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/

The advent of unprecedented technologies drastically altering the behavior of children and adolescents, compounded by prolonged isolation from a once-in-a-century pandemic, may have negatively impacted the normal connectivity of the human brain among youth, leading to the current alarming increase of depression, anxiety, and suicidality among this population.

The human brain is comprised of multiple large-scale networks that are functionally connected and control feelings, thoughts, and behaviors. As clinical neuroscientists, psychiatrists must consider the profound impact of a massive societal shift in human behavior on the functional connectivity of brain networks in health and disease. The advent of smartphones, social media, and video game addiction may have disrupted the developing brain networks in children and adolescents, leading to the current escalating epidemic of mental disorders in youth.

The major networks in the human brain include the default mode network (DMN), the salience network, the limbic system, the dorsal attention network, the central executive network, and the visual system.¹ Each network connects several brain regions. Researchers can use functional MRI to detect the connectivity of those networks. When blood flow increases concurrently across 2 or 3 networks, this indicates those networks are functionally connected.

There was an old “dogma” that brain regions use energy only when activated and being used. Hans Berger, who developed the EEG in 1929, noticed electrical activity at rest and proposed that the brain is constantly busy, but his neurology peers did not take him seriously.² In the 1950s, Louis Sokoloff noticed that brain metabolism was the same whether a person is at rest or doing math. In the 1970s, David Ingvar discovered that the highest blood flow in the frontal lobe occurred when a person was at rest.³ Finally, in 2007, Raichle et al⁴ used positron emission tomography scans to confirm that the frontal lobe is most active when a person is not doing anything. He labeled this phenomenon the DMN, comprising the medial fronto-parietal cortex, the posterior cingulate gyrus, the precuneus, and the angular gyrus. Interestingly, the number of publications about the DMN has skyrocketed since 2007.

The many roles of the DMN

Ongoing research has revealed that the DMN is most active at rest, and its anatomical hubs mediate several key functions⁵:

• Posterior cingulate gyrus (the central core of the DMN): remembering the past and thinking about the future
• Medial prefrontal cortex: autobiographical memories, future goals and events, reflecting on one’s emotional self, and considering decisions about family members
• Dorsal medial subsystem: thinking about others, determining and inferring the purpose of other people’s actions
• Temporo-parietal junction: reflecting on the beliefs and emotions of others (known as “theory of mind”⁶)
• Lateral parietal junction: retrieval of social and conceptual knowledge
• Hippocampus: forming new memories, remembering the past, imagining the future
• Posterior-inferior parietal lobe: junction of auditory, visual, and somatic sensory information and attention
• Precuneus: Visual, sensory-motor, and attention.

Many terms have been used to describe the function of the DMN, including “daydreaming,” “auto-pilot,” “mind-wondering,” “reminiscing,” “contemplating,” “self-reflection,” “the neurological basis of the self,” and “seat of literary creativity.”

Psychiatric consequences of DMN deactivation

When another brain network, the attention network (which is also referred to as the task-positive network), is activated consciously and volitionally to perform a task that demands focus (such as text messaging, playing video games, or continuously interacting with social media sites), DMN activity declines.

Continue to: The DMN does not exist...

The DMN does not exist in infants, but starts to develop in childhood.⁷ It is enhanced by exercise, daydreaming, and sleep, activities that are common in childhood but have declined drastically with the widespread use of smartphones, video games, and social media, which for many youth occupy the bulk of their waking hours. Those tasks, which require continuous attention, deactivate the DMN. In fact, research has shown that addictive behavior decreases the connectivity of the DMN and suppresses its activity.⁸ Most children and adolescents can be regarded as essentially addicted to social media, text messaging, and video games. Unsurprisingly, serious psychiatric consequences follow.⁹

DMN dysfunction has been reported in several psychiatric conditions, including depression, posttraumatic stress disorder, autism, schizophrenia, anxiety, obsessive-compulsive disorder, and substance use.^10-12 Impaired social interactions and communications, negative ruminations, suicidal ideas, and impaired encoding of long-term memories are some of the adverse effects of DMN dysfunction. The good news is that the DMN’s connectivity and functioning can be modulated and restored by meditation, mentalizing, exercise, psychotherapy, antidepressants, and psychedelics.^13,14

The lockdown and stress of the COVID-19 pandemic added insult to injury and exacerbated mental illness in children by isolating them from each other and intensifying their technological addiction to fill the void of isolation. This crisis in youth mental health continues unabated, and calls for action to prevent grim outcomes. DMN dysfunction in youth can be reversed with treatment, but access to mental health care has become more challenging due to workforce shortages and insurance restrictions. Psychiatrists and parents must work diligently to treat psychiatrically affected youth, which has become a DaMN serious problem…

The advent of unprecedented technologies drastically altering the behavior of children and adolescents, compounded by prolonged isolation from a once-in-a-century pandemic, may have negatively impacted the normal connectivity of the human brain among youth, leading to the current alarming increase of depression, anxiety, and suicidality among this population.

The human brain is comprised of multiple large-scale networks that are functionally connected and control feelings, thoughts, and behaviors. As clinical neuroscientists, psychiatrists must consider the profound impact of a massive societal shift in human behavior on the functional connectivity of brain networks in health and disease. The advent of smartphones, social media, and video game addiction may have disrupted the developing brain networks in children and adolescents, leading to the current escalating epidemic of mental disorders in youth.

The major networks in the human brain include the default mode network (DMN), the salience network, the limbic system, the dorsal attention network, the central executive network, and the visual system.¹ Each network connects several brain regions. Researchers can use functional MRI to detect the connectivity of those networks. When blood flow increases concurrently across 2 or 3 networks, this indicates those networks are functionally connected.

There was an old “dogma” that brain regions use energy only when activated and being used. Hans Berger, who developed the EEG in 1929, noticed electrical activity at rest and proposed that the brain is constantly busy, but his neurology peers did not take him seriously.² In the 1950s, Louis Sokoloff noticed that brain metabolism was the same whether a person is at rest or doing math. In the 1970s, David Ingvar discovered that the highest blood flow in the frontal lobe occurred when a person was at rest.³ Finally, in 2007, Raichle et al⁴ used positron emission tomography scans to confirm that the frontal lobe is most active when a person is not doing anything. He labeled this phenomenon the DMN, comprising the medial fronto-parietal cortex, the posterior cingulate gyrus, the precuneus, and the angular gyrus. Interestingly, the number of publications about the DMN has skyrocketed since 2007.

The many roles of the DMN

Ongoing research has revealed that the DMN is most active at rest, and its anatomical hubs mediate several key functions⁵:

• Posterior cingulate gyrus (the central core of the DMN): remembering the past and thinking about the future
• Medial prefrontal cortex: autobiographical memories, future goals and events, reflecting on one’s emotional self, and considering decisions about family members
• Dorsal medial subsystem: thinking about others, determining and inferring the purpose of other people’s actions
• Temporo-parietal junction: reflecting on the beliefs and emotions of others (known as “theory of mind”⁶)
• Lateral parietal junction: retrieval of social and conceptual knowledge
• Hippocampus: forming new memories, remembering the past, imagining the future
• Posterior-inferior parietal lobe: junction of auditory, visual, and somatic sensory information and attention
• Precuneus: Visual, sensory-motor, and attention.

Many terms have been used to describe the function of the DMN, including “daydreaming,” “auto-pilot,” “mind-wondering,” “reminiscing,” “contemplating,” “self-reflection,” “the neurological basis of the self,” and “seat of literary creativity.”

Psychiatric consequences of DMN deactivation

When another brain network, the attention network (which is also referred to as the task-positive network), is activated consciously and volitionally to perform a task that demands focus (such as text messaging, playing video games, or continuously interacting with social media sites), DMN activity declines.

Continue to: The DMN does not exist...

The DMN does not exist in infants, but starts to develop in childhood.⁷ It is enhanced by exercise, daydreaming, and sleep, activities that are common in childhood but have declined drastically with the widespread use of smartphones, video games, and social media, which for many youth occupy the bulk of their waking hours. Those tasks, which require continuous attention, deactivate the DMN. In fact, research has shown that addictive behavior decreases the connectivity of the DMN and suppresses its activity.⁸ Most children and adolescents can be regarded as essentially addicted to social media, text messaging, and video games. Unsurprisingly, serious psychiatric consequences follow.⁹

DMN dysfunction has been reported in several psychiatric conditions, including depression, posttraumatic stress disorder, autism, schizophrenia, anxiety, obsessive-compulsive disorder, and substance use.^10-12 Impaired social interactions and communications, negative ruminations, suicidal ideas, and impaired encoding of long-term memories are some of the adverse effects of DMN dysfunction. The good news is that the DMN’s connectivity and functioning can be modulated and restored by meditation, mentalizing, exercise, psychotherapy, antidepressants, and psychedelics.^13,14

The lockdown and stress of the COVID-19 pandemic added insult to injury and exacerbated mental illness in children by isolating them from each other and intensifying their technological addiction to fill the void of isolation. This crisis in youth mental health continues unabated, and calls for action to prevent grim outcomes. DMN dysfunction in youth can be reversed with treatment, but access to mental health care has become more challenging due to workforce shortages and insurance restrictions. Psychiatrists and parents must work diligently to treat psychiatrically affected youth, which has become a DaMN serious problem…

The advent of unprecedented technologies drastically altering the behavior of children and adolescents, compounded by prolonged isolation from a once-in-a-century pandemic, may have negatively impacted the normal connectivity of the human brain among youth, leading to the current alarming increase of depression, anxiety, and suicidality among this population.

The human brain is comprised of multiple large-scale networks that are functionally connected and control feelings, thoughts, and behaviors. As clinical neuroscientists, psychiatrists must consider the profound impact of a massive societal shift in human behavior on the functional connectivity of brain networks in health and disease. The advent of smartphones, social media, and video game addiction may have disrupted the developing brain networks in children and adolescents, leading to the current escalating epidemic of mental disorders in youth.

The major networks in the human brain include the default mode network (DMN), the salience network, the limbic system, the dorsal attention network, the central executive network, and the visual system.¹ Each network connects several brain regions. Researchers can use functional MRI to detect the connectivity of those networks. When blood flow increases concurrently across 2 or 3 networks, this indicates those networks are functionally connected.

There was an old “dogma” that brain regions use energy only when activated and being used. Hans Berger, who developed the EEG in 1929, noticed electrical activity at rest and proposed that the brain is constantly busy, but his neurology peers did not take him seriously.² In the 1950s, Louis Sokoloff noticed that brain metabolism was the same whether a person is at rest or doing math. In the 1970s, David Ingvar discovered that the highest blood flow in the frontal lobe occurred when a person was at rest.³ Finally, in 2007, Raichle et al⁴ used positron emission tomography scans to confirm that the frontal lobe is most active when a person is not doing anything. He labeled this phenomenon the DMN, comprising the medial fronto-parietal cortex, the posterior cingulate gyrus, the precuneus, and the angular gyrus. Interestingly, the number of publications about the DMN has skyrocketed since 2007.

The many roles of the DMN

Ongoing research has revealed that the DMN is most active at rest, and its anatomical hubs mediate several key functions⁵:

• Posterior cingulate gyrus (the central core of the DMN): remembering the past and thinking about the future
• Medial prefrontal cortex: autobiographical memories, future goals and events, reflecting on one’s emotional self, and considering decisions about family members
• Dorsal medial subsystem: thinking about others, determining and inferring the purpose of other people’s actions
• Temporo-parietal junction: reflecting on the beliefs and emotions of others (known as “theory of mind”⁶)
• Lateral parietal junction: retrieval of social and conceptual knowledge
• Hippocampus: forming new memories, remembering the past, imagining the future
• Posterior-inferior parietal lobe: junction of auditory, visual, and somatic sensory information and attention
• Precuneus: Visual, sensory-motor, and attention.

Many terms have been used to describe the function of the DMN, including “daydreaming,” “auto-pilot,” “mind-wondering,” “reminiscing,” “contemplating,” “self-reflection,” “the neurological basis of the self,” and “seat of literary creativity.”

Psychiatric consequences of DMN deactivation

When another brain network, the attention network (which is also referred to as the task-positive network), is activated consciously and volitionally to perform a task that demands focus (such as text messaging, playing video games, or continuously interacting with social media sites), DMN activity declines.

Continue to: The DMN does not exist...

