Current Psychiatry

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

In general, when a medication goes off patent, marketing for it significantly slows down or comes to a halt. Studies have shown that physicians’ prescribing habits are influenced by pharmaceutical representatives and companies.¹ This phenomenon may have an unforeseen adverse effect: once an effective and inexpensive medication “goes generic,” its use may fall out of favor. Additionally, physicians may have concerns about prescribing generic medications, such as perceiving them as less effective and conferring more adverse effects compared with brand-name formulations.² One such generic medication is buspirone, which originally was branded as BuSpar.

Anxiety disorders are the most common psychiatric diagnoses, and at times are the most challenging to treat.³ Anecdotally, we often see benzodiazepines prescribed as first-line monotherapy for acute and chronic anxiety, but because these agents can cause physical dependence and a withdrawal reaction, alternative anxiolytic medications should be strongly considered. Despite its age, buspirone still plays a role in the treatment of anxiety, and its off-label use can also be useful in certain populations and scenarios. In this article, we delve into buspirone’s mechanism of action, discuss its advantages and challenges, and what you need to know when prescribing it.

How buspirone works

Buspirone was originally described as an anxiolytic agent that was pharmacologically unrelated to traditional anxiety-reducing medications (ie, benzodiazepines and barbiturates).⁴ It has a high affinity for the 5-hydroxytryptamine 1A (5HT1A) receptor and may also act as a central dopamine antagonist at D2 receptors.^4,5 It is FDA-approved only for the treatment of generalized anxiety disorder (GAD).⁴ Buspirone also is commonly used as an augmenting agent to selective serotonin reuptake inhibitors (SSRIs) in the treatment of medication-resistant or partially treated depression.⁶ When a patient who is depressed appears to have marginal to no response to an adequate trial of a first-line agent, buspirone is thought to replenish depleted stores and/or increase synthesis of serotonin. Additionally, it acts directly on 5HT1A autoreceptors to achieve the desired desensitization of those receptors. All of these proposed mechanisms are thought to improve symptoms of depression.⁶

The antidepressants vortioxetine and vilazodone exhibit dual-action at both serotonin reuptake transporters and 5HT1A receptors; thus, they work like an SSRI and buspirone combined.⁶ Although some patients may find it more convenient to take a dual-action pill over 2 separate ones, some insurance companies do not cover these newer agents. Additionally, prescribing buspirone separately allows for more precise dosing, which may lower the risk of adverse effects.

Buspirone is a major substrate for cytochrome P450 (CYP) 3A4 and a minor for CYP2D6, so caution must be advised if considering buspirone for a patient receiving any CYP3A4 inducers and/or inhibitors,⁷ including grapefruit juice.⁸

Dose adjustments are not necessary for age and sex, which allows for highly consistent dosing.⁴ However, as with prescribing medications in any geriatric population, lower starting doses and slower titration of buspirone may be necessary to avoid potential adverse effects due to the alterations of pharmacodynamic and pharmacokinetic processes that occur as patients age.⁹

Advantages of buspirone

Works well as an add-on to other medications. While buspirone in adequate doses may be helpful as monotherapy in GAD, it can also be helpful in other, more complex psychiatric scenarios. Sumiyoshi et al¹⁰ observed improvement in scores on the Digit Symbol Substitution Test when buspirone was added to a second-generation antipsychotic (SGA), which suggests buspirone may help improve attention in patients with schizophrenia. It has been postulated that buspirone may also be helpful for cognitive dysfunction in patients with Alzheimer’s disease.¹¹ Buspirone has been used to treat comorbid anxiety and alcohol use disorder, resulting in reduced anxiety, longer latency to relapse, and fewer drinking days during a 12-week treatment program.¹² Buspirone has been more effective than placebo for treating post-stroke anxiety.¹³

Continue to: Patients who receive...

Patients who receive an SSRI, such as citalopram, but are not able to achieve a substantial improvement in their depressive and/or anxious symptoms may benefit from the addition of buspirone to their treatment regimen.^14,15

A favorable adverse-effect profile. There are no absolute contraindications to buspirone except a history of hypersensitivity.⁴ Buspirone generally is well tolerated and carries a low risk of adverse effects. The most common adverse effects are dizziness and nausea.⁶ Buspirone is not sedating.

Potentially safe for patients who are pregnant. Unlike many other first-line agents for anxiety, such as SSRIs, buspirone has an FDA Category B classification, meaning animal studies have shown no adverse events during pregnancy.⁴ The FDA Pregnancy and Lactation Labeling Rule applies only to medications that entered the market on or after June 30, 2001; unfortunately, buspirone is excluded from this updated categorization.¹⁶ As with any medication being considered for pregnant or lactating women, the prescriber and patient must weigh the benefits vs the risks to determine if buspirone is appropriate for any individual patient.

