Micrograph showing DLBCL

New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).

Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.

The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.

Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.

The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.

The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.

“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.

“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”

The researchers classified these subtypes as clusters (C) 1 to 5.

C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.

C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.

Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.

C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.

Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88^L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.

Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”

Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.

“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.

She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.

Another group of researchers recently identified 4 genetic subtypes of DLBCL.

Micrograph showing DLBCL

New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).

Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.

The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.

Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.

The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.

The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.

“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.

“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”

The researchers classified these subtypes as clusters (C) 1 to 5.

C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.

C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.

Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.

C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.

Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88^L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.

Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”

Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.

“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.

She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.

Another group of researchers recently identified 4 genetic subtypes of DLBCL.

Micrograph showing DLBCL

New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).

Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.

The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.

Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.

The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.

The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.

“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.

“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”

The researchers classified these subtypes as clusters (C) 1 to 5.

C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.

C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.

Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.

C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.

Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88^L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.

Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”

Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.

“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.

She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.

Another group of researchers recently identified 4 genetic subtypes of DLBCL.

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Parkinson’s disease (PD) can be a tough diagnosis to navigate. Patients with this neurologic movement disorder can present with a highly variable constellation of symptoms,¹ ranging from the well-known tremor and bradykinesia to difficulties with activities of daily living (particularly dressing and getting out of a car²) to nonspecific symptoms, such as pain, fatigue, hyposmia, and erectile dysfunction.³

Furthermore, medications more recently approved by the US Food and Drug Administration (FDA) have left many health care providers confused about what constitutes appropriate first-, second-, and third-line therapies, as well as add-on therapy for symptoms secondary to dopaminergic agents. What follows is a stepwise approach to managing PD that incorporates these newer therapies so that you can confidently and effectively manage patients with PD with little or no consultation.

First, though, we review who’s at greatest risk—and what you’ll see.

Family history tops list of risk factors for PD

While PD occurs in less than 1% of the population ≥40 years of age, its prevalence increases with age, becoming significantly higher by age 60 years, with a slight predominance toward males.⁴

A variety of factors increase the risk of developing PD. A well-conducted meta-analysis showed that the strongest risk factor is having a family member, particularly a first-degree relative, with a history of PD or tremor.⁵ Repeated head injury, with or without loss of consciousness, is also a factor;⁵ risk increases with each occurrence.⁶ Other risk factors include exposure to pesticides, rural living, and exposure to well water.⁵

Researchers have conducted several studies regarding the effects of elevated cholesterol and hypertension on the risk of PD, but results are still without consensus.⁵ A study published in 2017 reported a significantly increased risk of PD associated with having hepatitis B or C, but the mechanism for the association—including whether it is a consequence of treatment—is unknown.⁷

Smoking and coffee drinking. Researchers have found that cigarette smoking, beer consumption, and high coffee intake are protective against PD,⁵ but the benefits are outweighed by the risks associated with these strategies.⁸ The most practical protective factors are a high dietary intake of vitamin E and increased nut consumption.⁹ Dietary vitamin E can be found in almonds, spinach, sweet potatoes, sunflower seeds, and avocados. Studies have not found the same benefit with vitamin E supplements.⁹

Motor symptoms. The key diagnostic criterium for PD is bradykinesia with at least one of the following: muscular rigidity, resting tremor (particularly a pill-rolling tremor) that improves with purposeful function, or postural instability.² Other physical findings may include masking of facies and speech changes, such as becoming quiet, stuttering, or speaking monotonously without inflection.¹ Cogwheeling, stooped posture, and a shuffling gait or difficulty initiating gait (freezing) are all neurologic signs that point toward a PD diagnosis.²

A systematic review found that the clinical features most strongly associated with a diagnosis of Parkinson's Disease were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.

A systematic review found that the clinical features most strongly associated with a diagnosis of PD were trouble turning in bed, a shuffling gait, tremor, difficulty opening jars, micrographia, and loss of balance.¹⁰ Typically these symptoms are asymmetric.¹

Symptoms that point to other causes. Falling within the first year of symptoms is strongly associated with movement disorders other than PD—notably progressive supranuclear palsy.¹¹ Other symptoms that point toward an alternate diagnosis include a poor response to levodopa, symmetry at the onset of symptoms, rapid progression of disease, and the absence of a tremor.¹¹ It is important to ensure that the patient is not experiencing drug-induced symptoms as can occur with some antipsychotics and antiemetics.

Nonmotor symptoms. Neuropsychiatric symptoms are common in patients with PD. Up to 58% of patients experience depression, and 49% complain of anxiety.¹² Hallucinations are present in many patients and are more commonly visual than auditory in nature.¹³ Patients experience fatigue, daytime sleepiness, and inner restlessness at higher rates than do age-matched controls.³ Research also shows that symptoms such as constipation, mood disorders, erectile dysfunction, and hyposmia may predate the onset of motor symptoms.⁵

Insomnia is a common symptom that is likely multifactorial in etiology. Causes to consider include motor disturbance, nocturia, reversal of sleep patterns, and reemergence of PD symptoms after a period of quiescence.¹⁴ Additionally, hypersalivation and PD dementia can develop as complications of PD.

Symptoms, such as constipation, mood disorders, erectile dysfunction, and hyposmia, may predate the onset of motor symptoms in Parkinson's disease.

A clinical diagnosis. Although PD can be difficult to diagnose in the early stages, the diagnosis seldom requires testing.² A recent systematic review concluded that a clinical diagnosis of PD, when compared with pathology, was correct 74% of the time when the diagnosis was made by nonexperts and correct 84% of the time when the diagnosis was made by movement disorder experts.¹⁵

Imaging. Computed tomography and magnetic resonance imaging can be useful in ruling out other diagnoses in the differential, including vascular disease and normal pressure hydrocephalus,² but will not reveal findings suggestive of PD.

Other diagnostic tests. A levodopa challenge can confirm PD if the diagnosis is unclear.¹¹ In addition, an olfactory test (presenting various odors to the patient for identification) can differentiate PD from progressive supranuclear palsy and corticobasal degeneration; however, it will not distinguish PD from multiple system atrophy.¹¹ If the diagnosis remains unclear, consider a consultation with a neurologist.

Treatment centers on alleviating motor symptoms

The general guiding principle of therapy (TABLE^16,17) is to alleviate the motor symptoms (bradykinesia, rigidity, and postural instability) associated with the disease. Experts recommend that treatment commence when symptoms begin to have disabling effects or become a source of discomfort for the patient.¹

Carbidopa/levodopa is still often the first choice

Multiple systematic reviews support the use of carbidopa/levodopa as first-line treatment, with the dose kept as low as possible to maintain function, while minimizing motor fluctuations (also referred to as “off” time symptoms) and dyskinesia.^11,16 Initial dosing is carbidopa 25 mg/levodopa 100 mg tid. Each can be titrated up to address symptoms to a maximum daily dosing of carbidopa 200 mg/levodopa 2000 mg.¹⁷

“Off” time—the return of Parkinson symptoms when the medication’s effect wanes—can become more unpredictable and more difficult to manage as the disease advances.¹¹ Of note: The American Academy of Neurology (AAN) says there is no improvement in the amount of off time a patient experiences by changing to a sustained-release form of carbidopa/levodopa compared with an immediate-release version.¹¹ In addition to the on-off phenomenon, common adverse effects associated with carbidopa/levodopa include nausea, somnolence, dizziness, and headaches. Less common adverse effects include orthostatic hypotension, confusion, and hallucinations.¹⁷

Other medications for the treatment of motor symptoms

Second-line agents include dopamine agonists (pramipexole, ropinirole, and bromocriptine) and monoamine oxidase type B (MAO-B) inhibitors (selegiline, rasagiline) (TABLE^16,17). The dopamine agonists work by directly stimulating dopamine receptors, while the MAO-B inhibitors block dopamine metabolism, thus enhancing dopaminergic activity in the substantia nigra.

The pros/cons of these 2 classes. Research shows that both dopamine agonists and MAO-B inhibitors are less effective than carbidopa/levodopa at quelling the motor symptoms associated with PD. They can, however, delay the onset of motor complications when compared with carbidopa/levodopa.¹⁶

One randomized trial found no long-term benefits to beginning treatment with a levodopa-sparing therapy; however, few patients with earlier disease onset (<60 years of age) were included in the study.¹⁸ Given the typically longer duration of their illness, there is potential for this group of patients to develop a higher rate of motor symptoms secondary to carbidopa/levodopa. Thus, considering dopamine agonists and MAO-B inhibitors as initial therapy in patients ages <60 years may be helpful, since they typically will be taking medication longer.

Dopamine agonists. Pramipexole and ropinirole can be used as monotherapy or as an adjunct to levodopa to treat bradykinesia, postural instability, and rigidity. Bromocriptine, an ergot-derived dopamine agonist, is considered an agent of last resort because additional monitoring is required. Potential adverse effects mandate baseline testing and annual repeat testing, including measures of erythrocyte sedimentation rate and renal function and a chest x-ray.¹⁶ Consider this agent only if all second- and third-line therapies have provided inadequate control.¹⁶

Adverse effects. Dopamine agonists cause such adverse effects as orthostatic hypotension, drowsiness, dizziness, insomnia, abnormal dreams, nausea, constipation, and hallucinations. A Cochrane review notes that these adverse effects have led to higher drop-out rates than seen for carbidopa/levodopa in studies that compared the 2.¹⁹

Patients should be counseled about an additional adverse effect associated with dopamine agonists—the possible development of an impulse-control disorder, such as gambling, binge eating, or hypersexuality.¹ If a patient develops any of these behaviors, promptly lower the dose of the dopamine agonist or stop the medication.¹⁶

The MAO-B inhibitors selegiline and rasagiline may also be considered for initial therapy but are more commonly used as adjunct therapy. Use of selegiline as monotherapy for PD is an off-label indication. Adverse effects for this class of agents include headache, dizziness, insomnia, nausea, and hypotension.

Dopaminergic therapies come at the price of the development of off-time motor symptoms and dyskinesia.^1,20 In general, these complications are managed by the addition of a dopamine agonist, MAO-B inhibitor, or a catechol-O-methyltransferase (COMT) inhibitor (entacapone).¹

Rasagiline and entacapone are a good place to start and should be offered to patients to reduce off-time symptoms, according to the AAN (a Level A recommendation based on multiple high-level studies; see here for an explanation of Strength of Recommendation).²⁰ As noted above, entacapone is a COMT inhibitor; it increases the plasma half-life of levodopa and decreases variations in peak-trough levels. Rasagiline is an MAO-B inhibitor and works to block dopamine metabolism.

The newest medication, safinamide, has been shown to increase “on” time by one hour per day when compared with placebo; however, it has not yet been tested against existing therapies.²¹ Other medications that can be considered to reduce drug-induced motor complications include pergolide, pramipexole, ropinirole, and tolcapone.²⁰ Carbidopa/levodopa and bromocriptine are not recommended for the treatment of dopaminergic motor complications.²⁰ Both sustained-release carbidopa/levodopa and bromocriptine are no longer recommended to decrease off time due to ineffectiveness.²⁰

The only medication that has evidence for reducing dyskinesias in patients with PD is amantadine;²⁰ however, it has no effect on other motor symptoms and should not be considered first line.¹⁶ Additionally, as an antiviral agent active against some strains of influenza, it should not be taken 2 weeks before or after receiving the influenza vaccine.

When tremor dominates …

Recently approved safinamide has been shown to increase "on" time by one hour per day when compared with placebo.