The DMN does not exist in infants, but starts to develop in childhood.⁷ It is enhanced by exercise, daydreaming, and sleep, activities that are common in childhood but have declined drastically with the widespread use of smartphones, video games, and social media, which for many youth occupy the bulk of their waking hours. Those tasks, which require continuous attention, deactivate the DMN. In fact, research has shown that addictive behavior decreases the connectivity of the DMN and suppresses its activity.⁸ Most children and adolescents can be regarded as essentially addicted to social media, text messaging, and video games. Unsurprisingly, serious psychiatric consequences follow.⁹

DMN dysfunction has been reported in several psychiatric conditions, including depression, posttraumatic stress disorder, autism, schizophrenia, anxiety, obsessive-compulsive disorder, and substance use.^10-12 Impaired social interactions and communications, negative ruminations, suicidal ideas, and impaired encoding of long-term memories are some of the adverse effects of DMN dysfunction. The good news is that the DMN’s connectivity and functioning can be modulated and restored by meditation, mentalizing, exercise, psychotherapy, antidepressants, and psychedelics.^13,14

The lockdown and stress of the COVID-19 pandemic added insult to injury and exacerbated mental illness in children by isolating them from each other and intensifying their technological addiction to fill the void of isolation. This crisis in youth mental health continues unabated, and calls for action to prevent grim outcomes. DMN dysfunction in youth can be reversed with treatment, but access to mental health care has become more challenging due to workforce shortages and insurance restrictions. Psychiatrists and parents must work diligently to treat psychiatrically affected youth, which has become a DaMN serious problem…

Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.

Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.

In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.¹ The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.² Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.²

Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.³ Many formulations of both medications are available,⁴ which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.⁵

Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.⁶ While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.³

Methylphenidate

Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 1^3,7).⁴ The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.⁴ Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.⁸ However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁴

Amphetamine

Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 2^3,7,9).⁴ One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.⁴ However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁶

Continue to: Impaired medication absorption after bariatric surgery

Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al¹⁰ found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or entero­hepatic recirculation. Childress et al¹¹ found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.¹² In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).¹³ One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,¹⁴ while another suggested impaired absorption following the same procedure.¹⁵ A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.¹⁶

When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.¹⁷ For medications that are not available as a liquid, an IR formulation is recommended.¹⁸

Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.¹⁷ The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.⁴

In March 2022, the FDA approved a dextro­amphetamine transdermal patch.⁹ It is available in 4 sizes/dosages: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours.⁹ Like the methylphenidate transdermal patch, the onset of action is approximately 2 hours, and it is recommended that patients wear it for 9 hours.⁹

CASE CONTINUED

Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.

Continue to: Following consultation with the pharmacist...

Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methyl­phenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.

Related Resources

• DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
• Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344

Drug Brand Names

Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys

Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.

Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.

In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.¹ The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.² Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.²

Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.³ Many formulations of both medications are available,⁴ which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.⁵

Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.⁶ While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.³

Methylphenidate

Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 1^3,7).⁴ The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.⁴ Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.⁸ However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁴

Amphetamine

Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 2^3,7,9).⁴ One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.⁴ However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁶

Continue to: Impaired medication absorption after bariatric surgery

Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al¹⁰ found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or entero­hepatic recirculation. Childress et al¹¹ found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.¹² In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).¹³ One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,¹⁴ while another suggested impaired absorption following the same procedure.¹⁵ A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.¹⁶

When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.¹⁷ For medications that are not available as a liquid, an IR formulation is recommended.¹⁸

Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.¹⁷ The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.⁴

In March 2022, the FDA approved a dextro­amphetamine transdermal patch.⁹ It is available in 4 sizes/dosages: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours.⁹ Like the methylphenidate transdermal patch, the onset of action is approximately 2 hours, and it is recommended that patients wear it for 9 hours.⁹

CASE CONTINUED

Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.

Continue to: Following consultation with the pharmacist...

Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methyl­phenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.

Related Resources

• DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
• Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344

Drug Brand Names

Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys

Ms. H, age 30, presents to the outpatient clinic for a follow-up visit, where she reports difficulty paying attention to conversations, starting and completing tasks, and meeting deadlines. These challenges occur at work and home. Her psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and generalized anxiety disorder. Approximately 10 years ago, she underwent Roux-en-Y gastric bypass surgery. Following surgery, Ms. H’s care team prescribed liquid formulations of medications whenever possible to minimize malabsorption. Ms. H may be a rapid metabolizer; she says the effects of her prescribed stimulants only last briefly, so she has to frequently redose. As a result, she often runs out of her monthly stimulant allotment earlier than expected.

Ms. H’s current medications include dextroamphetamine/amphetamine immediate-release (IR) 30 mg 3 times daily, atenolol 50 mg/d, and escitalopram oral solution 10 mg/d. Previous unsuccessful medication trials for her ADHD include methylphenidate IR 20 mg 3 times daily and lisdexamfetamine 70 mg/d. Ms. H reports that when her responsibilities increased at work or home, she took methylphenidate IR 20 mg up to 6 times daily to relieve her symptoms.

In the United States, ADHD affects an estimated 4.4% of adults age 18 to 44.¹ The actual rate may be higher, however, as recent research has called into question the hypothesis that approximately 50% of cases of childhood ADHD remit by adulthood.² Prevalence estimates relying on DSM-IV criteria (which were designed with children in mind) can underestimate this condition in adults. Newer data suggest that up to 90% of individuals with ADHD in childhood continue to experience significant ADHD symptoms into adulthood.²

Unless contraindications are present, methylphenidate or amphetamine-based stimulants are the medications of choice for treating adult ADHD.³ Many formulations of both medications are available,⁴ which allows clinicians to better tailor therapy to each patient’s pharmacokinetics and daily schedule. Although there can be differences in response and tolerability, methylphenidate and amphetamine offer comparable efficacy and a similar adverse effect profile.⁵

Because amphetamine is more potent than methylphenidate, clinicians commonly start treatment with an amphetamine dose that is one-half to two-thirds the dose of methylphenidate.⁶ While both classes of stimulants inhibit the reuptake of dopamine and norepinephrine into presynaptic neurons, amphetamines also promote the release of dopamine and norepinephrine from their storage sites in presynaptic nerve terminals.³

Methylphenidate

Methylphenidate IR has an average onset of action of 30 to 45 minutes and its effects last approximately 3 to 4 hours. The extended-release (XR) formulations have varying onsets of action, with durations of action up to 12 hours (Table 1^3,7).⁴ The XR products usually immediately release a certain percentage of the medication, eliminating the need for an additional IR tablet. One methylphenidate XR product (Jornay) as well as serdexmethylphenidate/dexmethylphenidate (Azstarys) offer durations of action of 24 to 36 hours. Methylphenidate is primarily metabolized by carboxylesterase 1 (CES1) to the inactive metabolite ritalinic acid. Most of the medication (60% to 80%) is excreted in the urine as ritalinic acid.⁴ Theoretically, genetic variations in the CES1 and concomitant use of medications that compete with or alter this pathway may impact methylphenidate pharmacokinetics.⁸ However, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁴

Amphetamine

Dextroamphetamine/amphetamine IR has an average onset of action of 30 to 45 minutes and its effects last approximately 4 to 6 hours. XR formulations have varying onsets of action, with durations of action up to 13 hours (Table 2^3,7,9).⁴ One XR product, mixed salts of single amphetamine entity (Mydayis), has a duration of action of 16 hours. In XR formulations, a certain percentage of the medication is typically released immediately, eliminating the need for an additional IR tablet. Amphetamine is primarily metabolized by cytochrome P450 (CYP) 2D6 hydroxylation and oxidative deamination. Genetic variability in amphetamine metabolism may be relevant due to CYP2D6 polymorphisms. Ultra-rapid metabolizers might need higher doses, while poor metabolizers might require smaller amounts and may be more susceptible to adverse effects.⁴ However, there is currently insufficient data supporting gene/medication concentration relationships. As is the case with methylphenidate, plasma levels have not yet shown to be helpful in guiding treatment selection or dosing.⁶

Continue to: Impaired medication absorption after bariatric surgery

Medication malabsorption following bariatric surgery is a significant concern. In a systematic review of 22 studies, Padwal et al¹⁰ found that in one-third of these studies, decreased absorption following bariatric surgery may be present in patients taking medications that have poor absorption, high lipophilicity, or entero­hepatic recirculation. Childress et al¹¹ found that methylphenidate IR and dextroamphetamine/amphetamine are both well absorbed, with bioavailability percentages of 100% and 90%, respectively. Additional research shows both stimulants have rapid absorption rates but relatively poor bioavailability.¹² In one study analyzing the dissolution of common psychiatric medications, methylphenidate was shown to dissolve slightly more in the Roux-en-Y gastric bypass surgery model (80 mg) compared to controls (70 mg).¹³ One case indicated potential methylphenidate toxicity following Roux-en-Y gastric bypass surgery,¹⁴ while another suggested impaired absorption following the same procedure.¹⁵ A case-control design study assessing the impact of Roux-en-Y gastric bypass surgery on the pharmacokinetic properties of lisdexamfetamine found no significant differences between the Roux-en-Y group (n = 10) and nonsurgical controls (n = 10). The investigators concluded that while data suggest adjusting lisdexamfetamine dosing following Roux-en-Y gastric bypass surgery is unnecessary, there may be interindividual differences, and individualized dosing regimens may be needed.¹⁶

When managing patients who might be experiencing medication malabsorption, it may be helpful to use dosage forms that avoid disintegration, acidic environments, and slow dissolution. Because they are more rapidly absorbed and not susceptible to disintegration and dissolution, liquid formulations are recommended.¹⁷ For medications that are not available as a liquid, an IR formulation is recommended.¹⁸

Using nonoral routes of administration that avoid the anatomical changes of the gastrointestinal tract should be considered for patients who have undergone Roux-en-Y gastric bypass surgery.¹⁷ The methylphenidate transdermal patch, a medication delivery system that avoids gut and hepatic first-pass metabolism, can improve medication bioavailability, reduce dose frequency, and stabilize medication delivery. It is available in 4 sizes/dosages: 10 mg/9 hours, 15 mg/9 hours, 20 mg/9 hours, and 30 mg/9 hours. Methylphenidate is delivered at a steady rate based upon patch size. The onset of action of the patch is approximately 2 hours, and patients should wear the patch for 9 hours, then remove it. Methylphenidate will still be absorbed up to 2 to 3 hours after patch removal. Appropriate application and removal of the patch is important for optimal effectiveness and to avoid adverse effects.⁴

In March 2022, the FDA approved a dextro­amphetamine transdermal patch.⁹ It is available in 4 sizes/dosages: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours.⁹ Like the methylphenidate transdermal patch, the onset of action is approximately 2 hours, and it is recommended that patients wear it for 9 hours.⁹

CASE CONTINUED

Ms. H emphasizes her desire to maintain functionality in all areas of life, while her care team reiterates the risks of continuing to take high-dose stimulants. Both Ms. H and her care team acknowledge that stimulant usage could be worsening her anxiety, and that Roux-en-Y gastric bypass surgery may be a possible explanation for her dosing challenges.

Continue to: Following consultation with the pharmacist...

Following consultation with the pharmacist, the care team explains the possible pharmacokinetic benefits of using the methyl­phenidate transdermal patch. After completing the prior authorization paperwork, Ms. H is started on the 30 mg/d patch. This dose was selected because she previously tolerated high-dose stimulants, including methylphenidate IR 20 mg up to 6 times daily. At a follow-up visit 1 month after starting the patch, Ms. H reports an improvement in her ADHD symptoms and says she is not experiencing any adverse effects.

Related Resources

• DeMarco R, Rana R, Powell K, et al. How bariatric surgery affects psychotropic drug absorption. Current Psychiatry. 2022;21(8):39-44. doi:10.12788/cp.0271
• Santos MG, Majarwitz DJ, Saeed SA. Adult ADHD: 6 studies of pharmacologic interventions. Current Psychiatry. 2023;22(4):16-27. doi:10.12788/cp.0344

Drug Brand Names

Amphetamine sulfate • Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo
Atenolol • Tenormin
Dexmethylphenidate • Focalin, Focalin XR
Dextroamphetamine transdermal • Xelstrym
Dextroamphetamine • Dexedrine, Dexedrine Spansule, ProCentra, Zenzedi
Escitalopram • Lexapro
Lisdexamfetamine • Vyvanse
Methylphenidate • Aptensio XR, Adhansia XR, Concerta, Cotempla, Jornay PM, Metadate CD, Metadate ER, Methylin, Qullichew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA
Methylphenidate transdermal • Daytrana
Mixed amphetamine salts • Adderall, Adderall XR
Mixed salts of a single-entity amphetamine • Mydayis
Serdexmethylphenidate and dexmethylphenidate • Azstarys

CASE A relapse and crisis

Ms. G, age 32, is brought to the emergency department (ED) by police after being found in a stupor-like state in a public restroom. The consultation-liaison (CL) psychiatry team assesses her for concerns of self-harm and suicide behavior. Ms. G discloses that she “huffs” an average of 4 canisters of air dusters daily to cope with psychosocial stressors and achieve a euphoric state. She recently lost her job, which led to homelessness, financial difficulties, a relapse to aerosol use after 2 years of abstinence, and stealing aerosol cans. The latest incident follows 2 prior arrests, which led officers to bring her to the ED for medical evaluation. Ms. G has a history of bipolar disorder (BD), generalized anxiety disorder (GAD), insomnia, and inhalant use disorder.