No adverse events have been reported from abrupt discontinuation of buspirone.¹⁷

Inexpensive. Buspirone is generic and extremely inexpensive. According to GoodRx.com, a 30-day supply of 5-mg tablets for twice-daily dosing can cost $4.¹⁸ A maximum daily dose (prescribed as 2 pills, 15 mg twice daily) may cost approximately $18/month.¹⁸ Thus, buspirone is a good option for uninsured or underinsured patients, for whom this would be more affordable than other anxiolytic medications.

Continue to: May offset certain adverse effects

May offset certain adverse effects. Sexual dysfunction is a common adverse effect of SSRIs. One strategy to offset this phenomenon is to add bupropion. However, in a randomized controlled trial, Landén et al¹⁹ found that sexual adverse effects induced by SSRIs were greatly mitigated by adding buspirone, even within the first week of treatment. This improvement was more marked in women than in men, which is helpful because sexual dysfunction in women is generally resistant to other interventions.²⁰ Unlike bupropion, buspirone is not contraindicated in patients with seizure and/or eating disorders.⁴ Additionally, the American Psychiatric Association practice guidelines for the treatment of major depressive disorder identify buspirone as a useful strategy in treating erectile dysfunction and orgasmic dysfunction due to SSRI treatment.¹⁵

Unlikely to cause extrapyramidal symptoms (EPS). Because of its central D2 antagonism, buspirone has a low potential (<1%) to produce EPS. Buspirone has even been shown to reverse haloperidol-induced EPS.²¹

The Table⁴ highlights key points to bear in mind when prescribing buspirone.

Challenges with buspirone

Response is not immediate. Unlike benzodiazepines, buspirone does not have an immediate onset of action.²² With buspirone monotherapy, response may be seen in approximately 2 to 4 weeks.²³ Therefore, patients transitioning from a quick-onset benzodiazepine to buspirone may not report a good response. However, as noted above, when using buspirone to treat SSRI-induced sexual dysfunction, response may emerge within 1 week.¹⁹ Buspirone also lacks the euphoric and sedative qualities of benzodiazepines that patients may prefer.

Not for patients with hepatic and renal impairment. Because plasma levels of buspirone are elevated in patients with hepatic and renal impairment, this medication is not ideal for use in these populations.⁴

Continue to: Contraindicated in patients receiving MAOIs

Contraindicated in patients receiving MAOIs. Buspirone should not be prescribed to patients with depression who are receiving treatment with a monoamine oxidase inhibitor (MAOI) because the combination may precipitate a hypertensive reaction.⁴ A minimum washout period of 14 days from the MAOI is necessary before initiating buspirone.⁹

Idiosyncratic adverse effects. As with all pharmaceuticals, buspirone may produce idiosyncratic adverse effects. Faber and Sansone²⁴ reported a case of a woman who experienced hair loss 3 months into treatment with buspirone. After cessation, her alopecia resolved.

Questionable efficacy for some anxiety subtypes. Buspirone has been studied as a treatment of other common psychiatric conditions, such as social phobia and anxiety in the setting of smoking cessation. However, it has not proven to be effective over placebo in treating these anxiety subtypes.^25,26

Short half-life. Because of its relatively short half-life (2 to 3 hours), buspirone requires dosing 2 to 3 times a day, which could increase the risk of noncompliance.⁴ However, some patients might prefer multiple dosing throughout the day due to perceived better coverage of their anxiety symptoms.

Limited incentive for future research. Because buspirone is available only as a generic formulation, there is little financial incentive for pharmaceutical companies and other interested parties to study what may be valuable uses for buspirone. For example, there is no data available on comparative augmentation of buspirone and SGAs with antidepressants for depression and/or anxiety. There is also little data available about buspirone prescribing trends or why buspirone may be under­utilized in clinical practice today.

Continue to: Unfortunately, historical and longitudinal...

Unfortunately, historical and longitudinal data on the prescribing practices of buspirone is limited because the original branded medication, BuSpar, is no longer on the market. However, this medication offers multiple advantages over other agents used to treat anxiety, and it should not be forgotten when formulating a treatment regimen for patients with anxiety and/or depression.

Bottom Line

Buspirone is a safe, low-cost, effective treatment option for patients with anxiety and may be helpful as an augmenting agent for depression. Because of its efficacy and high degree of tolerability, it should be prioritized higher in our treatment algorithms and be a part of our routine pharmacologic armamentarium.

Related Resources

• Howland RH. Buspirone: Back to the future. J Psychosoc Nurs Ment Health Serv. 2015;53(11):21-24.
• Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol. 2018;28(1):2-9.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Citalopram • Celexa
Haloperidol • Haldol
Vilazodone • Viibryd
Vortioxetine • Trintellix

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

Medical knowledge is growing faster than ever, as is the challenge of keeping up with this ever-growing body of information. Clinicians need a system or method to help them sort and evaluate the quality of new information before they can apply it to clinical care. Without such a system, when facing an overload of information, most of us tend to take the first or the most easily accessed information, without considering the quality of such information. As a result, the use of poor-quality information affects the quality and outcome of care we provide, and costs billions of dollars annually in problems associated with underuse, overuse, and misuse of treatments.