For many patients with PD, tremor is more difficult to treat than is bradykinesia, rigidity, and gait disturbance.¹⁶ For patients with tremor-predominant PD (characterized by prominent tremor of one or more limbs and a relative lack of significant rigidity and bradykinesia), first-line treatment choices are dopamine agonists (ropinirole, pramipexole), carbidopa/levodopa, and anticholinergic medications, including benztropine and trihexyphenidyl.²² Second-line choices include clozapine, amantadine, clonazepam, and propranolol.²²

Treating nonmotor symptoms

Treatment of hypersalivation should start with an evaluation by a speech pathologist. If it doesn’t improve, then adjuvant treatment with glycopyrrolate may be considered.¹⁶ Carbidopa/levodopa has the best evidence for treating periodic limb movements of sleep,¹⁴ although dopamine agonists may also be considered.¹⁶ More research is needed to find an effective therapy to improve insomnia in patients with PD, but for now consider a nighttime dose of carbidopa/levodopa or melatonin.¹⁴

Treating cognitive disorders associated with PD

Depression. Treatment of depression in patients with PD is difficult. Multiple systematic reviews have been unable to find a difference in those treated with antidepressants and those not.²³ In practice, the use of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and a combination of an SSRI and a norepinephrine reuptake inhibitor are commonly used. Additionally, some evidence suggests that pramipexole improves depressive symptoms, but additional research is needed.¹

Dementia. Dementia occurs in up to 83% of those who have had PD for more than 20 years.¹ Treatment includes the use of rivastigmine (a cholinesterase inhibitor).¹ Further research is needed to determine whether donepezil improves dementia symptoms in patients with PD.¹

Psychotic symptoms. Query patients and their families periodically about hallucinations and delusions.¹⁶ If such symptoms are present and not well tolerated by the patient and/or family, treatment options include quetiapine and clozapine.¹ While clozapine is more effective, it requires frequent hematologic monitoring due to the risk of agranulocytosis.¹ And quetiapine carries a black box warning about early death. Exercise caution when prescribing these medications, particularly if a patient is cognitively impaired, and always start with low doses.¹

A newer medication, pimavanserin (a second-generation antipsychotic), was recently approved by the FDA to treat hallucinations and delusions of PD psychosis, although any improvement this agent provides may not be clinically significant.²⁴ Unlike clozapine, no additional monitoring is needed and there are no significant safety concerns with the use of pimavanserin, which makes it a reasonable first choice for hallucinations and delusions. Other neuroleptic medications should not be used as they tend to worsen Parkinson symptoms.¹

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective at reducing falls when compared to the same amount of resistance training and strength training, and that the benefits remained 3 months after the completion of the 24-week study.²⁵ To date, tai chi is the only intervention that has been shown to affect fall risk.

The only medication that has evidence for reducing dyskinesias in patients with Parkinson's disease is amantadine.

Guidelines recommend that physical therapy be available to all patients.¹⁶ A Cochrane review performed in 2013 determined that physical therapy improves walking endurance and balance but does not affect quality of life in terms of fear of falling.²⁶

When meds no longer help, consider deep brain stimulation as a last resort

Deep brain stimulation consists of surgical implantation of a device to deliver electrical current to a targeted area of the brain. It can be considered for patients with PD who are no longer responsive to carbidopa/levodopa, not experiencing neuropsychiatric symptoms, and are experiencing significant motor complications despite optimal medical management.¹⁴ Referral to a specialist is recommended for these patients to assess their candidacy for this procedure.

Prognosis: Largely unchanged

While medications can improve quality of life and function, PD remains a chronic and progressive disorder that is associated with significant morbidity. A study performed in 2013 showed that older age at onset, cognitive dysfunction, and motor symptoms nonresponsive to levodopa were associated with faster progression toward disability.²⁷

Keep an eye on patients’ bone mineral density (BMD), as patients with PD tend to have lower BMD,²⁸ a 2-fold increase in the risk of fracture for both men and women,²⁹ and a higher prevalence of vitamin D deficiency.³⁰

One study showed that tai chi, performed for an hour twice weekly, was significantly more effective than the same amount of resistance and strength training at reducing falls.

Also, watch for signs of infection because the most commonly cited cause of death in those with PD is pneumonia rather than a complication of the disease itself.¹¹

End-of-life discussions. As with any potentially life-limiting disease, family physicians should have ongoing discussions with patients and families about goals of care and the importance of completing advanced care directives while the patient is in good health.

CORRESPONDENCE
Michael Mendoza, MD, MPH, MS, FAAFP, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Rigel Pharmaceuticals

Fostamatinib has produced “clinically meaningful” responses in adults with persistent or chronic immune thrombocytopenia (ITP), according to researchers.

In a pair of phase 3 trials, 18% of patients who received fostamatinib had a stable response, which was defined as having a platelet count of at least 50,000/µL for at least 4 of 6 clinic visits.

In comparison, 2% of patients who received placebo achieved a stable response.

The most common adverse events (AEs) in these trials were diarrhea, hypertension, and nausea. Most AEs were deemed mild or moderate.

These results were published in the American Journal of Hematology. The trials—known as FIT1 and FIT2—were sponsored by Rigel Pharmaceuticals, Inc., the company marketing fostamatinib.

Fostamatinib is an oral Syk inhibitor that was recently approved by the US Food and Drug Administration.

Patients and treatment

Researchers evaluated fostamatinib in the parallel FIT1 and FIT2 trials, which included 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment.

In each study, patients were randomized 2:1 to receive fostamatinib or placebo for 24 weeks. In FIT1, 76 patients were randomized—51 to fostamatinib and 25 to placebo. In FIT2, 74 patients were randomized—50 to fostamatinib and 24 to placebo.

All patients initially received fostamatinib at 100 mg twice daily. Most (88%) were escalated to 150 mg twice daily at week 4 or later. Patients could also receive stable concurrent ITP therapy—glucocorticoids (< 20 mg prednisone equivalent per day), azathioprine, or danazol—and rescue therapy if needed.

The median age was 54 (range, 20-88) in the fostamatinib recipients and 53 (range, 20-78) in the placebo recipients. Sixty-one percent and 60%, respectively, were female. And 93% and 92%, respectively, were white.

The median duration of ITP was 8.7 years for fostamatinib recipients and 7.8 years for placebo recipients. Both fostamatinib and placebo recipients had a median of 3 prior unique treatments for ITP (range, 1-13 and 1-10, respectively).

Prior ITP treatments (in the fostamatinib and placebo arms, respectively) included corticosteroids (93% vs 96%), immunoglobulins (51% vs 55%), thrombopoietin receptor agonists (47% vs 51%), immunosuppressants (44% vs 45%), splenectomy (34% vs 39%), and rituximab (34% vs 29%), among other treatments.

Overall, the patients’ median platelet count at baseline was 16,000/µL. Mean baseline platelet counts were 16,052/µL (range, 1000-51,000) in fostamatinib recipients and 19,818/µL (range, 1000-156,000) in placebo recipients.

Response

The efficacy of fostamatinib was based on stable platelet response, defined as a platelet count of at least 50,000/µL on at least 4 of 6 biweekly clinic visits between weeks 14 and 24, without the use of rescue therapy.

Overall, 18% (18/101) of patients on fostamatinib and 2% (1/49) of those on placebo achieved this endpoint (P=0.0003).

In FIT1, 18% of patients in the fostamatinib arm and 0% of those in the placebo arm achieved a stable platelet response (P=0.026). In FIT2, rates of stable response were 18% and 4%, respectively (P=0.152).

A secondary endpoint was overall response, which was defined retrospectively as at least 1 platelet count ≥ 50,000/μL within the first 12 weeks on treatment.

Forty-three percent (43/101) of fostamatinib recipients achieved an overall response, as did 14% (7/49) of patients on placebo (P=0.0006).

In FIT1, the rate of overall response was 37% in the fostamatinib arm and 8% in the placebo arm (P=0.007). In FIT2, overall response rates were 48% and 21%, respectively (P=0.025).

The researchers said they observed responses to fostamatinib across all patient subgroups, regardless of age, sex, prior therapy, baseline platelet count, or duration of ITP at study entry.

Role of concomitant therapy

The researchers noted that 2 of the 18 patients with a stable platelet response were on concomitant treatment. Both were on steroids, one of them for 62 days before the first dose of fostamatinib and the other for 14 years.

Four of the 43 patients with an overall platelet response were on concomitant therapy. Three were on steroids—for 62 days, 67 days, and 14 years prior to first dose of fostamatinib—and 1 was on azathioprine—for 197 days prior to the first dose of fostamatinib.

The researchers said the effects of these therapies probably would have been evident prior to study entry, so they aren’t likely to have influenced the results.

Safety

In both trials, the rate of AEs was 83% in the fostamatinib recipients (32% mild, 35% moderate, and 16% severe AEs) and 75% in the placebo recipients (42% mild, 19% moderate, and 15% severe AEs.).

AEs occurring in at least 5% of patients (in the fostamatinib and placebo arms, respectively) included diarrhea (31% vs 15%), hypertension (28% vs 13%), nausea (19% vs 8%), dizziness (11% vs 8%), ALT increase (11% vs 0%), AST increase (9% vs 0%), respiratory infection (11% vs 6%), rash (9% vs 2%), abdominal pain (6% vs 2%), fatigue (6% vs 2%), chest pain (6% vs 2%), and neutropenia (6% vs 0%).

Moderate or severe bleeding-related AEs occurred in 9% of patients who had an overall response to fostamatinib and 16% of patients on placebo.

Serious AEs considered related to study drug occurred in 4 patients on fostamatinib and 1 patient on placebo. The placebo recipient experienced a bleeding event, and the fostamatinib-related events were consistent with the AE profile of the drug (hypertension, diarrhea, etc.), according to Rigel Pharmaceuticals.

There were 2 deaths. One placebo recipient died of probable sepsis 19 days after withdrawing from the study due to epistaxis. One fostamatinib recipient developed plasma cell myeloma, stopped treatment on day 19, and died 71 days later.

Rigel Pharmaceuticals

Fostamatinib has produced “clinically meaningful” responses in adults with persistent or chronic immune thrombocytopenia (ITP), according to researchers.

In a pair of phase 3 trials, 18% of patients who received fostamatinib had a stable response, which was defined as having a platelet count of at least 50,000/µL for at least 4 of 6 clinic visits.

In comparison, 2% of patients who received placebo achieved a stable response.

The most common adverse events (AEs) in these trials were diarrhea, hypertension, and nausea. Most AEs were deemed mild or moderate.

These results were published in the American Journal of Hematology. The trials—known as FIT1 and FIT2—were sponsored by Rigel Pharmaceuticals, Inc., the company marketing fostamatinib.

Fostamatinib is an oral Syk inhibitor that was recently approved by the US Food and Drug Administration.

Patients and treatment

Researchers evaluated fostamatinib in the parallel FIT1 and FIT2 trials, which included 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment.

In each study, patients were randomized 2:1 to receive fostamatinib or placebo for 24 weeks. In FIT1, 76 patients were randomized—51 to fostamatinib and 25 to placebo. In FIT2, 74 patients were randomized—50 to fostamatinib and 24 to placebo.

All patients initially received fostamatinib at 100 mg twice daily. Most (88%) were escalated to 150 mg twice daily at week 4 or later. Patients could also receive stable concurrent ITP therapy—glucocorticoids (< 20 mg prednisone equivalent per day), azathioprine, or danazol—and rescue therapy if needed.

The median age was 54 (range, 20-88) in the fostamatinib recipients and 53 (range, 20-78) in the placebo recipients. Sixty-one percent and 60%, respectively, were female. And 93% and 92%, respectively, were white.

The median duration of ITP was 8.7 years for fostamatinib recipients and 7.8 years for placebo recipients. Both fostamatinib and placebo recipients had a median of 3 prior unique treatments for ITP (range, 1-13 and 1-10, respectively).

Prior ITP treatments (in the fostamatinib and placebo arms, respectively) included corticosteroids (93% vs 96%), immunoglobulins (51% vs 55%), thrombopoietin receptor agonists (47% vs 51%), immunosuppressants (44% vs 45%), splenectomy (34% vs 39%), and rituximab (34% vs 29%), among other treatments.

Overall, the patients’ median platelet count at baseline was 16,000/µL. Mean baseline platelet counts were 16,052/µL (range, 1000-51,000) in fostamatinib recipients and 19,818/µL (range, 1000-156,000) in placebo recipients.

Response

The efficacy of fostamatinib was based on stable platelet response, defined as a platelet count of at least 50,000/µL on at least 4 of 6 biweekly clinic visits between weeks 14 and 24, without the use of rescue therapy.

Overall, 18% (18/101) of patients on fostamatinib and 2% (1/49) of those on placebo achieved this endpoint (P=0.0003).

In FIT1, 18% of patients in the fostamatinib arm and 0% of those in the placebo arm achieved a stable platelet response (P=0.026). In FIT2, rates of stable response were 18% and 4%, respectively (P=0.152).

A secondary endpoint was overall response, which was defined retrospectively as at least 1 platelet count ≥ 50,000/μL within the first 12 weeks on treatment.