HISTORY Inhalant abuse and suicide attempt

Ms. G reports a longstanding history of severe inhalant abuse, primarily with air dusters due to their accessibility and low cost. She previously underwent inpatient rehab for inhalant abuse, and received inpatient psychiatry treatment 5 years ago for a suicide attempt by overdose linked to psychosocial stressors. In addition to BD, GAD, insomnia, and inhalant use disorder, Ms. G has a history of neuropathy, seizures, and recurrent hypokalemia. She is single and does not have insurance.

[polldaddy:12318871]

The authors’ observations

Inhalant abuse is the intentional inhalation of volatile substances to achieve an altered mental state. Inhalants are commercially available products that can produce intoxication if inhaled, such as glue, toluene, spray paint, gasoline, and lighter fluid (Table 1¹).

The epidemiology of inhalant abuse is difficult to accurately report due to a lack of recognition and social stigma. Due to inhalants’ ease of access and low cost, this form of substance abuse is popular among adolescents, adults of low socioeconomic status, individuals who live in rural areas, and those living in institutions. Inhalants act as reinforcers, producing a euphoric state. Rapid pulmonary absorption and lipid solubility of the substance rapidly alters the brain. Inhalant abuse can result in chemical and thermal burns, withdrawal symptoms, persistent mental illness, and catastrophic medical emergencies such as ventricular arrhythmias leading to disruptive myocardial electrical propagation. Chronic abuse can cause irreversible neurological and neuropsychological effects, cardiomyopathy, rapid airway compromise, pulmonary debilitations, renal tubular acidosis, bone marrow toxicity, reduced immunity, and peripheral neuropathy.² Ms. G’s diagnosis of inhalant use disorder was based on her mental state and history of severe inhalant misuse, specifically with air dusters. Several additional factors further support this diagnosis, including the fact she survived a suicide attempt by overdose 5 years ago, had an inpatient rehabilitation placement for inhalant abuse, experiences insomnia, and was attempting to self-treat a depressive episode relapse with inhalants.

EVALUATION Depressed but cooperative

After being monitored in the ED for several hours, Ms. G is no longer in a stupor-like state. She has poor body habitus, appears older than her stated age, and is unkempt in appearance/attire. She is mildly distressed but relatively cooperative and engaged during the interview. Ms. G has a depressed mood and is anxious, with mood-congruent affect, and is tearful at times, especially when discussing recent stressors. She denies suicidality, homicidality, paranoia, delusions, and hallucinations. Her thought process is linear, goal-directed, and logical. She has fair insight, but relatively poor and impulsive judgment. The nursing staff expresses concerns that Ms. G was possibly responding to internal stimuli and behaving bizarrely during her initial presentation; this was not evident upon examination.

Ms. G reports having acute-on-chronic headaches, intermittent myalgias and weakness in her lower extremities (acute), and polyneuropathy (chronic). She denies a history of manic episodes or psychosis but reports previous relative hypomanic episodes that vacillated with periods of recurrent depressive episodes. Ms. G denies using illicit substances other than tobacco and inhalants. She says she had adhered to her outpatient psychiatric management services and medication regimen (duloxetine 60 mg/d at bedtime for mood/migraines, trazodone 150 mg/d at bedtime for insomnia, ziprasidone 40 mg/d at bedtime for BD, carbamazepine 200 mg twice daily for neuro­pathy/migraines, gabapentin 400 mg 3 times daily for neuropathy migraines/anxiety, and propranolol 10 mg 3 times daily for anxiety/tremors/migraine prophylaxis) until 4 days before her current presentation to the ED, when she used inhalants and was arrested.

Ms. G’s vitals are mostly unremarkable, but her heart rate is 116 beats per minute. There are no acute findings on physical examination. She is not pregnant, and her creatinine, glomerular filtration rate, complete blood count, and thyroid-stimulating hormone are all within normal limits. Her blood sugar is high (120 mg/dL; reference range 70 to 100 mg/dL). She has slight transaminitis with high aspartate aminotransferase (93 U/L; reference range 17 to 59 U/L) and high alanine aminotransferase (69 U/L; reference range 20 to 35 U/L); chronic hypokalemia (2.4 mmol/L; reference range 3.5 to 5.2 mmol/L), which leads the primary team to initiate a potassium replacement protocol; lactic acidosis (2.2 mmol/L; normal levels <2 mmol/L); and creatine kinase (CK) 5,930 U/L.

[polldaddy:12318873]

Continue to: The authors' observations

Efforts to improve the laboratory diagnosis of inhalant abuse are ongoing, but they have not yet been widely implemented. Systemic screening and assessment of inhalant use can help prevent and treat complications. For Ms. G, we considered several possible complications, including hypoglycemia. Although the classic triad of myalgia, weakness, and myoglobinuria (tea-colored urine) was not present, elevated CK levels in the context of Ms. G’s intermittent myalgia and lower extremity weakness led us to suspect she was experiencing moderate rhabdomyolysis (Table 2³).

Rhabdomyolysis can be caused by several factors, including drug abuse, trauma, neuromuscular syndrome, and immobility. Treatment is mainly supportive, with a focus on preserving the ABCs (airway, breathing, circulation) and renal function through vigorous rehydration.⁴ We postulated Ms. G’s rhabdomyolysis was caused by muscle damage directly resulting from inhalant abuse and compounded by her remaining in prolonged fixed position on the ground after overdosing on inhalants.

TREATMENT Rehydration and psychotropics

The treatment team initiates IV fluid hydration of chloride 0.9% 150 mL/h and monitors Ms. G until she is stable and the trajectory of her CK levels begins to decline. On hospital Day 2, Ms. G’s CK decreases to 2,475 U/L and her lactic acid levels normalize. Ms. G restarts her regimen of duloxetine 60 mg/d, trazodone 150 mg/d, ziprasidone 40 mg/d, carbamazepine 200 mg twice daily, gabapentin 400 mg 3 times daily, and propranolol 10 mg 3 times daily. The team adds quetiapine 25 mg as needed for hallucinations, paranoia, and/or anxiety. Ms. G is closely monitored due to the potential risk of toxicity-induced or withdrawal-induced psychotic symptoms.

[polldaddy:12318869]

The authors’ observations

Presently, there are no effective treatments for acute inhalant intoxication or withdrawal, which makes supportive care and vigilant monitoring the only options.⁵ Although clinical research has not led to any FDA-approved treatments for chronic inhalant use disorder, a multipronged biopsychosocial treatment approach is critical in light of the negative consequences of inhalant abuse, including poor academic performance, criminal behavior, abuse of other substances, social maladjustment, low self-esteem, and suicidality.⁶

Ms. G had a moderate form of rhabdomyolysis, which was managed with IV fluid rehydration. Education and counseling were crucial to help Ms. G understand the unintended complications and potentially life-threatening consequences of inhalant abuse, with rehabilitation services to encourage abstinence. Ms. G had previously undergone successful inpatient rehabilitation and was willing to start such services again. She reported success with gabapentin for her polyneuropathy and migraines, which may be long-term consequences of prolonged inhalant abuse with neurological lesions. Ziprasidone may have mitigated some of the impulsivity and hypomanic symptoms of her BD that could make her more likely to engage in risky self-harm behaviors.

Continue to: After extensive discussion...

OUTCOME Improved outlook and discharge

Ms. G reports improved mood and willingness to change her substance use habits. The treatment team counsels her on the acute risk of fatal arrhythmias and end-organ complications of inhalant abuse. They warn her about the potential long-term effects of mood alterations, neurological lesions, and polyneuropathy that could possibly worsen with substance abuse. Ms. G expresses appreciation for this counseling, the help associated with her aftercare, and the referral to restart the 30-day inpatient rehabilitation services. The team arranges follow-up with outpatient psychiatry and outpatient therapy services to enhance Ms. G’s coping skills and mitigate her reliance on inhalants to regulate her mood.

Bottom Line

Inhalant use is a poorly understood form of substance abuse that disproportionately affects vulnerable populations. It can lead to life-threatening medical emergencies such as rhabdomyolysis. Clinicians need to be able to identify and manage inhalant abuse and associated complications, as well as provide appropriate education and counseling to prevent further misuse.

Related Resources

• Gude J, Bisen V, Fujii K. Medication-induced rhabdomyolysis. Current Psychiatry. 2023;22(2):39-40. doi:10.12788/cp.0332
• Waldman W, Kabata PM, Dines AM, et al. Rhabdomyolysis related to acute recreational drug toxicity--a Euro-DEN study. PLoS One. 2021;16(3):e0246297. doi:10.1371/journal. pone.0246297

Drug Brand Names

Carbamazepine • Tegretol
Duloxetine • Cymbalta
Gabapentin • Neurontin
Propranolol • Inderal
Quetiapine • Seroquel
Trazodone • Oleptro
Ziprasidone • Geodon

CASE A relapse and crisis

Ms. G, age 32, is brought to the emergency department (ED) by police after being found in a stupor-like state in a public restroom. The consultation-liaison (CL) psychiatry team assesses her for concerns of self-harm and suicide behavior. Ms. G discloses that she “huffs” an average of 4 canisters of air dusters daily to cope with psychosocial stressors and achieve a euphoric state. She recently lost her job, which led to homelessness, financial difficulties, a relapse to aerosol use after 2 years of abstinence, and stealing aerosol cans. The latest incident follows 2 prior arrests, which led officers to bring her to the ED for medical evaluation. Ms. G has a history of bipolar disorder (BD), generalized anxiety disorder (GAD), insomnia, and inhalant use disorder.

HISTORY Inhalant abuse and suicide attempt

Ms. G reports a longstanding history of severe inhalant abuse, primarily with air dusters due to their accessibility and low cost. She previously underwent inpatient rehab for inhalant abuse, and received inpatient psychiatry treatment 5 years ago for a suicide attempt by overdose linked to psychosocial stressors. In addition to BD, GAD, insomnia, and inhalant use disorder, Ms. G has a history of neuropathy, seizures, and recurrent hypokalemia. She is single and does not have insurance.

[polldaddy:12318871]

The authors’ observations

Inhalant abuse is the intentional inhalation of volatile substances to achieve an altered mental state. Inhalants are commercially available products that can produce intoxication if inhaled, such as glue, toluene, spray paint, gasoline, and lighter fluid (Table 1¹).

The epidemiology of inhalant abuse is difficult to accurately report due to a lack of recognition and social stigma. Due to inhalants’ ease of access and low cost, this form of substance abuse is popular among adolescents, adults of low socioeconomic status, individuals who live in rural areas, and those living in institutions. Inhalants act as reinforcers, producing a euphoric state. Rapid pulmonary absorption and lipid solubility of the substance rapidly alters the brain. Inhalant abuse can result in chemical and thermal burns, withdrawal symptoms, persistent mental illness, and catastrophic medical emergencies such as ventricular arrhythmias leading to disruptive myocardial electrical propagation. Chronic abuse can cause irreversible neurological and neuropsychological effects, cardiomyopathy, rapid airway compromise, pulmonary debilitations, renal tubular acidosis, bone marrow toxicity, reduced immunity, and peripheral neuropathy.² Ms. G’s diagnosis of inhalant use disorder was based on her mental state and history of severe inhalant misuse, specifically with air dusters. Several additional factors further support this diagnosis, including the fact she survived a suicide attempt by overdose 5 years ago, had an inpatient rehabilitation placement for inhalant abuse, experiences insomnia, and was attempting to self-treat a depressive episode relapse with inhalants.

EVALUATION Depressed but cooperative

After being monitored in the ED for several hours, Ms. G is no longer in a stupor-like state. She has poor body habitus, appears older than her stated age, and is unkempt in appearance/attire. She is mildly distressed but relatively cooperative and engaged during the interview. Ms. G has a depressed mood and is anxious, with mood-congruent affect, and is tearful at times, especially when discussing recent stressors. She denies suicidality, homicidality, paranoia, delusions, and hallucinations. Her thought process is linear, goal-directed, and logical. She has fair insight, but relatively poor and impulsive judgment. The nursing staff expresses concerns that Ms. G was possibly responding to internal stimuli and behaving bizarrely during her initial presentation; this was not evident upon examination.

Ms. G reports having acute-on-chronic headaches, intermittent myalgias and weakness in her lower extremities (acute), and polyneuropathy (chronic). She denies a history of manic episodes or psychosis but reports previous relative hypomanic episodes that vacillated with periods of recurrent depressive episodes. Ms. G denies using illicit substances other than tobacco and inhalants. She says she had adhered to her outpatient psychiatric management services and medication regimen (duloxetine 60 mg/d at bedtime for mood/migraines, trazodone 150 mg/d at bedtime for insomnia, ziprasidone 40 mg/d at bedtime for BD, carbamazepine 200 mg twice daily for neuro­pathy/migraines, gabapentin 400 mg 3 times daily for neuropathy migraines/anxiety, and propranolol 10 mg 3 times daily for anxiety/tremors/migraine prophylaxis) until 4 days before her current presentation to the ED, when she used inhalants and was arrested.

