date and location, which she was not able to do on initial presentation. She feels safe, states a clear plan for self-care, and is discharged in the care of her partner. Though Ms. A’s memory improved soon after she received lorazepam, this improvement also could be attributed to the natural course of time, as TGA tends to resolve on its own within 24 hours.

Bottom Line

Transient global amnesia (TGA) is an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. It represents an interesting diagnosis at the intersection of psychiatry and neurology. TGA has many established psychiatric risk factors and features—some of which may resemble conversion disorder—but these may only apply to a particular subset of patients, which reflects the heterogeneity of the condition.

Related Resources

• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part I: pathophysiology and etiology. J Clin Med. 2022;11(12): 3373. doi:10.3390/jcm1112337
• Sparaco M, Pascarella R, Muccio CF, et al. Forgetting the unforgettable: transient global amnesia part II: a clinical road map. J Clin Med. 2022;11(14):3940. doi:10.3390/ jcm11143940

Drug Brand Names

Flumazenil • Romazicon
Lorazepam • Ativan
Midazolam • Versed

Ms. A, age 48, is a physician’s assistant with no psychiatric history. She presents to the emergency department (ED) with her partner and daughter due to a 15-minute episode of acute-onset memory loss and concern for stroke. In the ED, Ms. A is confused and repeatedly asks, “Where are we?” “How did we get here?” and “What day is it?” Her partner denies Ms. A has focal neurologic deficits or seizures.

Ms. A had only slept 4 hours the night before she came to the ED because she had just learned that her daughter works in the sex industry. According to her daughter, Ms. A was raped by a soldier many years ago. At that time, her perpetrator told Ms. A that he would kill her entire family if she ever told anyone. As a result, she never pursued any psychological or psychiatric treatment.

During the evaluation, Ms. A shares details regarding her social and medical history; however, she does not recall receiving bad news the night before. She asks the interviewer several times how she got to the hospital, and when a cranial nerve exam is performed, she states, “I am not the patient!”

Ms. A’s vital signs and physical exam are unremarkable. Urinalysis is significant for a ketones level of 20 mmol/L (reference range: negative for ketones), and a urine human chorionic gonadotropin test is negative. A neurologic exam does not identify any focal deficits. No imaging is performed.

Transient global amnesia (TGA) describes an episode of anterograde, and possibly retrograde, amnesia that lasts up to 24 hours. On presentation, patients experiencing TGA repeatedly ask, “Where am I?” “What day is it?” and “How did I get here?” However, semantic memory—such as knowledge of the world and autobiographical information—is preserved.¹ The first case of TGA was described in 1956, and its diagnostic criteria were most recently modified in 1990 (Table²).

Though TGA is the most common cause of acute-onset amnesia, it is rare, affecting approximately 3 to 10 individuals per 100,000. The average age of onset is 61 to 63, with most cases occurring after age 50. TGA is generally thought to affect males and females equally, though some studies suggest a female predominance.³ In most cases (approximately 90%), there is a precipitating event such as physical or emotional stress, change in temperature, or sexual intercourse.⁴

In this article, we provide an overview of the classification, presentation, differential diagnosis, workup, and treatment of TGA. While TGA is a neurologic diagnosis, in a subset of patients it can present with psychiatric features resembling conversion disorder. For such patients, we argue that TGA can be considered a neuropsychiatric condition (Box 1^5-12). This classification may empower emergency psychiatry clinicians and psychotherapists to identify and treat the condition, which is not described by the current psychiatric diagnostic system.

Box 1

Continue to: Differential diagnosis and workup

The differential diagnosis for acute-onset memory loss in the absence of other neurologic or psychiatric features is broad. It includes:

• dissociative amnesia
• ischemic amnesia
• transient epileptic amnesia
• toxic and metabolic amnesia
• posttraumatic amnesia.

Dissociative amnesia (DA), otherwise known as psychogenic amnesia, is “an inability to recall important autobiographical information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting.”¹³ According to this definition, DA features only retro­grade amnesia, as opposed to TGA, which features anterograde amnesia, with possible retrograde amnesia. A subtype of DA—specifically, “continuous amnesia” or “anterograde dissociative amnesia”— is in DSM-5.¹³ However, the diagnostic criteria are unclear, and no cases have been identified in the literature since 1903, before TGA became a diagnostic entity.^5,14 Moreover, patients with DA cannot recall autobiographical information, which is not a feature of TGA. Within DSM-5, TGA is an exclusion criterion for DA.¹³ Thus, an episode of anterograde amnesia with acute onset best meets criteria for TGA, even if there are substantial psychiatric risk factors.

Ischemic amnesia—including stroke and transient ischemic attack (TIA)—is often the primary concern of patients with TGA and their families upon initial presentation, as was the case with Ms. A.^6,15 TIA presenting with isolated, acute-onset amnesia would be highly unusual, because these attacks usually present with focal symptoms including motor deficits, sensory deficits, visual field deficits, and aphasia or dysarthria. A patient with amnesia experiencing a TIA would likely have symptoms lasting from seconds to minutes, which is much shorter than a typical TGA episode.¹⁶