Forty-three percent (43/101) of fostamatinib recipients achieved an overall response, as did 14% (7/49) of patients on placebo (P=0.0006).

In FIT1, the rate of overall response was 37% in the fostamatinib arm and 8% in the placebo arm (P=0.007). In FIT2, overall response rates were 48% and 21%, respectively (P=0.025).

The researchers said they observed responses to fostamatinib across all patient subgroups, regardless of age, sex, prior therapy, baseline platelet count, or duration of ITP at study entry.

Role of concomitant therapy

The researchers noted that 2 of the 18 patients with a stable platelet response were on concomitant treatment. Both were on steroids, one of them for 62 days before the first dose of fostamatinib and the other for 14 years.

Four of the 43 patients with an overall platelet response were on concomitant therapy. Three were on steroids—for 62 days, 67 days, and 14 years prior to first dose of fostamatinib—and 1 was on azathioprine—for 197 days prior to the first dose of fostamatinib.

The researchers said the effects of these therapies probably would have been evident prior to study entry, so they aren’t likely to have influenced the results.

Safety

In both trials, the rate of AEs was 83% in the fostamatinib recipients (32% mild, 35% moderate, and 16% severe AEs) and 75% in the placebo recipients (42% mild, 19% moderate, and 15% severe AEs.).

AEs occurring in at least 5% of patients (in the fostamatinib and placebo arms, respectively) included diarrhea (31% vs 15%), hypertension (28% vs 13%), nausea (19% vs 8%), dizziness (11% vs 8%), ALT increase (11% vs 0%), AST increase (9% vs 0%), respiratory infection (11% vs 6%), rash (9% vs 2%), abdominal pain (6% vs 2%), fatigue (6% vs 2%), chest pain (6% vs 2%), and neutropenia (6% vs 0%).

Moderate or severe bleeding-related AEs occurred in 9% of patients who had an overall response to fostamatinib and 16% of patients on placebo.

Serious AEs considered related to study drug occurred in 4 patients on fostamatinib and 1 patient on placebo. The placebo recipient experienced a bleeding event, and the fostamatinib-related events were consistent with the AE profile of the drug (hypertension, diarrhea, etc.), according to Rigel Pharmaceuticals.

There were 2 deaths. One placebo recipient died of probable sepsis 19 days after withdrawing from the study due to epistaxis. One fostamatinib recipient developed plasma cell myeloma, stopped treatment on day 19, and died 71 days later.

Rigel Pharmaceuticals

Fostamatinib has produced “clinically meaningful” responses in adults with persistent or chronic immune thrombocytopenia (ITP), according to researchers.

In a pair of phase 3 trials, 18% of patients who received fostamatinib had a stable response, which was defined as having a platelet count of at least 50,000/µL for at least 4 of 6 clinic visits.

In comparison, 2% of patients who received placebo achieved a stable response.

The most common adverse events (AEs) in these trials were diarrhea, hypertension, and nausea. Most AEs were deemed mild or moderate.

These results were published in the American Journal of Hematology. The trials—known as FIT1 and FIT2—were sponsored by Rigel Pharmaceuticals, Inc., the company marketing fostamatinib.

Fostamatinib is an oral Syk inhibitor that was recently approved by the US Food and Drug Administration.

Patients and treatment

Researchers evaluated fostamatinib in the parallel FIT1 and FIT2 trials, which included 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment.

In each study, patients were randomized 2:1 to receive fostamatinib or placebo for 24 weeks. In FIT1, 76 patients were randomized—51 to fostamatinib and 25 to placebo. In FIT2, 74 patients were randomized—50 to fostamatinib and 24 to placebo.

All patients initially received fostamatinib at 100 mg twice daily. Most (88%) were escalated to 150 mg twice daily at week 4 or later. Patients could also receive stable concurrent ITP therapy—glucocorticoids (< 20 mg prednisone equivalent per day), azathioprine, or danazol—and rescue therapy if needed.

The median age was 54 (range, 20-88) in the fostamatinib recipients and 53 (range, 20-78) in the placebo recipients. Sixty-one percent and 60%, respectively, were female. And 93% and 92%, respectively, were white.

The median duration of ITP was 8.7 years for fostamatinib recipients and 7.8 years for placebo recipients. Both fostamatinib and placebo recipients had a median of 3 prior unique treatments for ITP (range, 1-13 and 1-10, respectively).

Prior ITP treatments (in the fostamatinib and placebo arms, respectively) included corticosteroids (93% vs 96%), immunoglobulins (51% vs 55%), thrombopoietin receptor agonists (47% vs 51%), immunosuppressants (44% vs 45%), splenectomy (34% vs 39%), and rituximab (34% vs 29%), among other treatments.

Overall, the patients’ median platelet count at baseline was 16,000/µL. Mean baseline platelet counts were 16,052/µL (range, 1000-51,000) in fostamatinib recipients and 19,818/µL (range, 1000-156,000) in placebo recipients.

Response

The efficacy of fostamatinib was based on stable platelet response, defined as a platelet count of at least 50,000/µL on at least 4 of 6 biweekly clinic visits between weeks 14 and 24, without the use of rescue therapy.

Overall, 18% (18/101) of patients on fostamatinib and 2% (1/49) of those on placebo achieved this endpoint (P=0.0003).

In FIT1, 18% of patients in the fostamatinib arm and 0% of those in the placebo arm achieved a stable platelet response (P=0.026). In FIT2, rates of stable response were 18% and 4%, respectively (P=0.152).

A secondary endpoint was overall response, which was defined retrospectively as at least 1 platelet count ≥ 50,000/μL within the first 12 weeks on treatment.

Forty-three percent (43/101) of fostamatinib recipients achieved an overall response, as did 14% (7/49) of patients on placebo (P=0.0006).

In FIT1, the rate of overall response was 37% in the fostamatinib arm and 8% in the placebo arm (P=0.007). In FIT2, overall response rates were 48% and 21%, respectively (P=0.025).

The researchers said they observed responses to fostamatinib across all patient subgroups, regardless of age, sex, prior therapy, baseline platelet count, or duration of ITP at study entry.

Role of concomitant therapy

The researchers noted that 2 of the 18 patients with a stable platelet response were on concomitant treatment. Both were on steroids, one of them for 62 days before the first dose of fostamatinib and the other for 14 years.

Four of the 43 patients with an overall platelet response were on concomitant therapy. Three were on steroids—for 62 days, 67 days, and 14 years prior to first dose of fostamatinib—and 1 was on azathioprine—for 197 days prior to the first dose of fostamatinib.

The researchers said the effects of these therapies probably would have been evident prior to study entry, so they aren’t likely to have influenced the results.

Safety

In both trials, the rate of AEs was 83% in the fostamatinib recipients (32% mild, 35% moderate, and 16% severe AEs) and 75% in the placebo recipients (42% mild, 19% moderate, and 15% severe AEs.).

AEs occurring in at least 5% of patients (in the fostamatinib and placebo arms, respectively) included diarrhea (31% vs 15%), hypertension (28% vs 13%), nausea (19% vs 8%), dizziness (11% vs 8%), ALT increase (11% vs 0%), AST increase (9% vs 0%), respiratory infection (11% vs 6%), rash (9% vs 2%), abdominal pain (6% vs 2%), fatigue (6% vs 2%), chest pain (6% vs 2%), and neutropenia (6% vs 0%).

Moderate or severe bleeding-related AEs occurred in 9% of patients who had an overall response to fostamatinib and 16% of patients on placebo.

Serious AEs considered related to study drug occurred in 4 patients on fostamatinib and 1 patient on placebo. The placebo recipient experienced a bleeding event, and the fostamatinib-related events were consistent with the AE profile of the drug (hypertension, diarrhea, etc.), according to Rigel Pharmaceuticals.

There were 2 deaths. One placebo recipient died of probable sepsis 19 days after withdrawing from the study due to epistaxis. One fostamatinib recipient developed plasma cell myeloma, stopped treatment on day 19, and died 71 days later.

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. F, age 35, is homeless and has a history of cocaine and alcohol use disorders. He is admitted voluntarily to the psychiatric unit because he has homicidal thoughts toward Ms. S, who works in the shelter where he has been staying. Mr. F reports that he is thinking of killing Ms. S if he is discharged because she has been rude to him. He states that he has access to several firearms, but he will not disclose the location. He has been diagnosed with unspecified depressive disorder and exhibited antisocial personality disorder traits. He is being treated with sertraline. However, his mood appears to be relatively stable, except for occasional angry verbal outbursts. The outbursts have been related to intrusive peers or staff turning the television off for group meetings. Mr. F has been joking with peers, eating well, and sleeping appropriately. He reports no suicidal thoughts and has not been physically violent on the unit. However, Mr. F has had a history of violence since his teenage years. He has been incarcerated twice for assault and once for drug possession.

How would you approach assessing and managing Mr. F’s risk for violence?

We all have encountered a patient similar to Mr. F on the psychiatric unit or in the emergency department—a patient who makes violent threats and appears angry, intimidating, manipulative, and/or demanding, despite exhibiting no evidence of mania or psychosis. This patient often has a history of substance abuse and a lifelong pattern of viewing violence as an acceptable way of addressing life’s problems. Many psychiatrists suspect that more time on the inpatient unit is unlikely to reduce this patient’s risk of violence. Why? Because the violence risk does not stem from a treatable mental illness. Further, psychiatrists may be apprehensive about this patient’s potential for violence after discharge and their liability in the event of a bad outcome. No one wants their name associated with a headline that reads “Psychiatrist discharged man less than 24 hours before he killed 3 people.”

The purported relationship between mental illness and violence often is sensationalized in the media. However, research reveals that the vast majority of violence is in fact not due to symptoms of mental illness.^1,2 A common clinical challenge in psychiatry involves evaluating individuals at elevated risk of violence and determining how to address their risk factors for violence. When the risk is primarily due to psychosis and can be reduced with antipsychotic medication, the job is easy. But how should we proceed when the risk stems from factors other than mental illness?

This article reviews risk factors for violence, discusses targeted violence against a specific victim, and offers practical tips for assessing and managing risk, particularly when the risk for violence is not due to mental illness.

Violence and mental illness: A tenuous link

Violence is a major public health concern in the United States. Although in recent years the rates of homicide and aggravated assault have decreased dramatically, there are approximately 16,000 homicides annually in the United States, and more than 1.6 million injuries from assaults treated in emergency departments each year.³ Homicide continues to be one of the leading causes of death among teenagers and young adults.⁴

The most effective methods of preventing widespread violence are public health approaches, such as parent- and family-focused programs, early childhood education, programs in school, and public policy changes.³ However, as psychiatrists, we are routinely asked to assess the risk of violence for an individual patient and devise strategies to mitigate violence risk.

Continue to: Although certain mental illnesses...

Although certain mental illnesses increase the relative risk of violence (compared with people without mental illness),^5,6 recent studies suggest that mental illness plays only a “minor role in explaining violence in populations.”⁷ It is estimated that as little as 4% of the violence in the United States can be attributed to mental illness.¹ According to a 1998 meta-analysis of 48 studies of criminal recidivism, the risk factors for violent recidivism were “almost identical” among offenders who had a mental disorder and those who did not.⁸

Approaches to assessing violence risk

Psychiatrists can assess the risk of future violence via 3 broad approaches.^9,10

Unaided clinical judgment is when a mental health professional estimates violence risk based on his or her own experience and intuition, with knowledge of violence risk factors, but without the use of structured tools.