Ms. G’s vitals are mostly unremarkable, but her heart rate is 116 beats per minute. There are no acute findings on physical examination. She is not pregnant, and her creatinine, glomerular filtration rate, complete blood count, and thyroid-stimulating hormone are all within normal limits. Her blood sugar is high (120 mg/dL; reference range 70 to 100 mg/dL). She has slight transaminitis with high aspartate aminotransferase (93 U/L; reference range 17 to 59 U/L) and high alanine aminotransferase (69 U/L; reference range 20 to 35 U/L); chronic hypokalemia (2.4 mmol/L; reference range 3.5 to 5.2 mmol/L), which leads the primary team to initiate a potassium replacement protocol; lactic acidosis (2.2 mmol/L; normal levels <2 mmol/L); and creatine kinase (CK) 5,930 U/L.

[polldaddy:12318873]

Continue to: The authors' observations

Efforts to improve the laboratory diagnosis of inhalant abuse are ongoing, but they have not yet been widely implemented. Systemic screening and assessment of inhalant use can help prevent and treat complications. For Ms. G, we considered several possible complications, including hypoglycemia. Although the classic triad of myalgia, weakness, and myoglobinuria (tea-colored urine) was not present, elevated CK levels in the context of Ms. G’s intermittent myalgia and lower extremity weakness led us to suspect she was experiencing moderate rhabdomyolysis (Table 2³).

Rhabdomyolysis can be caused by several factors, including drug abuse, trauma, neuromuscular syndrome, and immobility. Treatment is mainly supportive, with a focus on preserving the ABCs (airway, breathing, circulation) and renal function through vigorous rehydration.⁴ We postulated Ms. G’s rhabdomyolysis was caused by muscle damage directly resulting from inhalant abuse and compounded by her remaining in prolonged fixed position on the ground after overdosing on inhalants.

TREATMENT Rehydration and psychotropics

The treatment team initiates IV fluid hydration of chloride 0.9% 150 mL/h and monitors Ms. G until she is stable and the trajectory of her CK levels begins to decline. On hospital Day 2, Ms. G’s CK decreases to 2,475 U/L and her lactic acid levels normalize. Ms. G restarts her regimen of duloxetine 60 mg/d, trazodone 150 mg/d, ziprasidone 40 mg/d, carbamazepine 200 mg twice daily, gabapentin 400 mg 3 times daily, and propranolol 10 mg 3 times daily. The team adds quetiapine 25 mg as needed for hallucinations, paranoia, and/or anxiety. Ms. G is closely monitored due to the potential risk of toxicity-induced or withdrawal-induced psychotic symptoms.

[polldaddy:12318869]

The authors’ observations

Presently, there are no effective treatments for acute inhalant intoxication or withdrawal, which makes supportive care and vigilant monitoring the only options.⁵ Although clinical research has not led to any FDA-approved treatments for chronic inhalant use disorder, a multipronged biopsychosocial treatment approach is critical in light of the negative consequences of inhalant abuse, including poor academic performance, criminal behavior, abuse of other substances, social maladjustment, low self-esteem, and suicidality.⁶

Ms. G had a moderate form of rhabdomyolysis, which was managed with IV fluid rehydration. Education and counseling were crucial to help Ms. G understand the unintended complications and potentially life-threatening consequences of inhalant abuse, with rehabilitation services to encourage abstinence. Ms. G had previously undergone successful inpatient rehabilitation and was willing to start such services again. She reported success with gabapentin for her polyneuropathy and migraines, which may be long-term consequences of prolonged inhalant abuse with neurological lesions. Ziprasidone may have mitigated some of the impulsivity and hypomanic symptoms of her BD that could make her more likely to engage in risky self-harm behaviors.

Continue to: After extensive discussion...

OUTCOME Improved outlook and discharge

Ms. G reports improved mood and willingness to change her substance use habits. The treatment team counsels her on the acute risk of fatal arrhythmias and end-organ complications of inhalant abuse. They warn her about the potential long-term effects of mood alterations, neurological lesions, and polyneuropathy that could possibly worsen with substance abuse. Ms. G expresses appreciation for this counseling, the help associated with her aftercare, and the referral to restart the 30-day inpatient rehabilitation services. The team arranges follow-up with outpatient psychiatry and outpatient therapy services to enhance Ms. G’s coping skills and mitigate her reliance on inhalants to regulate her mood.

Bottom Line

Inhalant use is a poorly understood form of substance abuse that disproportionately affects vulnerable populations. It can lead to life-threatening medical emergencies such as rhabdomyolysis. Clinicians need to be able to identify and manage inhalant abuse and associated complications, as well as provide appropriate education and counseling to prevent further misuse.

Related Resources

• Gude J, Bisen V, Fujii K. Medication-induced rhabdomyolysis. Current Psychiatry. 2023;22(2):39-40. doi:10.12788/cp.0332
• Waldman W, Kabata PM, Dines AM, et al. Rhabdomyolysis related to acute recreational drug toxicity--a Euro-DEN study. PLoS One. 2021;16(3):e0246297. doi:10.1371/journal. pone.0246297

Drug Brand Names

Carbamazepine • Tegretol
Duloxetine • Cymbalta
Gabapentin • Neurontin
Propranolol • Inderal
Quetiapine • Seroquel
Trazodone • Oleptro
Ziprasidone • Geodon

CASE A relapse and crisis

Ms. G, age 32, is brought to the emergency department (ED) by police after being found in a stupor-like state in a public restroom. The consultation-liaison (CL) psychiatry team assesses her for concerns of self-harm and suicide behavior. Ms. G discloses that she “huffs” an average of 4 canisters of air dusters daily to cope with psychosocial stressors and achieve a euphoric state. She recently lost her job, which led to homelessness, financial difficulties, a relapse to aerosol use after 2 years of abstinence, and stealing aerosol cans. The latest incident follows 2 prior arrests, which led officers to bring her to the ED for medical evaluation. Ms. G has a history of bipolar disorder (BD), generalized anxiety disorder (GAD), insomnia, and inhalant use disorder.

HISTORY Inhalant abuse and suicide attempt

Ms. G reports a longstanding history of severe inhalant abuse, primarily with air dusters due to their accessibility and low cost. She previously underwent inpatient rehab for inhalant abuse, and received inpatient psychiatry treatment 5 years ago for a suicide attempt by overdose linked to psychosocial stressors. In addition to BD, GAD, insomnia, and inhalant use disorder, Ms. G has a history of neuropathy, seizures, and recurrent hypokalemia. She is single and does not have insurance.

[polldaddy:12318871]

The authors’ observations

Inhalant abuse is the intentional inhalation of volatile substances to achieve an altered mental state. Inhalants are commercially available products that can produce intoxication if inhaled, such as glue, toluene, spray paint, gasoline, and lighter fluid (Table 1¹).

The epidemiology of inhalant abuse is difficult to accurately report due to a lack of recognition and social stigma. Due to inhalants’ ease of access and low cost, this form of substance abuse is popular among adolescents, adults of low socioeconomic status, individuals who live in rural areas, and those living in institutions. Inhalants act as reinforcers, producing a euphoric state. Rapid pulmonary absorption and lipid solubility of the substance rapidly alters the brain. Inhalant abuse can result in chemical and thermal burns, withdrawal symptoms, persistent mental illness, and catastrophic medical emergencies such as ventricular arrhythmias leading to disruptive myocardial electrical propagation. Chronic abuse can cause irreversible neurological and neuropsychological effects, cardiomyopathy, rapid airway compromise, pulmonary debilitations, renal tubular acidosis, bone marrow toxicity, reduced immunity, and peripheral neuropathy.² Ms. G’s diagnosis of inhalant use disorder was based on her mental state and history of severe inhalant misuse, specifically with air dusters. Several additional factors further support this diagnosis, including the fact she survived a suicide attempt by overdose 5 years ago, had an inpatient rehabilitation placement for inhalant abuse, experiences insomnia, and was attempting to self-treat a depressive episode relapse with inhalants.

EVALUATION Depressed but cooperative

After being monitored in the ED for several hours, Ms. G is no longer in a stupor-like state. She has poor body habitus, appears older than her stated age, and is unkempt in appearance/attire. She is mildly distressed but relatively cooperative and engaged during the interview. Ms. G has a depressed mood and is anxious, with mood-congruent affect, and is tearful at times, especially when discussing recent stressors. She denies suicidality, homicidality, paranoia, delusions, and hallucinations. Her thought process is linear, goal-directed, and logical. She has fair insight, but relatively poor and impulsive judgment. The nursing staff expresses concerns that Ms. G was possibly responding to internal stimuli and behaving bizarrely during her initial presentation; this was not evident upon examination.

Ms. G reports having acute-on-chronic headaches, intermittent myalgias and weakness in her lower extremities (acute), and polyneuropathy (chronic). She denies a history of manic episodes or psychosis but reports previous relative hypomanic episodes that vacillated with periods of recurrent depressive episodes. Ms. G denies using illicit substances other than tobacco and inhalants. She says she had adhered to her outpatient psychiatric management services and medication regimen (duloxetine 60 mg/d at bedtime for mood/migraines, trazodone 150 mg/d at bedtime for insomnia, ziprasidone 40 mg/d at bedtime for BD, carbamazepine 200 mg twice daily for neuro­pathy/migraines, gabapentin 400 mg 3 times daily for neuropathy migraines/anxiety, and propranolol 10 mg 3 times daily for anxiety/tremors/migraine prophylaxis) until 4 days before her current presentation to the ED, when she used inhalants and was arrested.

Ms. G’s vitals are mostly unremarkable, but her heart rate is 116 beats per minute. There are no acute findings on physical examination. She is not pregnant, and her creatinine, glomerular filtration rate, complete blood count, and thyroid-stimulating hormone are all within normal limits. Her blood sugar is high (120 mg/dL; reference range 70 to 100 mg/dL). She has slight transaminitis with high aspartate aminotransferase (93 U/L; reference range 17 to 59 U/L) and high alanine aminotransferase (69 U/L; reference range 20 to 35 U/L); chronic hypokalemia (2.4 mmol/L; reference range 3.5 to 5.2 mmol/L), which leads the primary team to initiate a potassium replacement protocol; lactic acidosis (2.2 mmol/L; normal levels <2 mmol/L); and creatine kinase (CK) 5,930 U/L.

[polldaddy:12318873]

Continue to: The authors' observations

Efforts to improve the laboratory diagnosis of inhalant abuse are ongoing, but they have not yet been widely implemented. Systemic screening and assessment of inhalant use can help prevent and treat complications. For Ms. G, we considered several possible complications, including hypoglycemia. Although the classic triad of myalgia, weakness, and myoglobinuria (tea-colored urine) was not present, elevated CK levels in the context of Ms. G’s intermittent myalgia and lower extremity weakness led us to suspect she was experiencing moderate rhabdomyolysis (Table 2³).

Rhabdomyolysis can be caused by several factors, including drug abuse, trauma, neuromuscular syndrome, and immobility. Treatment is mainly supportive, with a focus on preserving the ABCs (airway, breathing, circulation) and renal function through vigorous rehydration.⁴ We postulated Ms. G’s rhabdomyolysis was caused by muscle damage directly resulting from inhalant abuse and compounded by her remaining in prolonged fixed position on the ground after overdosing on inhalants.

TREATMENT Rehydration and psychotropics

The treatment team initiates IV fluid hydration of chloride 0.9% 150 mL/h and monitors Ms. G until she is stable and the trajectory of her CK levels begins to decline. On hospital Day 2, Ms. G’s CK decreases to 2,475 U/L and her lactic acid levels normalize. Ms. G restarts her regimen of duloxetine 60 mg/d, trazodone 150 mg/d, ziprasidone 40 mg/d, carbamazepine 200 mg twice daily, gabapentin 400 mg 3 times daily, and propranolol 10 mg 3 times daily. The team adds quetiapine 25 mg as needed for hallucinations, paranoia, and/or anxiety. Ms. G is closely monitored due to the potential risk of toxicity-induced or withdrawal-induced psychotic symptoms.

[polldaddy:12318869]

The authors’ observations

Presently, there are no effective treatments for acute inhalant intoxication or withdrawal, which makes supportive care and vigilant monitoring the only options.⁵ Although clinical research has not led to any FDA-approved treatments for chronic inhalant use disorder, a multipronged biopsychosocial treatment approach is critical in light of the negative consequences of inhalant abuse, including poor academic performance, criminal behavior, abuse of other substances, social maladjustment, low self-esteem, and suicidality.⁶

Ms. G had a moderate form of rhabdomyolysis, which was managed with IV fluid rehydration. Education and counseling were crucial to help Ms. G understand the unintended complications and potentially life-threatening consequences of inhalant abuse, with rehabilitation services to encourage abstinence. Ms. G had previously undergone successful inpatient rehabilitation and was willing to start such services again. She reported success with gabapentin for her polyneuropathy and migraines, which may be long-term consequences of prolonged inhalant abuse with neurological lesions. Ziprasidone may have mitigated some of the impulsivity and hypomanic symptoms of her BD that could make her more likely to engage in risky self-harm behaviors.