Actuarial tools are statistical models that use formulae to show relationships between data (risk factors) and outcomes (violence).^10,11

Continue to: Structured professional judgment

Structured professional judgment is a hybrid of unaided clinical judgment and actuarial methods. Structured professional judgment tools help the evaluator identify empirically established risk factors. Once the information is collected, it is combined with clinical judgment in decision making.^9,10 There are now more than 200 structured tools available for assessing violence risk in criminal justice and forensic mental health populations.¹²

Clinical judgment, although commonly used in practice, is less accurate than actuarial tools or structured professional judgment.^10,11 In general, risk assessment tools offer moderate levels of accuracy in categorizing people at low risk vs high risk.^5,13 The tools have better ability to accurately categorize individuals at low risk, compared with high risk, where false positives are common.^12,14

Two types of risk factors

Risk factors for violence are commonly categorized as static or dynamic factors. Static factors are historical factors that cannot be changed with intervention (eg, age, sex, history of abuse). Dynamic factors can be changed with intervention (eg, substance abuse).¹⁵

Static risk factors. The best predictor of future violence is past violent behavior.^5,16,17 Violence risk increases with each prior episode of violence.⁵ Prior arrests for any crime, especially if the individual was a juvenile at the time of arrest for his or her first violent offense, increase future violence risk.⁵ Other important static violence risk factors include demographic factors such as age, sex, and socioeconomic status. Swanson et al⁶ reviewed a large pool of data (approximately 10,000 respondents) from the Epidemiologic Catchment Area survey. Being young, male, and of low socioeconomic status were all associated with violence in the community.⁶ The highest-risk age group for violence is age 15 to 24.⁵ Males perpetrate violence in the community at a rate 10 times that of females.¹⁸ However, among individuals with severe mental illness, men and women have similar rates of violence.^19,20 Unstable employment,²¹ less education,²² low intelligence,¹⁶ and a history of a significant head injury⁵ also are risk factors for violence.⁵

Continue to: Being abused as a child...

Being abused as a child, witnessing violence in the home,^5,16 and growing up with an unstable parental situation (eg, parental loss or separation) has been linked to violence.^16,23,24 Early disruptive behavior in childhood (eg, fighting, lying and stealing, truancy, and school problems) increases violence risk.^21,23

Personality factors are important static risk factors for violence. Antisocial personality disorder is the most common personality disorder linked with violence.¹⁷ Several studies consistently show psychopathy to be a strong predictor of both violence and criminal behavior.^5,25 A psychopath is a person who lacks empathy and close relationships, behaves impulsively, has superficially charming qualities, and is primarily interested in self-gratification.²⁶ Harris et al²⁷ studied 169 released forensic patients and found that 77% of the psychopaths (according to Psychopathy Checklist-Revised [PCL-R] scores) violently recidivated. In contrast, only 21% of the non-psychopaths violently recidivated.²⁷

Other personality factors associated with violence include a predisposition toward feelings of anger and hatred (as opposed to empathy, anxiety, or guilt, which may reduce risk), hostile attributional biases (a tendency to interpret benign behavior of others as intentionally antagonistic), violent fantasies, poor anger control, and impulsivity.⁵ Although personality factors tend to be longstanding and more difficult to modify, in the outpatient setting, therapeutic efforts can be made to modify hostile attribution biases, poor anger control, and impulsive behavior.

Dynamic risk factors. Substance abuse is strongly associated with violence.^6,17 The prevalence of violence is 12 times greater among individuals with alcohol use disorder and 16 times greater among individuals with other substance use disorders, compared with those with no such diagnoses.^5,6

Continue to: Steadman et al...

Steadman et al²⁸ compared 1,136 adult patients with mental disorders discharged from psychiatric hospitals with 519 individuals living in the same neighborhoods as the hospitalized patients. They found that the prevalence of violence among discharged patients without substance abuse was “statistically indistinguishable” from the prevalence of violence among community members, in the same neighborhood, who did not have symptoms of substance abuse.²⁸ Swanson et al⁶ found that the combination of a mental disorder plus an alcohol or substance use disorder substantially increased the risk of violence.

Other dynamic risk factors for violence include mental illness symptoms such as psychosis, especially threat/control-override delusions, where the individual believes that they are being threatened or controlled by an external force.¹⁷

Contextual factors to consider in violence risk assessments include current stressors, lack of social support, availability of weapons, access to drugs and alcohol, and the presence of similar circumstances that led to violent behavior in the past.⁵

How to assess the risk of targeted violence

Targeted violence is a predatory act of violence intentionally committed against a preselected person, group of people, or place.²⁹ Due to the low base rates of these incidents, targeted violence is difficult to study.^7,30 These risk assessments require a more specialized approach.

Continue to: In their 1999 article...

In their 1999 article, Borum et al³⁰ discussed threat assessment strategies utilized by the U.S. Secret Service and recommended investigating “pathways of ideas and behaviors that may lead to violent action.” Borum et al³⁰ summarized 3 fundamental principles of threat assessment (Table 1³⁰).

What to do when violence risk is not due to mental illness

Based on the information in Mr. F’s case scenario, it is likely that his homicidal ideation is not due to mental illness. Despite this, several risk factors for violence are present. Where do we go from here?

Scott and Resnick¹⁷ recommend considering the concept of dangerousness as 5 components (Table 2¹⁷). When this model of dangerousness is applied to Mr. F’s case, one can see that the magnitude of the harm is great because of threatened homicide. With regard to the imminence of the harm, it would help to clarify whether Mr. F plans to kill Ms. S immediately after discharge, or sometime in the next few months. Is his threat contingent on further provocations by Ms. S? Alternatively, does he intend to kill her for past grievances, regardless of further perceived insults?

Next, the frequency of a behavior relates to how often Mr. F has been aggressive in the past. The severity of his past aggression is also important. What is the most violent act he has ever done? Situational factors in this case include Mr. F’s access to weapons, financial problems, housing problems, and access to drugs and alcohol.¹⁷ Mr. F should be asked about what situations previously provoked his violent behavior. Consider how similar the present conditions are to past conditions to which Mr. F responded violently.⁵ The likelihood that a homicide will occur should take into account Mr. F’s risk factors for violence, as well as the seriousness of his intent to cause harm.

Continue to: Consider using a structured tool...

Consider using a structured tool, such as the Classification of Violence Risk, to help identify Mr. F’s risk factors for violence, or some other formal method to ensure that the proper data are collected. Violence risk assessments are more accurate when structured risk assessment tools are used, compared with clinical judgment alone.

It is important to review collateral sources of information. In Mr. F’s case, useful collateral sources may include his criminal docket (usually available online), past medical records, information from the shelter where he lives, and, potentially, friends or family.

Because Mr. F is making threats of targeted violence, be sure to ask about attack-related behaviors (Table 1³⁰).

Regarding the seriousness of Mr. F’s intent to cause harm, it may be helpful to ask him the following questions:

1. How likely are you to carry out this act of violence?
2. Do you have a plan? Have you taken any steps toward this plan?
3. Do you see other, nonviolent solutions to this problem?
4. What do you hope that we can do for you to help with this problem?

Continue to: Mr. F's answers...

Mr. F’s answers may suggest the possibility of a hidden agenda. Some patients express homicidal thoughts in order to stay in the hospital. If Mr. F expresses threats that are contingent on discharge and declines to engage in problem-solving discussions, this would cast doubt on the genuineness of his threat. However, doubt about the genuineness of the threat alone is not sufficient to simply discharge Mr. F. Assessment of his intent needs to be considered with other relevant risk factors, risk reduction strategies, and any Tarasoff duties that may apply.

In addition to risk factors, consider mitigating factors. For example, does Mr. F express concern over prison time as a reason to not engage in violence? It would be more ominous if Mr. F says that he does not care if he goes to prison because life is lousy being homeless and unemployed. At this point, an estimation can be made regarding whether Mr. F is a low-, moderate-, or high-risk of violence.

The next step is to organize Mr. F’s risk factors into static (historical) and dynamic (subject to intervention) factors. This will be helpful in formulating a strategy to manage risk because continued hospitalization can only address dynamic risk factors. Often in these cases, the static risk factors are far more numerous than the dynamic risk factors.

Once the data are collected and organized, the final step is to devise a risk management strategy. Some interventions, such as substance use treatment, will be straightforward. A mood-stabilizing medication could be considered, if clinically appropriate, to help reduce aggression and irritability.³¹ Efforts should be made to eliminate Mr. F’s access to firearms; however, in this case, it sounds unlikely that he will cooperate with those efforts. Ultimately, you may find yourself with a list of risk factors that are unlikely to be altered with further hospitalization, particularly if Mr. F’s homicidal thoughts and intent are due to antisocial personality traits.

Continue to: In that case...

In that case, the most important step will be to carry out your duty to warn/protect others prior to Mr. F’s discharge. Most states either require or permit mental health professionals to take reasonable steps to protect victims from violence when certain conditions are present, such as an explicit threat or identifiable victim (see Related Resources).

Once dynamic risk factors have been addressed, and duty to warn/protect is carried out, if there is no further clinical indication for hospitalization, it would be appropriate to discharge Mr. F. Continued homicidal threats stemming from antisocial personality traits, in the absence of a treatable mental illness (or other modifiable risk factors for violence that can be actively addressed), is not a reason for continued hospitalization. It may be useful to obtain a second opinion from a colleague in such scenarios. A second opinion may offer additional risk management ideas. In the event of a bad outcome, this will also help to show that the decision to discharge the patient was not taken lightly.

The psychiatrist should document a thoughtful risk assessment, the strategies that were implemented to reduce risk, the details of the warning, and the reasoning why continued hospitalization was not indicated (Table 3).

CASE CONTINUED

Decision to discharge

In Mr. F’s case, the treating psychiatrist determined that Mr. F’s risk of violence toward Ms. S was moderate. The psychiatrist identified several static risk factors for violence that raised Mr. F’s risk, but also noted that Mr. F’s threats were likely a manipulative effort to prolong his hospital stay. The psychiatrist carried out his duty to protect by notifying police and Ms. S of the nature of the threat prior to Mr. F’s discharge. The unit social worker helped Mr. F schedule an intake appointment for a substance use disorder treatment facility. Mr. F ultimately stated that he no longer experienced homicidal ideas once a bed was secured for him in a substance use treatment program. The psychiatrist carefully documented Mr. F’s risk assessment and the reasons why Mr. F’s risk would not be significantly altered by further inpatient hospitalization. Mr. F was discharged, and Ms. S remained unharmed.

Continue to: Bottom Line

Use a structured approach to identify risk factors for violence. Address dynamic risk factors, including access to weapons. Carry out the duty to warn/protect if applicable. Document your decisions and actions carefully, and then discharge the patient if clinically indicated. Do not be “held hostage” by a patient’s homicidal ideation.

Related Resources

• Dolan M, Doyle M. Violence risk prediction. Clinical and actuarial measures and the role of the psychopathy checklist. Br J Psychiatry. 2000;177:303-311.
• Douglas KS, Hart SD, Webster CD, et al. HCR-20V3: Assessing risk of violence–user guide. Burnaby, Canada: Mental Health, Law, and Policy Institute, Simon Fraser University; 2013.
• National Conference of State Legislatures. Mental health professionals’ duty to warn. http://www.ncsl.org/research/health/mental-health-professionals-duty-to-warn.aspx. Published September 28, 2015.

Drug Brand Names

Sertraline • Zoloft

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm³, and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder.¹ The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS.² Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs).^1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART.³

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection.³ Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously.³ These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued.³

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6.⁴

Continue to: The DDIs arise because...

Table 1,^6-14,19-28 Table 2,^15-28 Table 3,^6-14,19-28 and Table 4^15-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.

These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.^19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.^6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.

Continue to: Consider adverse effect profiles

Consider adverse effect profiles

When selecting an antipsychotic agent for a patient receiving HIV therapy, also consider adverse effect profiles. The emergence of adverse effects can greatly impact patients’ quality of life, leading to consequences of medication nonadherence and exacerbation of mental illness.