Continue to: After extensive discussion...

OUTCOME Improved outlook and discharge

Ms. G reports improved mood and willingness to change her substance use habits. The treatment team counsels her on the acute risk of fatal arrhythmias and end-organ complications of inhalant abuse. They warn her about the potential long-term effects of mood alterations, neurological lesions, and polyneuropathy that could possibly worsen with substance abuse. Ms. G expresses appreciation for this counseling, the help associated with her aftercare, and the referral to restart the 30-day inpatient rehabilitation services. The team arranges follow-up with outpatient psychiatry and outpatient therapy services to enhance Ms. G’s coping skills and mitigate her reliance on inhalants to regulate her mood.

Bottom Line

Inhalant use is a poorly understood form of substance abuse that disproportionately affects vulnerable populations. It can lead to life-threatening medical emergencies such as rhabdomyolysis. Clinicians need to be able to identify and manage inhalant abuse and associated complications, as well as provide appropriate education and counseling to prevent further misuse.

Related Resources

• Gude J, Bisen V, Fujii K. Medication-induced rhabdomyolysis. Current Psychiatry. 2023;22(2):39-40. doi:10.12788/cp.0332
• Waldman W, Kabata PM, Dines AM, et al. Rhabdomyolysis related to acute recreational drug toxicity--a Euro-DEN study. PLoS One. 2021;16(3):e0246297. doi:10.1371/journal. pone.0246297

Drug Brand Names

Carbamazepine • Tegretol
Duloxetine • Cymbalta
Gabapentin • Neurontin
Propranolol • Inderal
Quetiapine • Seroquel
Trazodone • Oleptro
Ziprasidone • Geodon

For patients with schizophrenia, adherence to antipsychotic treatment reduces the rate of relapse of psychosis, lowers the rate of rehospitalization, and reduces the severity of illness.¹ Despite this, patients may want to discontinue their medications for multiple reasons, including limited insight, adverse effects, or a negative attitude toward medication.¹ Understanding a patient’s reason for wanting to discontinue their antipsychotic is critical to providing patient-centered care, building the therapeutic alliance, and offering potential solutions.

Clinicians can recall the mnemonic “A SPORT” (Table) to help ensure they have a thorough discussion with patients about the risks of discontinuation and potential solutions.

Points to cover

First, explore and acknowledge if a patient is experiencing adverse effects from their antipsychotic, which may be causing them to have a negative attitude toward medications. If a patient is experiencing adverse effects from their antipsychotic, offer interventions to mitigate those effects, such as adding an anticholinergic agent to address extrapyramidal symptoms. Decreasing the antipsychotic dosage might reduce the adverse effects burden while still optimizing the benefits from the antipsychotic. Additionally, switching to an alternate medication with a more favorable adverse effect profile may be an option. Whether the patient is experiencing intolerable adverse effects or just has a negative view of their prescribed antipsychotic, it is important to discuss switching medications.

Identifying patient attitudes and their general perspective toward their medication and illness is key. Similarly, a patient’s impaired insight into their mental illness has been associated with treatment discontinuation.² A strong therapeutic alliance with your patient is of the utmost importance in these situations.

Long-acting injectable antipsychotics (LAIs) are useful clinical tools for patients who struggle to adhere to oral medications. Educating patients and caregivers about other formulations—namely LAIs—can help clarify any misconceptions they may have. One study found that patients who were prescribed oral antipsychotics thought LAIs would be painful, have worse adverse effects, and would not be beneficial in preventing relapse.³ In addition to LAIs, other formulations of antipsychotic medications, such as patches, sublingual tablets, or liquids, may be an option.

For patients to be able to provide informed consent regarding the decision to discontinue their antipsychotic, it is important to educate them about the risks of not taking an antipsychotic, such as an increased risk of relapse, hospitalization, and poor outcomes. Explain that patients with first-episode psychosis who achieve remission of symptoms while taking an antipsychotic can remain in remission with continued treatment, but there is a 5-fold increased risk of relapse when discontinuing an antipsychotic during first-episode psychosis.⁴

Lastly, despite discussing the risks and benefits, if a patient is determined to discontinue their antipsychotic, we recommend a slow taper of medication rather than abrupt discontinuation. Research has shown that more than one-half of patients who abruptly discontinue an antipsychotic experience withdrawal symptoms, including (but not limited to) nausea, vomiting, abdominal pain, and headaches, as well as anxiety, restlessness, and insomnia.⁵ These symptoms may occur within 4 weeks after discontinuation.⁵ While there are no clear guidelines on deprescribing antipsychotics, it is best to individualize the taper based on patient response. Family and caregiver involvement, close follow-up, and symptom monitoring should be integrated into the tapering process.⁶

For patients with schizophrenia, adherence to antipsychotic treatment reduces the rate of relapse of psychosis, lowers the rate of rehospitalization, and reduces the severity of illness.¹ Despite this, patients may want to discontinue their medications for multiple reasons, including limited insight, adverse effects, or a negative attitude toward medication.¹ Understanding a patient’s reason for wanting to discontinue their antipsychotic is critical to providing patient-centered care, building the therapeutic alliance, and offering potential solutions.

Clinicians can recall the mnemonic “A SPORT” (Table) to help ensure they have a thorough discussion with patients about the risks of discontinuation and potential solutions.

Points to cover

First, explore and acknowledge if a patient is experiencing adverse effects from their antipsychotic, which may be causing them to have a negative attitude toward medications. If a patient is experiencing adverse effects from their antipsychotic, offer interventions to mitigate those effects, such as adding an anticholinergic agent to address extrapyramidal symptoms. Decreasing the antipsychotic dosage might reduce the adverse effects burden while still optimizing the benefits from the antipsychotic. Additionally, switching to an alternate medication with a more favorable adverse effect profile may be an option. Whether the patient is experiencing intolerable adverse effects or just has a negative view of their prescribed antipsychotic, it is important to discuss switching medications.

Identifying patient attitudes and their general perspective toward their medication and illness is key. Similarly, a patient’s impaired insight into their mental illness has been associated with treatment discontinuation.² A strong therapeutic alliance with your patient is of the utmost importance in these situations.

Long-acting injectable antipsychotics (LAIs) are useful clinical tools for patients who struggle to adhere to oral medications. Educating patients and caregivers about other formulations—namely LAIs—can help clarify any misconceptions they may have. One study found that patients who were prescribed oral antipsychotics thought LAIs would be painful, have worse adverse effects, and would not be beneficial in preventing relapse.³ In addition to LAIs, other formulations of antipsychotic medications, such as patches, sublingual tablets, or liquids, may be an option.

For patients to be able to provide informed consent regarding the decision to discontinue their antipsychotic, it is important to educate them about the risks of not taking an antipsychotic, such as an increased risk of relapse, hospitalization, and poor outcomes. Explain that patients with first-episode psychosis who achieve remission of symptoms while taking an antipsychotic can remain in remission with continued treatment, but there is a 5-fold increased risk of relapse when discontinuing an antipsychotic during first-episode psychosis.⁴

Lastly, despite discussing the risks and benefits, if a patient is determined to discontinue their antipsychotic, we recommend a slow taper of medication rather than abrupt discontinuation. Research has shown that more than one-half of patients who abruptly discontinue an antipsychotic experience withdrawal symptoms, including (but not limited to) nausea, vomiting, abdominal pain, and headaches, as well as anxiety, restlessness, and insomnia.⁵ These symptoms may occur within 4 weeks after discontinuation.⁵ While there are no clear guidelines on deprescribing antipsychotics, it is best to individualize the taper based on patient response. Family and caregiver involvement, close follow-up, and symptom monitoring should be integrated into the tapering process.⁶

For patients with schizophrenia, adherence to antipsychotic treatment reduces the rate of relapse of psychosis, lowers the rate of rehospitalization, and reduces the severity of illness.¹ Despite this, patients may want to discontinue their medications for multiple reasons, including limited insight, adverse effects, or a negative attitude toward medication.¹ Understanding a patient’s reason for wanting to discontinue their antipsychotic is critical to providing patient-centered care, building the therapeutic alliance, and offering potential solutions.

Clinicians can recall the mnemonic “A SPORT” (Table) to help ensure they have a thorough discussion with patients about the risks of discontinuation and potential solutions.

Points to cover

First, explore and acknowledge if a patient is experiencing adverse effects from their antipsychotic, which may be causing them to have a negative attitude toward medications. If a patient is experiencing adverse effects from their antipsychotic, offer interventions to mitigate those effects, such as adding an anticholinergic agent to address extrapyramidal symptoms. Decreasing the antipsychotic dosage might reduce the adverse effects burden while still optimizing the benefits from the antipsychotic. Additionally, switching to an alternate medication with a more favorable adverse effect profile may be an option. Whether the patient is experiencing intolerable adverse effects or just has a negative view of their prescribed antipsychotic, it is important to discuss switching medications.

Identifying patient attitudes and their general perspective toward their medication and illness is key. Similarly, a patient’s impaired insight into their mental illness has been associated with treatment discontinuation.² A strong therapeutic alliance with your patient is of the utmost importance in these situations.

Long-acting injectable antipsychotics (LAIs) are useful clinical tools for patients who struggle to adhere to oral medications. Educating patients and caregivers about other formulations—namely LAIs—can help clarify any misconceptions they may have. One study found that patients who were prescribed oral antipsychotics thought LAIs would be painful, have worse adverse effects, and would not be beneficial in preventing relapse.³ In addition to LAIs, other formulations of antipsychotic medications, such as patches, sublingual tablets, or liquids, may be an option.

For patients to be able to provide informed consent regarding the decision to discontinue their antipsychotic, it is important to educate them about the risks of not taking an antipsychotic, such as an increased risk of relapse, hospitalization, and poor outcomes. Explain that patients with first-episode psychosis who achieve remission of symptoms while taking an antipsychotic can remain in remission with continued treatment, but there is a 5-fold increased risk of relapse when discontinuing an antipsychotic during first-episode psychosis.⁴

Lastly, despite discussing the risks and benefits, if a patient is determined to discontinue their antipsychotic, we recommend a slow taper of medication rather than abrupt discontinuation. Research has shown that more than one-half of patients who abruptly discontinue an antipsychotic experience withdrawal symptoms, including (but not limited to) nausea, vomiting, abdominal pain, and headaches, as well as anxiety, restlessness, and insomnia.⁵ These symptoms may occur within 4 weeks after discontinuation.⁵ While there are no clear guidelines on deprescribing antipsychotics, it is best to individualize the taper based on patient response. Family and caregiver involvement, close follow-up, and symptom monitoring should be integrated into the tapering process.⁶

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Mr. N, age 58, has a history of schizophrenia, tobacco use disorder, and alcohol use disorder. For many years, Mr. N has been receiving IM olanzapine 2.5 mg/d to treat his schizophrenia. He lives in a psychiatric hospital but was sent to our hospital after being found to have severe oropharyngeal dysphasia on a modified barium swallow study. There was concern for aspiration due to a history of choking episodes, which had been occurring for almost 1 month. During the modified barium swallow study, Mr. N was noted to have aspiration with deep laryngeal penetration during the pharyngeal stages of swallowing to all consistencies; this did not improve with the chin-tuck maneuver. In addition, during a CT scan of the cervical spine, an osteophyte was noted at the C5-C6 level, with possible impingement of the cervical esophagus and decreased upper esophageal sphincter opening.

Due to these findings, Mr. N was sent to our emergency department (ED) for further evaluation. In the ED, his vital signs were stable. He endorsed having a cough after eating, a sensation of having food stuck in his throat, and some hoarseness. His physical examination was notable for poor dentition. Results of a standard laboratory workup were all within normal limits. X-ray was notable for hazy opacities in the right upper to mid lung zones. Mr. N was admitted to the medical unit for further evaluation and management.

Narrowing the diagnosis

Because Mr. N was aspirating both liquids and solids, it was imperative that we identify the cause as soon as possible. The consultations that followed slowly guided the treatment team toward a diagnosis of antipsychotic-induced dysphagia. Otolaryngology identified insensate larynx during a flexible fiberoptic laryngoscopy exam, which was highly suggestive of a neurological dysfunction such as dystonia. Furthermore, an esophagogastroduodenoscopy found no structural abnormalities to explain Mr. N’s dysphagia, which ruled out impingement of the cervical esophagus by the osteophyte. An MRI of the brain ruled out structural abnormalities or evidence of stroke. Finally, a speech and language pathologist confirmed decreased laryngeal closure and airway protection with a repeat modified barium swallow, which led to aspiration during swallowing. Psychiatry recommended starting diphenhydramine to treat Mr. N’s extrapyramidal symptoms (EPS). A 6-day trial was initiated, with a single 50 mg IV dose on the first day followed by 25 mL oral twice daily for the remaining 5 days. In addition, olanzapine was discontinued.