Extrapyramidal symptoms. Patients with HIV have a higher sensitivity to treatment-emergent EPS from antipsychotics.² This sensitivity is generally thought to arise from the involvement of HIV on the basal ganglia. Historically, psychotic symptoms in HIV have been managed with second-generation antipsychotics (SGAs) at the lowest effective dose because these medications are less likely to cause EPS.^1,29 The antipsychotic with the lowest rate of EPS is clozapine, followed by quetiapine, olanzapine, ziprasidone, and aripiprazole. Conversely, high-potency first-generation antipsychotics (FGAs) have the highest rates of EPS, followed by intermediate-potency FGAs and risperidone.³⁰

Metabolic disturbances are another concern with concomitant antipsychotic/antiretroviral therapy. Patients with HIV who are receiving NRTIs or PIs can present with drug-induced lipodystrophy syndrome, which is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension, and ultimately may cause metabolic syndrome.²⁹ The prevalence of metabolic syndrome in patients receiving PI therapy has a vast range—2% to 84%—which can be attributed to inconsistent definitions, criteria, and assessment methodology.²⁹ Use of a PI is considered to be the most prominent risk factor for developing lipodystrophy.²⁹ Among the PIs, metabolic disturbances in regards to lipids are most often seen with lopinavir/ritonavir (LPV/r), saquinavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir.³¹ In comparison with LPV/r, darunavir showed improvement in lipids.³² Atazanavir (ATV) boosted with ritonavir has not shown clinically significant adverse effects on lipids.³¹ Additionally, amprenavir, LPV/r, and ritonavir demonstrated more glucose uptake inhibition via blockade of the glucose transporter type 4 than ATV.³¹ Of the NRTIs, lipodystrophy syndrome is most commonly seen with stavudine, which is used minimally in practice.²

The rates of metabolic disturbance with antipsychotic use range from 2% to 36%.² The American Psychiatric Association recommends selecting one of the SGAs least likely to affect metabolic parameters.²⁹ Aripiprazole and ziprasidone are associated with the lowest risk of weight gain, hyperglycemia, and hyperlipidemia. They are followed by risperidone and quetiapine, which are associated with moderate risk, and then clozapine and olanzapine, which are associated with high risk.^2,30,33

Continue to: Management of metabolic adverse effects involves...

Management of metabolic adverse effects involves switching the antiretroviral agent and/or antipsychotic agent to an alternative associated with lower metabolic risk. Antipsychotics with low metabolic risk include aripiprazole, lurasidone, and ziprasidone. Lifestyle modifications are encouraged. Additionally, medication interventions, such as metformin, are also recommended in patients meeting criteria for pre-diabetes or type 2 diabetes mellitus.² Lipid panels and metabolic parameters should be monitored periodically, according to guidelines.^25,34

Bone marrow toxicity and blood dyscrasias. Lastly, consider the risk of bone marrow suppression. Patients receiving clozapine for treatment-resistant schizophrenia should be closely monitored for neutropenia and agranulocytosis. Although zidovudine is rarely used, its use is associated with adverse myelosuppressive effects, and the combination of clozapine and zidovudine could pose danger to the patient.^2,35,36

CASE CONTINUED

Because Mr. S’s diagnosis of HIV puts him at a higher risk of developing EPS, and because he is already experiencing increased wrist rigidity, the treatment team decides to switch his antipsychotic therapy to an agent with a lower risk of EPS. His comorbidities, including type 2 diabetes mellitus, hypertension, and hyperlipidemia, are taken into account, and an SGA with a benign metabolic profile is considered. Aripiprazole and ziprasidone are favorable options. However, because efavirenz, ATZ, and ritonavir may cause QTc prolongation, ziprasidone, the SGA with the highest rate of QTc prolongation, is not the preferred option.

Mr. S’s SGA therapy is switched from risperidone to aripiprazole. Because potential CYP-related interactions between aripiprazole and Mr. S’s current antiretroviral therapy could lead to increased aripiprazole levels. Mr. S is started on a low dose (5 mg/d) with the goal to titrate based on response and tolerability. Increased levels of aripiprazole may increase the risk of akathisia, drowsiness, headaches, and fatigue. Mr. S is monitored closely for improvement of EPS, adverse effects of medication, and metabolic parameters. Furthermore, if the treatment team believes there is a more preferred antipsychotic for the patient that it did not prescribe because of the risk of DDIs, it may be worthwhile to consider discussing the HAART regimen with the patient’s infectious disease treatment team.

Continue to: Acknowledgements

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

Related Resources

• Cohen MA. HIV: How to provide compassionate care. Current Psychiatry. 2013;12(6):19-23,A,B.
• Khan AY, Zaidi SN. Reducing morbidity and mortality from common medical conditions in schizophrenia. Current Psychiatry. 2016;15(3):30-32,34-38,40.

Drug Brand Names

Abacavir • Ziagen
Amlodipine • Norvasc
Amprenavir • Agenerase
Aripiprazole • Abilify
Asenapine • Saphris
Atazanavir • Reyataz
Brexpiprazole • Rexulti
Bupropion ER • Wellbutrin SR
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Clonidine • Catapres
Clozapine • Clozaril
Darunavir • Prezista
Delavirdine • Rescriptor
Didanosine • Videx EC
Efavirenz • Sustiva
Efavirenz/emtricitabine/tenofovir disoproxil fumarate • Atripla
Enfuvirtide • Fuzeon
Emtricitabine • Emtriva
Etravirine • Intelence
Fluphenazine • Prolixin
Fosamprenavir • Lexiva
Gabapentin • Neurontin
Glipizide • Glucotrol
Haloperidol • Haldol
Iloperidone • Fanapt
Indinavir • Crixivan
Lamivudine • Epivir
Lopinavir/ritonavir • Kaletra
Loxapine • Loxitane
Lurasidone • Latuda
Maraviroc • Selzentry
Metformin • Glucophage
Metoclopramide • Reglan
Molindone • Moban
Nelfinavir • Viracept
Nevirapine • Viramune
Olanzapine • Zyprexa
Paliperidone • Invega
Perphenazine • Trilafon
Pimozide • Orap
Pravastatin • Pravachol
Quetiapine • Seroquel
Raltegravir • Isentress
Rilpivirine • Edurant
Risperidone • Risperdal
Ritonavir • Norvir
Saquinavir • Invirase
Stavudine • Zerit
Tenofovir disoproxil • Viread
Thioridazine • Mellaril
Thiothixene • Navane
Tipranavir • Aptivus
Trifluoperazine • Stelazine
Zidovudine • Retrovir
Ziprasidone • Geodon

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Cornel Stanciu, MD, talked with Thomas Penders, MS, MD. For most of his career, Dr. Penders has practiced in directorship roles. He currently serves as the leader of an addiction consultation service at the Walter B. Jones Center in Greenville, North Carolina, as well as working at the state level with federally qualified health centers to develop collaborative care models.

Dr. Stanciu: What led you to decide to pursue a director role?

Dr. Penders: Early in my career, I was offered opportunities to provide leadership for an organization in its efforts to assure quality and availability of appropriate medical and psychiatric care.

Dr. Stanciu: How has the director role evolved over the years?

Dr. Penders: Thirty years ago, when I got started, hospital administrations depended heavily on medical directors to provide advice on new service initiates. Medical directors were frequently provided with support by health care organizations when recommendations were made based on patient and community need as perceived by medical staff providers. There has been a dramatic shift in the relationship and role of medical directorship, particularly over the past decade. Budgetary constraints have influenced planning and operational decisions to the extent that these decisions are much more likely to be made based on financial analyses rather than on clinical needs identified by physicians. As a result, medical directors are encouraged to be mindful of the effect of their suggestions on the bottom line of the organization. This has resulted in a very significant shift away from programs that are needed but not funded, and toward programs that are revenue-positive or at least neutral.

Medical directors who do not conform in this way are unlikely to be part of the administration for very long in the present environment.

Continue to: What training qualifications are required or desirable to assume a medical leadership role (post residency fellowship, MBA, etc.)?

Dr. Stanciu: What training qualifications are required or desirable to assume a medical leadership role (post-residency fellowship, MBA, etc.)?

Dr. Penders: In addition to a foundation in evidence-based practices and knowledge of regulatory requirements, general leadership skills are probably the most important qualities for medical leadership. Hospitals are complex organizations with confusing reporting relationships. Negotiation skills and communication skills are critical to success. Because most modern health care organizations are well staffed with administrative personnel trained in business and finance, I would not suggest that an MBA is necessary or even important to a medical director’s success. Having said that, there are an increasing number of physicians assuming the role of chief executive officer in complex health care systems. In this case, MBA training will likely be advantageous.

I would suggest that the focus of training that occurs in MPH programs would provide more relevant tools for those in positions of medical leadership. Skills such as biostatistics and epidemiology provide those in such positions with the perspective required to understand the effectiveness of health care systems, and to relate to changes that might be beneficial to the populations they serve. A firm foundation in information systems and data analysis is becoming increasingly important as the payment system moves toward one that is value-based. Increasingly, health care systems decisions will be guided by the analysis of aggregated information gathered from electronic medical records.

Dr. Stanciu: What personal qualities makes a psychiatric physician well-suited for the role of a medical director?

Dr. Penders: Medical directors will confront a variety of difficult situations with colleagues, administrative staff, patients, and family members. A calm demeanor with an ability to reflect rather than react is important. As I previously mentioned, an ability to communicate, including strength as a listener, is another personality trait valued in this position.

Continue to: What are some of the challenges you face on a daily basis?

Dr. Stanciu: What are some of the challenges you face on a daily basis?

Dr. Penders: There are challenges in multiple areas. First and foremost, medical leadership is responsible for maintaining and improving the quality of patient care and experience. One can expect frequent conflicts to arise when providers vary from established standards or disagree with established policies.

Additionally, there appears to be an increasing lack of a distinct line between administrative and patient care decisions. It is often a challenge to manage the conflicting incentives involved when cost containment and quality care are seen to diverge.

Dr. Stanciu: What are the metrics that measure success by a medical administrator?

Dr. Penders: Some would say that the financial status of the organization is an important metric. Measures such as length of stay, patient satisfaction, and numbers of clinically relevant adverse events are how the success of medical leadership is assessed.

I would argue that patient outcomes as measured by standard clinical tools are the true measure of the success of the efforts of medical providers led by a medical director. Increasingly, measures of population health will likely be used to measure the overall success of health care organizations.

Continue to: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Stanciu: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Penders: Medical directors attend many professional meetings, both within their organizations and outside, which assures that information is provided on regulatory initiatives from government bodies and organizations such as the Joint Commission.

Hospital risk managers and attorneys also play a part in keeping everyone honest when it comes to changes in laws governing our work.

Dr. Stanciu: How is it working in a supervisory capacity with other physicians and the growing number of mid-level providers and their expanding scope of practice?

Dr. Penders: There is a variety of opinions today about the relationship between physicians and mid-level providers. Fairly recently, nurse practitioners and physician assistants were known as “extenders.” We don’t hear that term as much anymore, as these providers are becoming increasingly independent in their practice roles.

The supervisory challenge varies with each situation. Most hospital organizations have medical staff rules and regulations that define the relationships within hospitals. Efforts in outpatient care are often less well defined, and supervisory relationships can be tailored to the specific effort involved.

Continue to: Is there a stipend or additional compensation for administrative duties?

Dr. Stanciu: Is there a stipend or additional compensation for administrative duties?

Dr. Penders: Always. There is considerable time and effort needed on a flexibly “as needed” basis that serves as a justification for administrative compensation.

Dr. Stanciu: Any major differences when working in an independent facility vs a large corporation?

Dr. Penders: As health care organizations become larger and more complex, the role of medical directorships in the larger systems are generally defined by policies that can be restrictive. Small organizations may have less formal rules and allow some flexibility for the role of medical leadership in general.

Dr. Stanciu: What preparation do you suggest for trainees and early career psychiatrists who are contemplating such a role?

Dr. Penders: Become involved in quality and organizational initiatives whenever they are available. Generally, organizations will invite and value the input trainees can provide to these efforts. Functioning as a chief resident is real-world experience that can be invaluable.

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Cornel Stanciu, MD, talked with Thomas Penders, MS, MD. For most of his career, Dr. Penders has practiced in directorship roles. He currently serves as the leader of an addiction consultation service at the Walter B. Jones Center in Greenville, North Carolina, as well as working at the state level with federally qualified health centers to develop collaborative care models.

Dr. Stanciu: What led you to decide to pursue a director role?

Dr. Penders: Early in my career, I was offered opportunities to provide leadership for an organization in its efforts to assure quality and availability of appropriate medical and psychiatric care.

Dr. Stanciu: How has the director role evolved over the years?

Dr. Penders: Thirty years ago, when I got started, hospital administrations depended heavily on medical directors to provide advice on new service initiates. Medical directors were frequently provided with support by health care organizations when recommendations were made based on patient and community need as perceived by medical staff providers. There has been a dramatic shift in the relationship and role of medical directorship, particularly over the past decade. Budgetary constraints have influenced planning and operational decisions to the extent that these decisions are much more likely to be made based on financial analyses rather than on clinical needs identified by physicians. As a result, medical directors are encouraged to be mindful of the effect of their suggestions on the bottom line of the organization. This has resulted in a very significant shift away from programs that are needed but not funded, and toward programs that are revenue-positive or at least neutral.

Medical directors who do not conform in this way are unlikely to be part of the administration for very long in the present environment.

Continue to: What training qualifications are required or desirable to assume a medical leadership role (post residency fellowship, MBA, etc.)?

Dr. Stanciu: What training qualifications are required or desirable to assume a medical leadership role (post-residency fellowship, MBA, etc.)?

Dr. Penders: In addition to a foundation in evidence-based practices and knowledge of regulatory requirements, general leadership skills are probably the most important qualities for medical leadership. Hospitals are complex organizations with confusing reporting relationships. Negotiation skills and communication skills are critical to success. Because most modern health care organizations are well staffed with administrative personnel trained in business and finance, I would not suggest that an MBA is necessary or even important to a medical director’s success. Having said that, there are an increasing number of physicians assuming the role of chief executive officer in complex health care systems. In this case, MBA training will likely be advantageous.

I would suggest that the focus of training that occurs in MPH programs would provide more relevant tools for those in positions of medical leadership. Skills such as biostatistics and epidemiology provide those in such positions with the perspective required to understand the effectiveness of health care systems, and to relate to changes that might be beneficial to the populations they serve. A firm foundation in information systems and data analysis is becoming increasingly important as the payment system moves toward one that is value-based. Increasingly, health care systems decisions will be guided by the analysis of aggregated information gathered from electronic medical records.

Dr. Stanciu: What personal qualities makes a psychiatric physician well-suited for the role of a medical director?

Dr. Penders: Medical directors will confront a variety of difficult situations with colleagues, administrative staff, patients, and family members. A calm demeanor with an ability to reflect rather than react is important. As I previously mentioned, an ability to communicate, including strength as a listener, is another personality trait valued in this position.

Continue to: What are some of the challenges you face on a daily basis?

Dr. Stanciu: What are some of the challenges you face on a daily basis?

Dr. Penders: There are challenges in multiple areas. First and foremost, medical leadership is responsible for maintaining and improving the quality of patient care and experience. One can expect frequent conflicts to arise when providers vary from established standards or disagree with established policies.

Additionally, there appears to be an increasing lack of a distinct line between administrative and patient care decisions. It is often a challenge to manage the conflicting incentives involved when cost containment and quality care are seen to diverge.

Dr. Stanciu: What are the metrics that measure success by a medical administrator?

Dr. Penders: Some would say that the financial status of the organization is an important metric. Measures such as length of stay, patient satisfaction, and numbers of clinically relevant adverse events are how the success of medical leadership is assessed.

I would argue that patient outcomes as measured by standard clinical tools are the true measure of the success of the efforts of medical providers led by a medical director. Increasingly, measures of population health will likely be used to measure the overall success of health care organizations.

Continue to: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Stanciu: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Penders: Medical directors attend many professional meetings, both within their organizations and outside, which assures that information is provided on regulatory initiatives from government bodies and organizations such as the Joint Commission.

Hospital risk managers and attorneys also play a part in keeping everyone honest when it comes to changes in laws governing our work.

Dr. Stanciu: How is it working in a supervisory capacity with other physicians and the growing number of mid-level providers and their expanding scope of practice?

Dr. Penders: There is a variety of opinions today about the relationship between physicians and mid-level providers. Fairly recently, nurse practitioners and physician assistants were known as “extenders.” We don’t hear that term as much anymore, as these providers are becoming increasingly independent in their practice roles.

The supervisory challenge varies with each situation. Most hospital organizations have medical staff rules and regulations that define the relationships within hospitals. Efforts in outpatient care are often less well defined, and supervisory relationships can be tailored to the specific effort involved.

Continue to: Is there a stipend or additional compensation for administrative duties?

Dr. Stanciu: Is there a stipend or additional compensation for administrative duties?

Dr. Penders: Always. There is considerable time and effort needed on a flexibly “as needed” basis that serves as a justification for administrative compensation.

Dr. Stanciu: Any major differences when working in an independent facility vs a large corporation?

Dr. Penders: As health care organizations become larger and more complex, the role of medical directorships in the larger systems are generally defined by policies that can be restrictive. Small organizations may have less formal rules and allow some flexibility for the role of medical leadership in general.

Dr. Stanciu: What preparation do you suggest for trainees and early career psychiatrists who are contemplating such a role?

Dr. Penders: Become involved in quality and organizational initiatives whenever they are available. Generally, organizations will invite and value the input trainees can provide to these efforts. Functioning as a chief resident is real-world experience that can be invaluable.

Editor’s note: Career Choices features a psychiatry resident/fellow interviewing a psychiatrist about why he or she has chosen a specific career path. The goal is to inform trainees about the various psychiatric career options, and to give them a feel for the pros and cons of the various paths.

In this Career Choices, Cornel Stanciu, MD, talked with Thomas Penders, MS, MD. For most of his career, Dr. Penders has practiced in directorship roles. He currently serves as the leader of an addiction consultation service at the Walter B. Jones Center in Greenville, North Carolina, as well as working at the state level with federally qualified health centers to develop collaborative care models.

Dr. Stanciu: What led you to decide to pursue a director role?

Dr. Penders: Early in my career, I was offered opportunities to provide leadership for an organization in its efforts to assure quality and availability of appropriate medical and psychiatric care.

Dr. Stanciu: How has the director role evolved over the years?

Dr. Penders: Thirty years ago, when I got started, hospital administrations depended heavily on medical directors to provide advice on new service initiates. Medical directors were frequently provided with support by health care organizations when recommendations were made based on patient and community need as perceived by medical staff providers. There has been a dramatic shift in the relationship and role of medical directorship, particularly over the past decade. Budgetary constraints have influenced planning and operational decisions to the extent that these decisions are much more likely to be made based on financial analyses rather than on clinical needs identified by physicians. As a result, medical directors are encouraged to be mindful of the effect of their suggestions on the bottom line of the organization. This has resulted in a very significant shift away from programs that are needed but not funded, and toward programs that are revenue-positive or at least neutral.

Medical directors who do not conform in this way are unlikely to be part of the administration for very long in the present environment.

Continue to: What training qualifications are required or desirable to assume a medical leadership role (post residency fellowship, MBA, etc.)?

Dr. Stanciu: What training qualifications are required or desirable to assume a medical leadership role (post-residency fellowship, MBA, etc.)?

Dr. Penders: In addition to a foundation in evidence-based practices and knowledge of regulatory requirements, general leadership skills are probably the most important qualities for medical leadership. Hospitals are complex organizations with confusing reporting relationships. Negotiation skills and communication skills are critical to success. Because most modern health care organizations are well staffed with administrative personnel trained in business and finance, I would not suggest that an MBA is necessary or even important to a medical director’s success. Having said that, there are an increasing number of physicians assuming the role of chief executive officer in complex health care systems. In this case, MBA training will likely be advantageous.

I would suggest that the focus of training that occurs in MPH programs would provide more relevant tools for those in positions of medical leadership. Skills such as biostatistics and epidemiology provide those in such positions with the perspective required to understand the effectiveness of health care systems, and to relate to changes that might be beneficial to the populations they serve. A firm foundation in information systems and data analysis is becoming increasingly important as the payment system moves toward one that is value-based. Increasingly, health care systems decisions will be guided by the analysis of aggregated information gathered from electronic medical records.

Dr. Stanciu: What personal qualities makes a psychiatric physician well-suited for the role of a medical director?

Dr. Penders: Medical directors will confront a variety of difficult situations with colleagues, administrative staff, patients, and family members. A calm demeanor with an ability to reflect rather than react is important. As I previously mentioned, an ability to communicate, including strength as a listener, is another personality trait valued in this position.

Continue to: What are some of the challenges you face on a daily basis?

Dr. Stanciu: What are some of the challenges you face on a daily basis?

Dr. Penders: There are challenges in multiple areas. First and foremost, medical leadership is responsible for maintaining and improving the quality of patient care and experience. One can expect frequent conflicts to arise when providers vary from established standards or disagree with established policies.

Additionally, there appears to be an increasing lack of a distinct line between administrative and patient care decisions. It is often a challenge to manage the conflicting incentives involved when cost containment and quality care are seen to diverge.

Dr. Stanciu: What are the metrics that measure success by a medical administrator?

Dr. Penders: Some would say that the financial status of the organization is an important metric. Measures such as length of stay, patient satisfaction, and numbers of clinically relevant adverse events are how the success of medical leadership is assessed.

I would argue that patient outcomes as measured by standard clinical tools are the true measure of the success of the efforts of medical providers led by a medical director. Increasingly, measures of population health will likely be used to measure the overall success of health care organizations.

Continue to: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Stanciu: How do you keep up-to-date on the latest rules and regulations to ensure facility compliance?

Dr. Penders: Medical directors attend many professional meetings, both within their organizations and outside, which assures that information is provided on regulatory initiatives from government bodies and organizations such as the Joint Commission.

Hospital risk managers and attorneys also play a part in keeping everyone honest when it comes to changes in laws governing our work.

Dr. Stanciu: How is it working in a supervisory capacity with other physicians and the growing number of mid-level providers and their expanding scope of practice?

Dr. Penders: There is a variety of opinions today about the relationship between physicians and mid-level providers. Fairly recently, nurse practitioners and physician assistants were known as “extenders.” We don’t hear that term as much anymore, as these providers are becoming increasingly independent in their practice roles.

The supervisory challenge varies with each situation. Most hospital organizations have medical staff rules and regulations that define the relationships within hospitals. Efforts in outpatient care are often less well defined, and supervisory relationships can be tailored to the specific effort involved.

Continue to: Is there a stipend or additional compensation for administrative duties?

Dr. Stanciu: Is there a stipend or additional compensation for administrative duties?

Dr. Penders: Always. There is considerable time and effort needed on a flexibly “as needed” basis that serves as a justification for administrative compensation.

Dr. Stanciu: Any major differences when working in an independent facility vs a large corporation?

Dr. Penders: As health care organizations become larger and more complex, the role of medical directorships in the larger systems are generally defined by policies that can be restrictive. Small organizations may have less formal rules and allow some flexibility for the role of medical leadership in general.

Dr. Stanciu: What preparation do you suggest for trainees and early career psychiatrists who are contemplating such a role?

Dr. Penders: Become involved in quality and organizational initiatives whenever they are available. Generally, organizations will invite and value the input trainees can provide to these efforts. Functioning as a chief resident is real-world experience that can be invaluable.

Dextromethorphan (DXM) is commonly found in over-the-counter (OTC) cold and cough preparations. When used at the therapeutic doses DXM has cough-suppressant properties through its action on the medulla. However, OTC preparations containing DXM are being increasingly used recreationally for the drug’s psychoactive effects, a practice referred to as “robotripping.” Such use can result in a toxidrome of delirium with agitation, paranoia, and hallucinations.¹ Residents need to be able to recognize the signs of DXM abuse and manage its potentially serious complications.

How DXM works

DXM has a wide therapeutic window. A typical therapeutic dose for cough is up to 120 mg/d. The most common adverse effects are mild (fever, diaphoresis, dizziness, nausea). At higher dosages, it acts as a nonselective serotonin reuptake inhibitor, a sigma-1 receptor agonist, and an N-methyl-d-aspartate (NMDA) receptor antagonist. DXM produces psychoactive effects through its active metabolite, dextrorphan, which has high affinity for NMDA. In this way, it can produce dissociative and stimulant effects. Although the amount of DXM in commercially available cold and cough preparations is modest, instructions for extraction and purification are readily available on the Internet.

Adverse effects include hallucinations, disorientation, mania, and aggression with delusions of supernatural abilities and insensitivity to pain; these effects are similar to those produced by phencyclidine (PCP).^2-4 Physiologically, diaphoresis, hyperthermia, and tachycardia are often observed.^3,5 These presentations carry a significant risk of mortality, and appropriate recognition and management is needed.