Switching to a different diet and antipsychotic

Two days after starting diphenhydramine, Mr. N was switched to a puree diet. His ability to swallow improved, and he no longer coughed. However, on repeat modified barium swallow, aspiration was still noted for all types of liquids and solids. No structural improvements were seen.

Mr. N was discharged back to his psychiatric hospital, and his antipsychotic was changed from olanzapine to oral aripiprazole 2 mg/d. The aripiprazole dose was kept low to prevent the recurrence of dystonia and because at the time, his schizophrenia was asymptomatic. Mr. N was also prescribed oral diphenhydramine 25 mL twice daily.

At a 2-week follow-up appointment, Mr. N continued to show clinical improvement on the puree diet with thin liquids and continued the prescribed medication regimen.

Dysphagia as a manifestation of EPS

All antipsychotics, and particularly first-generation agents, are associated with EPS.¹ These symptoms may be the result of antagonistic binding of dopaminergic D2 receptors within mesolimbic and mesocortical pathways of the brain, as well as parts of basal ganglia such as the caudate nucleus.²

In addition to the examples listed in the Table,² EPS can present as dysphagia, esophageal dysmotility, or aspiration, none of which may be recognized as EPS. Research has found haloperidol, loxapine, trifluoperazine, olanzapine, risperidone, quetiapine, clozapine, and aripiprazole are associated with dysphagia.^3-6 Strategies to treat antipsychotic-induced dysphagia include discontinuing the antipsychotic, lowering the dose, and changing to another medication.⁷

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Mr. N, age 58, has a history of schizophrenia, tobacco use disorder, and alcohol use disorder. For many years, Mr. N has been receiving IM olanzapine 2.5 mg/d to treat his schizophrenia. He lives in a psychiatric hospital but was sent to our hospital after being found to have severe oropharyngeal dysphasia on a modified barium swallow study. There was concern for aspiration due to a history of choking episodes, which had been occurring for almost 1 month. During the modified barium swallow study, Mr. N was noted to have aspiration with deep laryngeal penetration during the pharyngeal stages of swallowing to all consistencies; this did not improve with the chin-tuck maneuver. In addition, during a CT scan of the cervical spine, an osteophyte was noted at the C5-C6 level, with possible impingement of the cervical esophagus and decreased upper esophageal sphincter opening.

Due to these findings, Mr. N was sent to our emergency department (ED) for further evaluation. In the ED, his vital signs were stable. He endorsed having a cough after eating, a sensation of having food stuck in his throat, and some hoarseness. His physical examination was notable for poor dentition. Results of a standard laboratory workup were all within normal limits. X-ray was notable for hazy opacities in the right upper to mid lung zones. Mr. N was admitted to the medical unit for further evaluation and management.

Narrowing the diagnosis

Because Mr. N was aspirating both liquids and solids, it was imperative that we identify the cause as soon as possible. The consultations that followed slowly guided the treatment team toward a diagnosis of antipsychotic-induced dysphagia. Otolaryngology identified insensate larynx during a flexible fiberoptic laryngoscopy exam, which was highly suggestive of a neurological dysfunction such as dystonia. Furthermore, an esophagogastroduodenoscopy found no structural abnormalities to explain Mr. N’s dysphagia, which ruled out impingement of the cervical esophagus by the osteophyte. An MRI of the brain ruled out structural abnormalities or evidence of stroke. Finally, a speech and language pathologist confirmed decreased laryngeal closure and airway protection with a repeat modified barium swallow, which led to aspiration during swallowing. Psychiatry recommended starting diphenhydramine to treat Mr. N’s extrapyramidal symptoms (EPS). A 6-day trial was initiated, with a single 50 mg IV dose on the first day followed by 25 mL oral twice daily for the remaining 5 days. In addition, olanzapine was discontinued.

Switching to a different diet and antipsychotic

Two days after starting diphenhydramine, Mr. N was switched to a puree diet. His ability to swallow improved, and he no longer coughed. However, on repeat modified barium swallow, aspiration was still noted for all types of liquids and solids. No structural improvements were seen.

Mr. N was discharged back to his psychiatric hospital, and his antipsychotic was changed from olanzapine to oral aripiprazole 2 mg/d. The aripiprazole dose was kept low to prevent the recurrence of dystonia and because at the time, his schizophrenia was asymptomatic. Mr. N was also prescribed oral diphenhydramine 25 mL twice daily.

At a 2-week follow-up appointment, Mr. N continued to show clinical improvement on the puree diet with thin liquids and continued the prescribed medication regimen.

Dysphagia as a manifestation of EPS

All antipsychotics, and particularly first-generation agents, are associated with EPS.¹ These symptoms may be the result of antagonistic binding of dopaminergic D2 receptors within mesolimbic and mesocortical pathways of the brain, as well as parts of basal ganglia such as the caudate nucleus.²

In addition to the examples listed in the Table,² EPS can present as dysphagia, esophageal dysmotility, or aspiration, none of which may be recognized as EPS. Research has found haloperidol, loxapine, trifluoperazine, olanzapine, risperidone, quetiapine, clozapine, and aripiprazole are associated with dysphagia.^3-6 Strategies to treat antipsychotic-induced dysphagia include discontinuing the antipsychotic, lowering the dose, and changing to another medication.⁷

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Mr. N, age 58, has a history of schizophrenia, tobacco use disorder, and alcohol use disorder. For many years, Mr. N has been receiving IM olanzapine 2.5 mg/d to treat his schizophrenia. He lives in a psychiatric hospital but was sent to our hospital after being found to have severe oropharyngeal dysphasia on a modified barium swallow study. There was concern for aspiration due to a history of choking episodes, which had been occurring for almost 1 month. During the modified barium swallow study, Mr. N was noted to have aspiration with deep laryngeal penetration during the pharyngeal stages of swallowing to all consistencies; this did not improve with the chin-tuck maneuver. In addition, during a CT scan of the cervical spine, an osteophyte was noted at the C5-C6 level, with possible impingement of the cervical esophagus and decreased upper esophageal sphincter opening.

Due to these findings, Mr. N was sent to our emergency department (ED) for further evaluation. In the ED, his vital signs were stable. He endorsed having a cough after eating, a sensation of having food stuck in his throat, and some hoarseness. His physical examination was notable for poor dentition. Results of a standard laboratory workup were all within normal limits. X-ray was notable for hazy opacities in the right upper to mid lung zones. Mr. N was admitted to the medical unit for further evaluation and management.

Narrowing the diagnosis

Because Mr. N was aspirating both liquids and solids, it was imperative that we identify the cause as soon as possible. The consultations that followed slowly guided the treatment team toward a diagnosis of antipsychotic-induced dysphagia. Otolaryngology identified insensate larynx during a flexible fiberoptic laryngoscopy exam, which was highly suggestive of a neurological dysfunction such as dystonia. Furthermore, an esophagogastroduodenoscopy found no structural abnormalities to explain Mr. N’s dysphagia, which ruled out impingement of the cervical esophagus by the osteophyte. An MRI of the brain ruled out structural abnormalities or evidence of stroke. Finally, a speech and language pathologist confirmed decreased laryngeal closure and airway protection with a repeat modified barium swallow, which led to aspiration during swallowing. Psychiatry recommended starting diphenhydramine to treat Mr. N’s extrapyramidal symptoms (EPS). A 6-day trial was initiated, with a single 50 mg IV dose on the first day followed by 25 mL oral twice daily for the remaining 5 days. In addition, olanzapine was discontinued.

Switching to a different diet and antipsychotic

Two days after starting diphenhydramine, Mr. N was switched to a puree diet. His ability to swallow improved, and he no longer coughed. However, on repeat modified barium swallow, aspiration was still noted for all types of liquids and solids. No structural improvements were seen.

Mr. N was discharged back to his psychiatric hospital, and his antipsychotic was changed from olanzapine to oral aripiprazole 2 mg/d. The aripiprazole dose was kept low to prevent the recurrence of dystonia and because at the time, his schizophrenia was asymptomatic. Mr. N was also prescribed oral diphenhydramine 25 mL twice daily.

At a 2-week follow-up appointment, Mr. N continued to show clinical improvement on the puree diet with thin liquids and continued the prescribed medication regimen.

Dysphagia as a manifestation of EPS

All antipsychotics, and particularly first-generation agents, are associated with EPS.¹ These symptoms may be the result of antagonistic binding of dopaminergic D2 receptors within mesolimbic and mesocortical pathways of the brain, as well as parts of basal ganglia such as the caudate nucleus.²

In addition to the examples listed in the Table,² EPS can present as dysphagia, esophageal dysmotility, or aspiration, none of which may be recognized as EPS. Research has found haloperidol, loxapine, trifluoperazine, olanzapine, risperidone, quetiapine, clozapine, and aripiprazole are associated with dysphagia.^3-6 Strategies to treat antipsychotic-induced dysphagia include discontinuing the antipsychotic, lowering the dose, and changing to another medication.⁷

In his recent editorial (“A ‘guest editorial’ … generated by ChatGPT?” Current Psychiatry, April 2023, p. 6-7, doi:10.12788/cp.0348), Dr. Nasrallah asked for feedback on the ChatGPT-generated editorial on myths surrounding psychiatry. I found the “product” equivalent to a diligent high schooler’s homework assignment. ChatGPT lacks the nuance of a historical perspective, one that has observed the ever-changing enthusiasms (from Freud’s “cure” for posttraumatic stress disorder through dopamine, then 5HT, now glutamate and psychedelics) because mental illness is so difficult to treat. For the guest editorial on myths, a little googling would have yielded the same content, if not a similar list of myths. Surely such an editorial would never be accepted in any psychiatry journal; maybe in Reader’s Digest!

Sara Hartley, MD
Berkeley, California

I just read the “guest editorial” generated by ChatGPT. Thank you for this article. Although this is truly an amazing advancement in artificial intelligence (AI), I feel this guest editorial was very basic. It did not read like scientific writing. It read more like it was written at an 11th- or 12th-grade level, though I am fully aware that the question was simple, and thus the answer was not very deep. I can’t deny that if I had been tested, chances are good I would have fallen among the 32% of my peers who would not have recognized it as AI. I appreciate that you (and your team) are working on a protocol regarding how to include content generated by or with the help of AI. God knows if (most likely, when) people with evil minds will use AI to spread false information that may dispute the accredited scientific data and research that guide the medical world and many other fields. I wonder if AI can serve as a search engine that is better or easier to use than PubMed (for example) and the other services we use for research and learning.

Alex Mustachi, PMHNP-BC
Suffern, New York

I wanted to let you know how much I enjoyed reading your recent editorial on AI and scientific writing. Sharing the 4 AI-generated “articles” with readers (“For artificial intelligence, the future is finally here,” Current Psychiatry, April 2023, p. 8-11,29, doi:10.12788/cp.0354) was a delightfully clever/engaging exercise. Other journals need to take a more proactive/targeted stand on this very important issue.

Martha Sajatovic, MD
Cleveland, Ohio

Continue to: The AI-generated samples...

The Al-generated samples were fascinating. As far as I superficially noted, the spelling, grammar, and punctuation were correct. That is better than one gets from most student compositions. However, the articles were completely lacking in depth or apparent insight. The article on anosognosia mentioned it can be present in up to 50% of cases of schizophrenia. In my experience, it is present in approximately 99.9% of cases. It clearly did not consider if anosognosia is also present in alcoholics, codependents, abusers, or people with bizarre political beliefs. But I guess the “intelligence” wasn’t asked that. The other samples also show shallow thinking and repetitive wording—pretty much like my high school junior compositions.

Maybe an appropriate use for AI is a task such as evaluating suicide notes. AI’s success causes one to feel nonplussed. Much more disconcerting was a recent news article that reported AI made up nonexistent references to a professor’s alleged sexual harassment, and then generated citations to its own made-up reference.¹ That is indeed frightening new territory. How does one fight against a machine to clear their own name?

Linda Miller, NP
Harrisonburg, Virginia

References

1. Verma P, Oremus W. ChatGPT invented a sexual harassment scandal and named a real law prof as the accused. The Washington Post. April 5, 2023. Accessed May 8, 2023. https://www.washingtonpost.com/technology/2023/04/05/chatgpt-lies/

Thank you, Dr. Nasrallah, for your latest thought-provoking articles on AI. Time and again you provide the profession with cutting-edge, relevant food for thought. Caveat emptor, indeed.

Lawrence E. Cormier, MD
Denver, Colorado

Continue to: We read with interest...

We read with interest Dr. Nasrallah’s editorial that invited readers to share their take on the quality of an AI-generated writing sample. I (MZP) was a computational neuroscience major at Columbia University and was accepted to medical school in 2022 at age 19. I identify with the character traits common among many young tech entrepreneurs driving the AI revolution—social awkwardness; discomfort with subjective emotions; restricted areas of interest; algorithmic thinking; strict, naive idealism; and an obsession with data. To gain a deeper understanding of Sam Altman, the CEO of OpenAI (the company that created ChatGPT), we analyzed a 2.5-hour interview that MIT research scientist Lex Fridman conducted with Altman.¹ As a result, we began to discern why AI-generated text feels so stiff and bland compared to the superior fluidity and expressiveness of human communication. As of now, the creation is a reflection of its creator.