4 Phases of intoxication

DXM users have described 4 progressive behavioral phases that vary with dosage.^3,6,7 First, at 1.5 to 2.5 mg/kg, users report stimulating effects with perceptual alterations similar to those produced by 3,4-methylenedioxymethamphetamine (“ecstasy”). The second phase, reached at 2.5 to 7.5 mg/kg, is similar to alcohol and marijuana intoxication but includes more pronounced dysfunction in motor, cognitive, and perceptual skills, and perhaps visual hallucinations.^3,6,7 The third phase, noted at 7.5 to 15 mg/kg, resembles ketamine intoxication, with strong dissociation and hallucinations.^3,6,7 At greater doses, out-of-body, trance-like experiences may occur. Delirious misperceptions often lead to violent behavior and limited perception of pain. Users may experience a long course of any of these phases, with presentations lasting for up to 1 to 2 weeks after discontinuing use.⁸

Management is mainly supportive

Early recognition of DXM use is essential for treatment. Unfortunately, without collateral reports, this can be challenging because specialized toxicology screens are needed to detect DXM. Basic screens sometimes show a false positive for PCP. Take an inventory of all substances in the patient’s possession, either by examining the patient’s belongings or by obtaining collateral information from the patient’s family or friends.

Supportive care should be implemented, with a primary goal of controlling agitation. Short-acting benzodiazepines are helpful. Low-dose, short-term antipsychotics have shown benefit when hallucinations and paranoia are prominent.³ Decreasing stimulation and avoiding physical restraints while attempting to control aggression and psychosis with these medications is recommended. Using physical restraints on an individual who is in a state of agitated delirium can lead to severe injuries, cardiac and respiratory arrest, and death.^9-11

Patients typically experience rapid and complete remission of symptoms after discontinuing DXM use. However, evidence suggests DXM users can develop tolerance as well as psychological and physiological dependence. DXM withdrawal can be quite protracted and may include anxiety, dysphoria, insomnia, and suicidality.

Dextromethorphan (DXM) is commonly found in over-the-counter (OTC) cold and cough preparations. When used at the therapeutic doses DXM has cough-suppressant properties through its action on the medulla. However, OTC preparations containing DXM are being increasingly used recreationally for the drug’s psychoactive effects, a practice referred to as “robotripping.” Such use can result in a toxidrome of delirium with agitation, paranoia, and hallucinations.¹ Residents need to be able to recognize the signs of DXM abuse and manage its potentially serious complications.

How DXM works

DXM has a wide therapeutic window. A typical therapeutic dose for cough is up to 120 mg/d. The most common adverse effects are mild (fever, diaphoresis, dizziness, nausea). At higher dosages, it acts as a nonselective serotonin reuptake inhibitor, a sigma-1 receptor agonist, and an N-methyl-d-aspartate (NMDA) receptor antagonist. DXM produces psychoactive effects through its active metabolite, dextrorphan, which has high affinity for NMDA. In this way, it can produce dissociative and stimulant effects. Although the amount of DXM in commercially available cold and cough preparations is modest, instructions for extraction and purification are readily available on the Internet.

Adverse effects include hallucinations, disorientation, mania, and aggression with delusions of supernatural abilities and insensitivity to pain; these effects are similar to those produced by phencyclidine (PCP).^2-4 Physiologically, diaphoresis, hyperthermia, and tachycardia are often observed.^3,5 These presentations carry a significant risk of mortality, and appropriate recognition and management is needed.

4 Phases of intoxication

DXM users have described 4 progressive behavioral phases that vary with dosage.^3,6,7 First, at 1.5 to 2.5 mg/kg, users report stimulating effects with perceptual alterations similar to those produced by 3,4-methylenedioxymethamphetamine (“ecstasy”). The second phase, reached at 2.5 to 7.5 mg/kg, is similar to alcohol and marijuana intoxication but includes more pronounced dysfunction in motor, cognitive, and perceptual skills, and perhaps visual hallucinations.^3,6,7 The third phase, noted at 7.5 to 15 mg/kg, resembles ketamine intoxication, with strong dissociation and hallucinations.^3,6,7 At greater doses, out-of-body, trance-like experiences may occur. Delirious misperceptions often lead to violent behavior and limited perception of pain. Users may experience a long course of any of these phases, with presentations lasting for up to 1 to 2 weeks after discontinuing use.⁸

Management is mainly supportive

Early recognition of DXM use is essential for treatment. Unfortunately, without collateral reports, this can be challenging because specialized toxicology screens are needed to detect DXM. Basic screens sometimes show a false positive for PCP. Take an inventory of all substances in the patient’s possession, either by examining the patient’s belongings or by obtaining collateral information from the patient’s family or friends.

Supportive care should be implemented, with a primary goal of controlling agitation. Short-acting benzodiazepines are helpful. Low-dose, short-term antipsychotics have shown benefit when hallucinations and paranoia are prominent.³ Decreasing stimulation and avoiding physical restraints while attempting to control aggression and psychosis with these medications is recommended. Using physical restraints on an individual who is in a state of agitated delirium can lead to severe injuries, cardiac and respiratory arrest, and death.^9-11

Patients typically experience rapid and complete remission of symptoms after discontinuing DXM use. However, evidence suggests DXM users can develop tolerance as well as psychological and physiological dependence. DXM withdrawal can be quite protracted and may include anxiety, dysphoria, insomnia, and suicidality.

Dextromethorphan (DXM) is commonly found in over-the-counter (OTC) cold and cough preparations. When used at the therapeutic doses DXM has cough-suppressant properties through its action on the medulla. However, OTC preparations containing DXM are being increasingly used recreationally for the drug’s psychoactive effects, a practice referred to as “robotripping.” Such use can result in a toxidrome of delirium with agitation, paranoia, and hallucinations.¹ Residents need to be able to recognize the signs of DXM abuse and manage its potentially serious complications.

How DXM works

DXM has a wide therapeutic window. A typical therapeutic dose for cough is up to 120 mg/d. The most common adverse effects are mild (fever, diaphoresis, dizziness, nausea). At higher dosages, it acts as a nonselective serotonin reuptake inhibitor, a sigma-1 receptor agonist, and an N-methyl-d-aspartate (NMDA) receptor antagonist. DXM produces psychoactive effects through its active metabolite, dextrorphan, which has high affinity for NMDA. In this way, it can produce dissociative and stimulant effects. Although the amount of DXM in commercially available cold and cough preparations is modest, instructions for extraction and purification are readily available on the Internet.

Adverse effects include hallucinations, disorientation, mania, and aggression with delusions of supernatural abilities and insensitivity to pain; these effects are similar to those produced by phencyclidine (PCP).^2-4 Physiologically, diaphoresis, hyperthermia, and tachycardia are often observed.^3,5 These presentations carry a significant risk of mortality, and appropriate recognition and management is needed.

4 Phases of intoxication

DXM users have described 4 progressive behavioral phases that vary with dosage.^3,6,7 First, at 1.5 to 2.5 mg/kg, users report stimulating effects with perceptual alterations similar to those produced by 3,4-methylenedioxymethamphetamine (“ecstasy”). The second phase, reached at 2.5 to 7.5 mg/kg, is similar to alcohol and marijuana intoxication but includes more pronounced dysfunction in motor, cognitive, and perceptual skills, and perhaps visual hallucinations.^3,6,7 The third phase, noted at 7.5 to 15 mg/kg, resembles ketamine intoxication, with strong dissociation and hallucinations.^3,6,7 At greater doses, out-of-body, trance-like experiences may occur. Delirious misperceptions often lead to violent behavior and limited perception of pain. Users may experience a long course of any of these phases, with presentations lasting for up to 1 to 2 weeks after discontinuing use.⁸

Management is mainly supportive

Early recognition of DXM use is essential for treatment. Unfortunately, without collateral reports, this can be challenging because specialized toxicology screens are needed to detect DXM. Basic screens sometimes show a false positive for PCP. Take an inventory of all substances in the patient’s possession, either by examining the patient’s belongings or by obtaining collateral information from the patient’s family or friends.

Supportive care should be implemented, with a primary goal of controlling agitation. Short-acting benzodiazepines are helpful. Low-dose, short-term antipsychotics have shown benefit when hallucinations and paranoia are prominent.³ Decreasing stimulation and avoiding physical restraints while attempting to control aggression and psychosis with these medications is recommended. Using physical restraints on an individual who is in a state of agitated delirium can lead to severe injuries, cardiac and respiratory arrest, and death.^9-11

Patients typically experience rapid and complete remission of symptoms after discontinuing DXM use. However, evidence suggests DXM users can develop tolerance as well as psychological and physiological dependence. DXM withdrawal can be quite protracted and may include anxiety, dysphoria, insomnia, and suicidality.

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

As the end of the academic year approaches, I always think of one last message to send to the freshly minted psychiatrists who will complete their 4 years of post-MD training. This year, I thought of emphasizing the principles of psychiatric practice, which the graduates will deliver for the next 4 to 5 decades of their professional lives. Those essential principles are coded in the DNA of psychiatric practice, just as the construction of all organs in the human body is coded within the DNA of the 22,000 genes that comprise our 23 chromosomes.

So here are the principles of psych­iatry that I propose govern the relationship of psychiatrists with their patients, encrypted within the DNA of our esteemed medical specialty:

• Provide total dedication to helping psychiatric patients recover from their illness and regain their wellness.
• Maintain total and unimpeachable confidentiality.
• Demonstrate unconditional acceptance and respect to every patient.
• Adopt a nonjudgmental stance toward all patients.
• Establish a strong therapeutic alliance as early as possible. It is the center of the doctor–patient relationship.
• Provide the same standard of care to all patients—the same care you would want your family members to receive.
• Provide evidence-based treatments first, and if no response, use unapproved treatments judiciously, but above all, do no harm.
• Educate patients, and their families, about the illness, and discuss the benefits and risks of various treatments.
• Do not practice “naked psychopharmacology.” Psychotherapy must always be provided side-by-side with medications.
• Support the patient’s family. Their burden often is very heavy.
• Emphasize adherence as a key patient responsibility, and address it at every visit.
• Do not hesitate to consult a seasoned colleague about your complex clinical cases.
• Deal effectively with negative countertransference. Recognize it, and refer the patient to another colleague if you cannot resolve it.
• Always inquire about thoughts of harming self or others and act accordingly.
• Always ask about alcohol and substance use, and about over-the-counter drugs as well. They all can complicate your patient’s treatment course and outcome.
• Never breach boundaries with your patient, and firmly guide the patient about breaching boundaries with you.
• Uphold the medical tenet that all “mental” disorders of thought, mood, affect, behavior, and cognition are generated by disruptions of brain structure and/or function, whether molecular, cellular, or connectomic, caused by various combinations of genetic and/or environmental etiologies.
• Check your patients’ physical health status, including all treatments they received from other specialists, and always rule out iatrogenesis and disruptive pharmacokinetic interactions that may trigger or exacerbate psychiatric symptoms.
• Learn and use clinical rating scales to quantify symptom severity and adverse effects at baseline and at each visit. Measuring the severity of psychosis, depression, or anxiety in psychiatry is like measuring fasting glucose, triglycerides, or blood pressure in internal medicine.
• Use rational adjunctive and augmentation therapies when indicated, but avoid irrational and hazardous polypharmacy.
• Document your clinical findings, diagnosis, and treatment plan conscientiously and accurately. The medical record is a clinical, billing, legal, and research document.
• Advocate tirelessly for psychiatric patients to increase their access to care, and fight the unfair and hurtful stigma vigorously until it is completely erased. A psychiatric disorder should have no more stigma than a broken leg or peptic ulcer, and insurance parity must be identical as well.
• Establish collaborative care for each of your patients and link them to a primary care provider if they do not already have one. Disorders of the body and the brain are bidirectional in their effects and psychiatric patients often suffer from multiple organ diseases.
• Do some pro bono care for indigent or uninsured patients, and actively ask companies to provide free drugs to patients who cannot afford the medication you believe they need.
• Recognize that every treatment you use as the current standard of care was at one time a research project. Know that the research of today is the treatment of tomorrow. So support the creation of new medical knowledge by referring patients to FDA clinical trials or to National Institutes of Health–funded biologic investigations.
• No matter how busy you are, write a case report or a letter to the editor about an unusual response or adverse effect. This generates hypotheses that researchers can pursue and test.
• Volunteer to serve as a clinical supervisor for medical students and residents from your local medical school. Most academic departments of psychiatry appreciate their community-based volunteer faculty.