Generally speaking, computer scientists are not warm and fuzzy types. Hence, ChatGPT strives to be neutral, accurate, and objective compared to more biased and fallible humans, and, consequently, its language lacks the emotive flair we have come to relish in normal human interactions. In the interview, Altman discusses several solutions that will soon raise the quality of ChatGPT’s currently deficient emotional quotient to approximate its superior IQ. Altruistically, Altman has opened ChatGPT to all, so we can freely interact and utilize its potential to increase our productivity exponentially. As a result, ChatGPT interfaces with millions of humans through RLHF (reinforcement learning from human feedback), which makes each iteration more in tune with our sensibilities.² Another initiative Altman is undertaking is to depart his Silicon Valley bubble for a road trip to interact with “regular people” and gain a better sense of how to make ChatGPT more user-friendly.¹

What’s so saddening about Dr. Nasrallah’s homework assignment is that he is asking us to evaluate with our mature adult standards an article that was written at the emotional stage of a child in early high school. But our hubris and complacency are entirely unfounded because ChatGPT is learning much faster than we ever could, and it will quickly surpass us all as it continues to evolve.

It is also quite disconcerting to hear how Altman is naively relying upon governmental regulation and corporate responsibility to manage the potential misuse of future artificial general intelligence for social, economic, and political control and upheaval. We know well the harmful effects of the internet and social media, particularly on our youth, yet our laws still lag far behind the fact that these technological innovations are simultaneously enhancing our knowledge while destroying our souls. As custodians of our world, dedicated to promoting and preserving mental well-being, we cannot wait much longer to intervene in properly parenting AI along its wisest developmental trajectory before it is too late.

Maxwell Zachary Price, BA
Nutley, New Jersey

Richard Louis Price, MD
New York, New York

References

1. Sam Altman: OpenAI CEO on GPT-4, ChatGPT, and the Future of AI. Lex Fridman Podcast #367. March 25, 2023. Accessed April 5, 2023. https://www.youtube.com/watch?v=L_Guz73e6fw

2. Heikkilä M. How OpenAI is trying to make ChatGPT safer and less biased. MIT Technology Review. Published February 21, 2023. Accessed April 5, 2023. https://www.technologyreview.com/2023/02/21/1068893/how-openai-is-trying-to-make-chatgpt-safer-and-less-biased/

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

In his recent editorial (“A ‘guest editorial’ … generated by ChatGPT?” Current Psychiatry, April 2023, p. 6-7, doi:10.12788/cp.0348), Dr. Nasrallah asked for feedback on the ChatGPT-generated editorial on myths surrounding psychiatry. I found the “product” equivalent to a diligent high schooler’s homework assignment. ChatGPT lacks the nuance of a historical perspective, one that has observed the ever-changing enthusiasms (from Freud’s “cure” for posttraumatic stress disorder through dopamine, then 5HT, now glutamate and psychedelics) because mental illness is so difficult to treat. For the guest editorial on myths, a little googling would have yielded the same content, if not a similar list of myths. Surely such an editorial would never be accepted in any psychiatry journal; maybe in Reader’s Digest!

Sara Hartley, MD
Berkeley, California

I just read the “guest editorial” generated by ChatGPT. Thank you for this article. Although this is truly an amazing advancement in artificial intelligence (AI), I feel this guest editorial was very basic. It did not read like scientific writing. It read more like it was written at an 11th- or 12th-grade level, though I am fully aware that the question was simple, and thus the answer was not very deep. I can’t deny that if I had been tested, chances are good I would have fallen among the 32% of my peers who would not have recognized it as AI. I appreciate that you (and your team) are working on a protocol regarding how to include content generated by or with the help of AI. God knows if (most likely, when) people with evil minds will use AI to spread false information that may dispute the accredited scientific data and research that guide the medical world and many other fields. I wonder if AI can serve as a search engine that is better or easier to use than PubMed (for example) and the other services we use for research and learning.

Alex Mustachi, PMHNP-BC
Suffern, New York

I wanted to let you know how much I enjoyed reading your recent editorial on AI and scientific writing. Sharing the 4 AI-generated “articles” with readers (“For artificial intelligence, the future is finally here,” Current Psychiatry, April 2023, p. 8-11,29, doi:10.12788/cp.0354) was a delightfully clever/engaging exercise. Other journals need to take a more proactive/targeted stand on this very important issue.

Martha Sajatovic, MD
Cleveland, Ohio

Continue to: The AI-generated samples...

The Al-generated samples were fascinating. As far as I superficially noted, the spelling, grammar, and punctuation were correct. That is better than one gets from most student compositions. However, the articles were completely lacking in depth or apparent insight. The article on anosognosia mentioned it can be present in up to 50% of cases of schizophrenia. In my experience, it is present in approximately 99.9% of cases. It clearly did not consider if anosognosia is also present in alcoholics, codependents, abusers, or people with bizarre political beliefs. But I guess the “intelligence” wasn’t asked that. The other samples also show shallow thinking and repetitive wording—pretty much like my high school junior compositions.

Maybe an appropriate use for AI is a task such as evaluating suicide notes. AI’s success causes one to feel nonplussed. Much more disconcerting was a recent news article that reported AI made up nonexistent references to a professor’s alleged sexual harassment, and then generated citations to its own made-up reference.¹ That is indeed frightening new territory. How does one fight against a machine to clear their own name?

Linda Miller, NP
Harrisonburg, Virginia

References

1. Verma P, Oremus W. ChatGPT invented a sexual harassment scandal and named a real law prof as the accused. The Washington Post. April 5, 2023. Accessed May 8, 2023. https://www.washingtonpost.com/technology/2023/04/05/chatgpt-lies/

Thank you, Dr. Nasrallah, for your latest thought-provoking articles on AI. Time and again you provide the profession with cutting-edge, relevant food for thought. Caveat emptor, indeed.

Lawrence E. Cormier, MD
Denver, Colorado

Continue to: We read with interest...

We read with interest Dr. Nasrallah’s editorial that invited readers to share their take on the quality of an AI-generated writing sample. I (MZP) was a computational neuroscience major at Columbia University and was accepted to medical school in 2022 at age 19. I identify with the character traits common among many young tech entrepreneurs driving the AI revolution—social awkwardness; discomfort with subjective emotions; restricted areas of interest; algorithmic thinking; strict, naive idealism; and an obsession with data. To gain a deeper understanding of Sam Altman, the CEO of OpenAI (the company that created ChatGPT), we analyzed a 2.5-hour interview that MIT research scientist Lex Fridman conducted with Altman.¹ As a result, we began to discern why AI-generated text feels so stiff and bland compared to the superior fluidity and expressiveness of human communication. As of now, the creation is a reflection of its creator.

Generally speaking, computer scientists are not warm and fuzzy types. Hence, ChatGPT strives to be neutral, accurate, and objective compared to more biased and fallible humans, and, consequently, its language lacks the emotive flair we have come to relish in normal human interactions. In the interview, Altman discusses several solutions that will soon raise the quality of ChatGPT’s currently deficient emotional quotient to approximate its superior IQ. Altruistically, Altman has opened ChatGPT to all, so we can freely interact and utilize its potential to increase our productivity exponentially. As a result, ChatGPT interfaces with millions of humans through RLHF (reinforcement learning from human feedback), which makes each iteration more in tune with our sensibilities.² Another initiative Altman is undertaking is to depart his Silicon Valley bubble for a road trip to interact with “regular people” and gain a better sense of how to make ChatGPT more user-friendly.¹

What’s so saddening about Dr. Nasrallah’s homework assignment is that he is asking us to evaluate with our mature adult standards an article that was written at the emotional stage of a child in early high school. But our hubris and complacency are entirely unfounded because ChatGPT is learning much faster than we ever could, and it will quickly surpass us all as it continues to evolve.

It is also quite disconcerting to hear how Altman is naively relying upon governmental regulation and corporate responsibility to manage the potential misuse of future artificial general intelligence for social, economic, and political control and upheaval. We know well the harmful effects of the internet and social media, particularly on our youth, yet our laws still lag far behind the fact that these technological innovations are simultaneously enhancing our knowledge while destroying our souls. As custodians of our world, dedicated to promoting and preserving mental well-being, we cannot wait much longer to intervene in properly parenting AI along its wisest developmental trajectory before it is too late.

Maxwell Zachary Price, BA
Nutley, New Jersey

Richard Louis Price, MD
New York, New York

References

1. Sam Altman: OpenAI CEO on GPT-4, ChatGPT, and the Future of AI. Lex Fridman Podcast #367. March 25, 2023. Accessed April 5, 2023. https://www.youtube.com/watch?v=L_Guz73e6fw

2. Heikkilä M. How OpenAI is trying to make ChatGPT safer and less biased. MIT Technology Review. Published February 21, 2023. Accessed April 5, 2023. https://www.technologyreview.com/2023/02/21/1068893/how-openai-is-trying-to-make-chatgpt-safer-and-less-biased/

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

In his recent editorial (“A ‘guest editorial’ … generated by ChatGPT?” Current Psychiatry, April 2023, p. 6-7, doi:10.12788/cp.0348), Dr. Nasrallah asked for feedback on the ChatGPT-generated editorial on myths surrounding psychiatry. I found the “product” equivalent to a diligent high schooler’s homework assignment. ChatGPT lacks the nuance of a historical perspective, one that has observed the ever-changing enthusiasms (from Freud’s “cure” for posttraumatic stress disorder through dopamine, then 5HT, now glutamate and psychedelics) because mental illness is so difficult to treat. For the guest editorial on myths, a little googling would have yielded the same content, if not a similar list of myths. Surely such an editorial would never be accepted in any psychiatry journal; maybe in Reader’s Digest!

Sara Hartley, MD
Berkeley, California

I just read the “guest editorial” generated by ChatGPT. Thank you for this article. Although this is truly an amazing advancement in artificial intelligence (AI), I feel this guest editorial was very basic. It did not read like scientific writing. It read more like it was written at an 11th- or 12th-grade level, though I am fully aware that the question was simple, and thus the answer was not very deep. I can’t deny that if I had been tested, chances are good I would have fallen among the 32% of my peers who would not have recognized it as AI. I appreciate that you (and your team) are working on a protocol regarding how to include content generated by or with the help of AI. God knows if (most likely, when) people with evil minds will use AI to spread false information that may dispute the accredited scientific data and research that guide the medical world and many other fields. I wonder if AI can serve as a search engine that is better or easier to use than PubMed (for example) and the other services we use for research and learning.

Alex Mustachi, PMHNP-BC
Suffern, New York

I wanted to let you know how much I enjoyed reading your recent editorial on AI and scientific writing. Sharing the 4 AI-generated “articles” with readers (“For artificial intelligence, the future is finally here,” Current Psychiatry, April 2023, p. 8-11,29, doi:10.12788/cp.0354) was a delightfully clever/engaging exercise. Other journals need to take a more proactive/targeted stand on this very important issue.

Martha Sajatovic, MD
Cleveland, Ohio

Continue to: The AI-generated samples...

The Al-generated samples were fascinating. As far as I superficially noted, the spelling, grammar, and punctuation were correct. That is better than one gets from most student compositions. However, the articles were completely lacking in depth or apparent insight. The article on anosognosia mentioned it can be present in up to 50% of cases of schizophrenia. In my experience, it is present in approximately 99.9% of cases. It clearly did not consider if anosognosia is also present in alcoholics, codependents, abusers, or people with bizarre political beliefs. But I guess the “intelligence” wasn’t asked that. The other samples also show shallow thinking and repetitive wording—pretty much like my high school junior compositions.

Maybe an appropriate use for AI is a task such as evaluating suicide notes. AI’s success causes one to feel nonplussed. Much more disconcerting was a recent news article that reported AI made up nonexistent references to a professor’s alleged sexual harassment, and then generated citations to its own made-up reference.¹ That is indeed frightening new territory. How does one fight against a machine to clear their own name?

Linda Miller, NP
Harrisonburg, Virginia

References

1. Verma P, Oremus W. ChatGPT invented a sexual harassment scandal and named a real law prof as the accused. The Washington Post. April 5, 2023. Accessed May 8, 2023. https://www.washingtonpost.com/technology/2023/04/05/chatgpt-lies/

Thank you, Dr. Nasrallah, for your latest thought-provoking articles on AI. Time and again you provide the profession with cutting-edge, relevant food for thought. Caveat emptor, indeed.

Lawrence E. Cormier, MD
Denver, Colorado

Continue to: We read with interest...