You, the readers of Current Psychiatry, include thousands of experienced psychiatrists with years of practice in the real world. I invite you to add to this list of principles by writing to me at [email protected]. Join me in providing the freshly minted psychiatrists words of wisdom about the DNA of psychiatry to guide them before they embark on their careers as psychiatric physicians.

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

The Goldwater Rule and free speech

In his editorial, “The toxic zeitgeist of hyper-partisanship: A psychiatric perspective” (From the Editor, Current Psychiatry, February 2018, p. 17-18), Dr. Nasrallah notes that he “adheres” to the APA’s Goldwater Rule. The Goldwater Rule and the reason for its creation and current implementation in the United States cannot be fully understood without appreciating the political circumstances that led to its creation in 1964. The conservative movement had been using the slogan “better dead than red” to criticize Democrats who they felt were soft on communism. Unfortunately, some psychiatrists took these words and the views of Arizona senator Barry Goldwater quite literally. They claimed they understood his psychological structure by listening to his political views, and feared that he would risk starting a nuclear war. Of course, no psychiatrist actually examined senator Goldwater. During the 1964 presidential campaign, a television commercial from President Lyndon B. Johnson’s campaign included a mushroom cloud of a nuclear explosion with an implicit reference to senator Goldwater and the “better dead than red” slogan. In the end, psychiatry, and particularly psychoanalysis, as well as President Johnson’s campaign, were embarrassed.

One’s political views do not inform us of his or her mental health status. This appreciation can be obtained only by a thorough psychological assessment. This is the basis of the Goldwater Rule, coupled with the ethical responsibility not to discuss patients’ private communications.

Today, this rule is tested by the behavior and actions of President Donald Trump. Proponents of the Goldwater Rule state that a psychiatrist cannot diagnose someone without performing a face-to-face diagnostic evaluation. This assumes psychiatrists diagnose patients only by interviewing them. However, any psychiatrist who has worked in an emergency room has signed involuntary commitment papers for a patient who refuses to talk to them. This clinical action typically is based on reports of the patient’s potential dangerousness from family, friends, or the police.

The diagnostic criteria for some personality disorders are based only on observed or reported behavior. They do not indicate a need for an interview.  The diagnosis of a personality disorder cannot be made solely by interviewing an individual without knowledge of his or her behavior. Interviewing Bernie Madoff would not have revealed his sociopathic behavior.

The critical question may not be whether one could ethically make a psychiatric diagnosis of the President (I believe you can), but rather would it indicate or imply that he is dangerous? History informs us that the existence of a psychiatric disorder does not determine a politician’s fitness for office or if they are dangerous. Behavioral accounts of President Abraham Lincoln and his self-reports seem to confirm that at times he was depressed, but he clearly served our country with distinction.

Finally, it is not clear whether the Goldwater Rule is legal. It arguably interferes with a psychiatrist’s right of free speech without the risk of being accused of unethical behavior. I wonder what would happen if it were tested in court. Does the First Amendment of the U.S. Constitution protect a psychiatrist’s right to speak freely?

Sidney Weissman, MD
Clinical Professor of Psychiatry and Behavioral Science
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

The current ‘political morass’

Thank you, Dr. Nasrallah, for the wonderful synopsis of the current political morass in your editorial (From the Editor, Current Psychiatry, February 2018, p. 17-18). You followed Descartes’ dictum: you thought about matters in a novel fashion. I will assertively share this with others. It is a good piece of teaching.

James Gallagher, MD
Private psychiatric practice
Des Moines, Iowa

Continue to: The biological etiology of compulsive sexual behavior

Dr. Grant’s article, “Compulsive sexual behavior: A nonjudgmental approach” (Evidence-Based Reviews, Current Psychiatry, February 2018, p. 34,38-40,45-46), puts a well-deserved spotlight on a relatively underrecognized problem that most psychiatrists will encounter at least once during clinical practice. While the article is overall helpful, it completely leaves out any possible biological etiology and underpinnings to the condition that may be important to address while evaluating someone with compulsive sexual behavior. Specifically, are there any endocrine issues that should be considered that may also impact our approach to its treatment?

Mukesh Sanghadia, MD, MRCPsych (UK), Diplomate ABPN
PsychiatristCommunity Research Foundation
San Diego, California

The author responds

Dr. Sanghadia highlights the lack of possible biological etiology of compulsive sexual behavior (CSB) in my article. This is a fair comment. The lack of agreed-upon diagnostic criteria, however, has resulted in a vast literature discussing sexual behaviors that may or may not be related to each other, and even suggest that what is currently referred to as CSB may in fact be quite heterogeneous. My article mentions the few neuroimaging and neurocognitive studies that address a more rigorously defined CSB. Other possible etiologies have been suggested for a range of out-of-control sexual behaviors, but have not been studied with a focus on this formal diagnostic category. For example, endocrine issues have been explored to some extent in individuals with paraphilic sexual behaviors (behaviors that appear to many to have no relationship to CSB as discussed in my article), and in those cases of paraphilic sexual behavior, a range of endocrine hormones have been examined—gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone. But these studies have yielded no conclusive outcomes in terms of findings or treatments.

In summary, the biology of CSB lags far behind that of other mental health disorders (and even other psychiatric disorders lack conclusive biological etiologies). Establishing this behavior as a legitimate diagnostic entity with agreed-upon criteria may be the first step in furthering our understanding of its possible biology.

Jon E. Grant, JD, MD, MPH
Professor
Department of Psychiatry and Behavioral Neuroscience
University of Chicago, Pritzker School of Medicine
Chicago, Illinois

Continue to: A different view of patients with schizophrenia

After treating patients with schizophrenia for more than 30 years, I’ve observed a continuous flood of information about them. This overload has been consistent since my residency back in the 1980s. Theories ranging from the psychoanalytic to the biologic are numerous and valuable additions to our understanding of those who suffer with this malady, yet they provide no summation or overview with which to understand it.

For instance, we know that schizophrenia usually begins in the late teens or early twenties. We know that antidopaminergic medications usually help to varying degrees. Psychosocial interventions may contribute greatly to the ultimate outcome. Substance use invariably makes it worse. Establishing a connection with the patient can often be helpful. Medication compliance is crucial.

It is more or less accepted that there is deterioration of higher brain functions, hypofrontality, as well as so-called dysconnectivity of white matter. There is a genetic vulnerability, and there seems to be an excess of inflammation and changes in mitochondria. Most patients have low functioning, poor compensation, and a lack of social adeptness. However, some patients can recover quite nicely. Although most of us would agree that this is not dementia, we’d also concede that these patients’ cognitive functioning is not what it used to be. Electroconvulsive therapy also can sometimes be helpful.

So, how are we to view our patients with schizophrenia in a way that can be illuminating and give us a deeper sense of understanding this quizzical disorder? It has been helpful to me to regard these individuals as a people whose brain function has been usurped by a more primitive organization that is characterized by:

• a reduction in mental development, where patients function in a more childlike way with magical thinking and impaired reality-testing
• atrophy of higher brain structures, leading to hallucinatory experiences
• a hyper-dominergic state
• a usually gradual onset with some evidence of struggle between the old and new brain organizations
• impaired prepulse inhibition that’s likely secondary to diffuseness of thought
• eventual demise of higher brain structures with an inability to respond to anti-dopaminergics. (Antipsychotics can push the brain organization closer to the adult structure attained before the onset of the disease, at least initially.)

The list goes on. Thinking about patients with schizophrenia in this way allows me to appreciate what I feel is a more encompassing view of who they are and how they got there. I have some theories about where this more primitive organization may have originated, but whatever its origin, in a small percentage of people it is there, ready to assume control of their thinking just as they are reaching reproductive age. Early intervention and medication compliance may minimize damage.

If a theory helps us gain a greater understanding of our patients, then it’s worth considering. This proposition fits much of what we know about schizophrenia. Reading patients’ firsthand accounts of the illness helps confirm, in my opinion, this point of view.

Steven Lesk, MD
Private psychiatric practice
Fridley, Minnesota

Continue to: Cognitive impairment in schizophrenia

The authors of “Suspicious, sleepless, and smoking” (Cases That Test Your Skills, Current Psychiatry, September 2017, p. 49-50,52-54) assert that “…the severity of cognitive impairment in schizophrenia has no association with the positive symptoms of schizophrenia” and they add, “Treatment of the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.” However, in the case they present, Mr. F appears to demonstrate just the opposite: He is given antipsychotics, and over the course of his hospital stay, both his positive symptoms and his cognition improve. His scores on the Montreal Cognitive Assessment increase from 9 (Day 11) to 15 (Day 16) to 21 (Day 24). Thus, in this particular case, treatment with antipsychotics is clearly associated with cognitive improvement.

During the past 15 years, I have routinely measured cognitive functioning in patients with schizophrenia. Some have no impairment, some have severe impairment, and some fall in between these extremes. Most often, impairment occurs in the area of executive function, which can lead to significant disability. Indeed, positive symptoms can clear up completely with treatment, but the deficits in executive functioning can remain.

I think it is fair to say that cognitive impairment is a common, although not nearly universal, feature of schizophrenia that sometimes improves with antipsychotic medication. I look forward to the advent of more clinicians paying attention to the issue of cognition in schizophrenia and, hopefully, better treatments for it.

John M. Mahoney, PhD
Shasta Psychiatric Hospital
Redding, California

The authors respond

We thank Dr. Mahoney for his thoughtful letter and queries into the case of Mr. F.

First, regarding the prevalence of cognitive impairment in schizophrenia, it is our opinion that cognitive impairment is a distinct, core, and nearly universal feature of schizophrenia. This also is the conclusion of many clinicians and researchers based on their significant work in the field; still, just as in our initial case study, we concede that these symptoms are not part of the DSM-5’s formal diagnostic criteria.

The core question Dr. Mahoney seems to pose is whether we contradicted ourselves. We assert that cognitive impairment in schizophrenia is not effectively treated with existing medications, and yet we described Mr. F’s cognitive improvement after he received risperidone, 2 mg/d, titrated up to 2 mg twice daily. We first pointed out that part of our treatment strategy was to target comorbid depression in this patient; nonetheless, Dr. Mahoney’s question remains valid, and we will attempt to answer.

Dr. Mahoney has observed that his patients with schizophrenia variably experience improved cognition, and notes that executive function is a particularly common lingering impairment. On this we wholly agree; this is a helpful point of clarification, and a useful distinction in light of the above question. Improvement in positive and negative symptoms of schizophrenia, as psychosis resolves, is a well-known and studied effect of antipsychotic therapy. As a result, the sensorium becomes more congruent with external reality, and one would expect the patient to display improved orientation. This then might be reasonably expected to produce mental status improvements; however, while some improvement is frequently observed, this is neither consistent nor complete improvement. In the case of Mr. F, we document improvement, but also significant continued impairment. Thus, we maintain that treating the cognitive symptoms of schizophrenia with antipsychotics has been largely ineffective.

We do not see this as a slight distinction or an argument of minutiae. That patients frequently experience some degree of lingering impairment is a salient point. Neurocognitive impairment is a strong contributor to and predictor of disability in schizophrenia, and neurocognitive abilities most strongly predict functional outcomes. From a patient’s point of view, these symptoms have real-world consequences. Thus, we believe they should be evaluated and treated as aggressively and consistently as other schizophrenia symptoms.

In our case, we attempted to convey one primary message: Despite the challenges of treatment, there are viable options that should be pursued in the treatment of schizophrenia-related cognitive impairments. Nonpharmacologic modalities have shown encouraging results. Cognitive remediation therapy produces durable cognitive improvement—especially when combined with adjunctive therapies, such as small group therapy and vocational rehabilitation, and when comorbid conditions (major depressive disorder in Mr. F’s case) are treated.

In summary, we reiterate that cognitive impairments in schizophrenia represent a strong predictor of patient-oriented outcomes; we maintain our assertion regarding their inadequate treatment with existing medications; and we suggest that future trials attempt to find effective alternative strategies. We encourage psychiatric clinicians to approach treatment of this facet of pathology with an open mind, and to utilize alternative multi-modal therapies for the benefit of their patients with schizophrenia while waiting for new safe and effective pharmaceutical regimens.

Jarrett Dawson, MD
Family medicine resident
Department of Psychiatry
Saint Louis University
St. Louis, Missouri

Catalina Belean, MD
Assistant Professor
Department of Psychiatry
Saint Louis University
St. Louis, Missouri