We read with interest Dr. Nasrallah’s editorial that invited readers to share their take on the quality of an AI-generated writing sample. I (MZP) was a computational neuroscience major at Columbia University and was accepted to medical school in 2022 at age 19. I identify with the character traits common among many young tech entrepreneurs driving the AI revolution—social awkwardness; discomfort with subjective emotions; restricted areas of interest; algorithmic thinking; strict, naive idealism; and an obsession with data. To gain a deeper understanding of Sam Altman, the CEO of OpenAI (the company that created ChatGPT), we analyzed a 2.5-hour interview that MIT research scientist Lex Fridman conducted with Altman.¹ As a result, we began to discern why AI-generated text feels so stiff and bland compared to the superior fluidity and expressiveness of human communication. As of now, the creation is a reflection of its creator.

Generally speaking, computer scientists are not warm and fuzzy types. Hence, ChatGPT strives to be neutral, accurate, and objective compared to more biased and fallible humans, and, consequently, its language lacks the emotive flair we have come to relish in normal human interactions. In the interview, Altman discusses several solutions that will soon raise the quality of ChatGPT’s currently deficient emotional quotient to approximate its superior IQ. Altruistically, Altman has opened ChatGPT to all, so we can freely interact and utilize its potential to increase our productivity exponentially. As a result, ChatGPT interfaces with millions of humans through RLHF (reinforcement learning from human feedback), which makes each iteration more in tune with our sensibilities.² Another initiative Altman is undertaking is to depart his Silicon Valley bubble for a road trip to interact with “regular people” and gain a better sense of how to make ChatGPT more user-friendly.¹

What’s so saddening about Dr. Nasrallah’s homework assignment is that he is asking us to evaluate with our mature adult standards an article that was written at the emotional stage of a child in early high school. But our hubris and complacency are entirely unfounded because ChatGPT is learning much faster than we ever could, and it will quickly surpass us all as it continues to evolve.

It is also quite disconcerting to hear how Altman is naively relying upon governmental regulation and corporate responsibility to manage the potential misuse of future artificial general intelligence for social, economic, and political control and upheaval. We know well the harmful effects of the internet and social media, particularly on our youth, yet our laws still lag far behind the fact that these technological innovations are simultaneously enhancing our knowledge while destroying our souls. As custodians of our world, dedicated to promoting and preserving mental well-being, we cannot wait much longer to intervene in properly parenting AI along its wisest developmental trajectory before it is too late.

Maxwell Zachary Price, BA
Nutley, New Jersey

Richard Louis Price, MD
New York, New York

References

1. Sam Altman: OpenAI CEO on GPT-4, ChatGPT, and the Future of AI. Lex Fridman Podcast #367. March 25, 2023. Accessed April 5, 2023. https://www.youtube.com/watch?v=L_Guz73e6fw

2. Heikkilä M. How OpenAI is trying to make ChatGPT safer and less biased. MIT Technology Review. Published February 21, 2023. Accessed April 5, 2023. https://www.technologyreview.com/2023/02/21/1068893/how-openai-is-trying-to-make-chatgpt-safer-and-less-biased/

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

Kadirawel Iswara, MD’s accomplishments go far beyond gastroenterology into humanitarian pursuits.

After the 2004 Indian Ocean earthquake and tsunami, he traveled to his home country of Sri Lanka to help people who were in need and establish an orphanage. He has applied his skills as a gastroenterologist in the U.S. military and the New York City Police Department.

Question: What gives you joy in day-to-day practice?

Dr. Iswara: One of the main joys is my colleagues, coworkers, fellows, and my patients. The patients come No. 1. As I walk into my practice area or in the hospital, there is a sense of inner happiness in my mind to see the smiles of the patients and the greetings I get from the patients and all the coworkers. I also see smiling patients with anxiety in their face, trying to get my attention to take care of them.

After I see the patient, I change to a different mode, a kind of a professional mode to give the best to the people whom I’m caring for, who are trusting me with their lives.

One thing I do in my mind before I even start the day, I do a silent prayer to guide me, to give compassionate care and safe care. I will not harm anyone who is depending on my care.
 

Q: Who was your mentor?

Dr. Iswara: I was lucky enough to have been trained by Baroukh El Kodsi, MD, at Maimonides Medical Center. He recently passed away and was a legend in Brooklyn. I was his first-generation trainee, and I was able to pass on my skills to my trainees. Now so many people who are in Brooklyn; they were trained by me, so it’s kind of growth by generations.

When I finished the training with Dr. Kodsi, he hired me as an associate director of the GI department at Maimonides. I became the program director, then division chief, then I became a director of advanced endoscopy. All these gastroenterology procedures started after 1975 while I was doing the training, so I was one of the pioneers to bring all this new technology to our hospital. I’m still involved in fellowship education.
 

Q: Can we talk more about your accomplishments? Perhaps you can discuss your AGA award and what you received it for.

Dr. Iswara: I’m humbled and honored by this role, and I’ll be forever grateful to AGA for this prestigious honor at the late stage of my career.

I have been a continuous AGA member for the last 45 years. I probably have one of the longest durations of being an actively practicing gastroenterologist in Brooklyn. I’ve also done academic work, teaching so many young gastroenterologists, motivating several of them to become leading gastroenterologists.
 

Q: If you could describe a scene of your vision for the future, what it would it be in terms of how gastroenterology is practiced?

Dr. Iswara: I’d like to see the newer generation practice more of a clinical medicine than technical medicine. Sometimes when I see the young people, they sit in front of the computer more than talking and touching the patient. There has to be some sort of a balance where the newer people should be taught more bedside personal care, touching the patient, looking at the patient’s face. They are kind of under pressure to write longer notes than to examine the patient, so I think this has to change.

Q: Describe how you would spend a free Saturday afternoon.

Dr. Iswara: When I was in the military, I was told that to prevent battle fatigue you had to take a rest. I really try to take a rest almost 2 hours every day in the daytime. This rejuvenates me.

We live in New York, and I love to go to shows, especially magic shows. I love magic and illusion. 

On free Saturday evenings, I also spend time with my grandchildren in the city, watching them in their baseball, soccer, swimming, and other activities. I love to spend time with them.
 

Lightning round

Texting or talking?
Texting

Favorite city in the U.S. besides the one you live?
Naples, Fla.

Favorite breakfast?
Pancakes

Dark Chocolate or milk chocolate?
Cadbury from England

Last movie you watched?
“To Sir, With Love”

Kadirawel Iswara, MD’s accomplishments go far beyond gastroenterology into humanitarian pursuits.

After the 2004 Indian Ocean earthquake and tsunami, he traveled to his home country of Sri Lanka to help people who were in need and establish an orphanage. He has applied his skills as a gastroenterologist in the U.S. military and the New York City Police Department.

Question: What gives you joy in day-to-day practice?

Dr. Iswara: One of the main joys is my colleagues, coworkers, fellows, and my patients. The patients come No. 1. As I walk into my practice area or in the hospital, there is a sense of inner happiness in my mind to see the smiles of the patients and the greetings I get from the patients and all the coworkers. I also see smiling patients with anxiety in their face, trying to get my attention to take care of them.

After I see the patient, I change to a different mode, a kind of a professional mode to give the best to the people whom I’m caring for, who are trusting me with their lives.

One thing I do in my mind before I even start the day, I do a silent prayer to guide me, to give compassionate care and safe care. I will not harm anyone who is depending on my care.
 

Q: Who was your mentor?

Dr. Iswara: I was lucky enough to have been trained by Baroukh El Kodsi, MD, at Maimonides Medical Center. He recently passed away and was a legend in Brooklyn. I was his first-generation trainee, and I was able to pass on my skills to my trainees. Now so many people who are in Brooklyn; they were trained by me, so it’s kind of growth by generations.

When I finished the training with Dr. Kodsi, he hired me as an associate director of the GI department at Maimonides. I became the program director, then division chief, then I became a director of advanced endoscopy. All these gastroenterology procedures started after 1975 while I was doing the training, so I was one of the pioneers to bring all this new technology to our hospital. I’m still involved in fellowship education.
 

Q: Can we talk more about your accomplishments? Perhaps you can discuss your AGA award and what you received it for.

Dr. Iswara: I’m humbled and honored by this role, and I’ll be forever grateful to AGA for this prestigious honor at the late stage of my career.

I have been a continuous AGA member for the last 45 years. I probably have one of the longest durations of being an actively practicing gastroenterologist in Brooklyn. I’ve also done academic work, teaching so many young gastroenterologists, motivating several of them to become leading gastroenterologists.
 

Q: If you could describe a scene of your vision for the future, what it would it be in terms of how gastroenterology is practiced?

Dr. Iswara: I’d like to see the newer generation practice more of a clinical medicine than technical medicine. Sometimes when I see the young people, they sit in front of the computer more than talking and touching the patient. There has to be some sort of a balance where the newer people should be taught more bedside personal care, touching the patient, looking at the patient’s face. They are kind of under pressure to write longer notes than to examine the patient, so I think this has to change.

Q: Describe how you would spend a free Saturday afternoon.

Dr. Iswara: When I was in the military, I was told that to prevent battle fatigue you had to take a rest. I really try to take a rest almost 2 hours every day in the daytime. This rejuvenates me.

We live in New York, and I love to go to shows, especially magic shows. I love magic and illusion. 

On free Saturday evenings, I also spend time with my grandchildren in the city, watching them in their baseball, soccer, swimming, and other activities. I love to spend time with them.
 

Lightning round

Texting or talking?
Texting

Favorite city in the U.S. besides the one you live?
Naples, Fla.

Favorite breakfast?
Pancakes

Dark Chocolate or milk chocolate?
Cadbury from England

Last movie you watched?
“To Sir, With Love”

Kadirawel Iswara, MD’s accomplishments go far beyond gastroenterology into humanitarian pursuits.

After the 2004 Indian Ocean earthquake and tsunami, he traveled to his home country of Sri Lanka to help people who were in need and establish an orphanage. He has applied his skills as a gastroenterologist in the U.S. military and the New York City Police Department.

Question: What gives you joy in day-to-day practice?

Dr. Iswara: One of the main joys is my colleagues, coworkers, fellows, and my patients. The patients come No. 1. As I walk into my practice area or in the hospital, there is a sense of inner happiness in my mind to see the smiles of the patients and the greetings I get from the patients and all the coworkers. I also see smiling patients with anxiety in their face, trying to get my attention to take care of them.

After I see the patient, I change to a different mode, a kind of a professional mode to give the best to the people whom I’m caring for, who are trusting me with their lives.

One thing I do in my mind before I even start the day, I do a silent prayer to guide me, to give compassionate care and safe care. I will not harm anyone who is depending on my care.
 

Q: Who was your mentor?

Dr. Iswara: I was lucky enough to have been trained by Baroukh El Kodsi, MD, at Maimonides Medical Center. He recently passed away and was a legend in Brooklyn. I was his first-generation trainee, and I was able to pass on my skills to my trainees. Now so many people who are in Brooklyn; they were trained by me, so it’s kind of growth by generations.

When I finished the training with Dr. Kodsi, he hired me as an associate director of the GI department at Maimonides. I became the program director, then division chief, then I became a director of advanced endoscopy. All these gastroenterology procedures started after 1975 while I was doing the training, so I was one of the pioneers to bring all this new technology to our hospital. I’m still involved in fellowship education.
 

Q: Can we talk more about your accomplishments? Perhaps you can discuss your AGA award and what you received it for.

Dr. Iswara: I’m humbled and honored by this role, and I’ll be forever grateful to AGA for this prestigious honor at the late stage of my career.

I have been a continuous AGA member for the last 45 years. I probably have one of the longest durations of being an actively practicing gastroenterologist in Brooklyn. I’ve also done academic work, teaching so many young gastroenterologists, motivating several of them to become leading gastroenterologists.
 

Q: If you could describe a scene of your vision for the future, what it would it be in terms of how gastroenterology is practiced?

Dr. Iswara: I’d like to see the newer generation practice more of a clinical medicine than technical medicine. Sometimes when I see the young people, they sit in front of the computer more than talking and touching the patient. There has to be some sort of a balance where the newer people should be taught more bedside personal care, touching the patient, looking at the patient’s face. They are kind of under pressure to write longer notes than to examine the patient, so I think this has to change.

Q: Describe how you would spend a free Saturday afternoon.

Dr. Iswara: When I was in the military, I was told that to prevent battle fatigue you had to take a rest. I really try to take a rest almost 2 hours every day in the daytime. This rejuvenates me.

We live in New York, and I love to go to shows, especially magic shows. I love magic and illusion. 

On free Saturday evenings, I also spend time with my grandchildren in the city, watching them in their baseball, soccer, swimming, and other activities. I love to spend time with them.
 

Lightning round

Texting or talking?
Texting

Favorite city in the U.S. besides the one you live?
Naples, Fla.

Favorite breakfast?
Pancakes

Dark Chocolate or milk chocolate?
Cadbury from England

Last movie you watched?
“To Sir, With Love”

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.