In an effort to sort and evaluate recently published research that is ready for clinical use, the first author (SAS) used the following 3-step methodology:

1. Searched literature for research findings suggesting readiness for clinical utilization published between July 1, 2018 and June 30, 2019.

2. Surveyed members of the American Association of Chairs of Departments of Psychiatry, the American Association of Community Psychiatrists, the American Association of Psychiatric Administrators, the North Carolina Psychiatric Association, the Group for the Advancement of Psychiatry, and many other colleagues by asking them: “Among the articles published from July 1, 2018 to June 30, 2019, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?”

3. Looked for appraisals in post-publication reviews such as NEJM Journal Watch, F1000 Prime, Evidence-Based Mental Health, commentaries in peer-reviewed journals, and other sources (see Related Resources).

We chose 12 articles based on their clinical relevance/applicability. Here in Part 1 we present brief descriptions of the 6 of top 12 papers chosen by this methodology; these studies are summarized in the Table.^1-6 The order in which they appear in this article is arbitrary. The remaining 6 studies will be reviewed in Part 2 in the February 2020 issue of Current Psychiatry.

1. Ray WA, Stein CM, Murray KT, et al. Association of antipsychotic treatment with risk of unexpected death among children and youths. JAMA Psychiatry. 2019;76(2):162-171.

Children and young adults are increasingly being prescribed antipsychotic medications. Studies have suggested that when these medications are used in adults and older patients, they are associated with an increased risk of death.^7-9 Whether or not these medications are associated with an increased risk of death in children and youth has been unknown. Ray et al¹ compared the risk of unexpected death among children and youths who were beginning treatment with an antipsychotic or control medications.

Study design

• This retrospective cohort study evaluated children and young adults age 5 to 24 who were enrolled in Medicaid in Tennessee between 1999 and 2014.
• New antipsychotic use at both a higher dose (>50 mg chlorpromazine equivalents) and a lower dose (≤50 mg chlorpromazine equivalents) was compared with new use of a control medication, including attention-deficit/hyperactivity disorder medications, antidepressants, and mood stabilizers.
• There were 189,361 participants in the control group, 28,377 participants in the lower-dose antipsychotic group, and 30,120 participants in the higher-dose antipsychotic group.

Outcomes

• The primary outcome was death due to injury or suicide or unexpected death occurring during study follow-up.
• The incidence of death in the higher-dose antipsychotic group (146.2 per 100,000 person-years) was significantly higher (P < .001) than the incidence of death in the control medications group (54.5 per 100,000 person years).
• There was no similar significant difference between the lower-dose antipsychotic group and the control medications group.

Continue to: Conclusion

Conclusion

• Higher-dose antipsychotic use is associated with increased rates of unexpected deaths in children and young adults.
• As with all association studies, no direct line connected cause and effect. However, these results reinforce recommendations for careful prescribing and monitoring of antipsychotic regimens for children and youths, and the need for larger antipsychotic safety studies in this population.
• Examining risks associated with specific antipsychotics will require larger datasets, but will be critical for our understanding of the risks and benefits.

2. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

Controlled studies have shown esketamine has efficacy for treatment-resistant depression (TRD), but these studies have been only short-term, and the long-term effects of esketamine for TRD have not been established. To fill that gap, Daly et al² assessed the efficacy of esketamine nasal spray plus an oral antidepressant vs a placebo nasal spray plus an oral antidepressant in delaying relapse of depressive symptoms in patients with TRD. All patients were in stable remission after an optimization course of esketamine nasal spray plus an oral antidepressant.

Study design

• Between October 2015 and February 2018, researchers conducted a phase III, multicenter, double-blind, randomized withdrawal study to evaluate the effect of continuation of esketamine on rates of relapse in patients with TRD who had responded to initial treatment with esketamine.
• Initially, 705 adults were enrolled. Of these participants, 455 proceeded to the optimization phase, in which they were treated with esketamine nasal spray plus an oral antidepressant.
• After 16 weeks of optimization treatment, 297 participants achieved remission or stable response and were randomized to a treatment group, which received continued esketamine nasal spray plus an oral antidepressant, or to a control group, which received a placebo nasal spray plus an oral antidepressant.

Outcomes

• Treatment with esketamine nasal spray and an oral antidepressant was associated with decreased rates of relapse compared with treatment with placebo nasal spray and an oral antidepressant. This was the case among patients who had achieved remission as well as those who had achieved stable response.
• Continued treatment with esketamine decreased the risk of relapse by 51%, with 40 participants in the treatment group experiencing relapse compared with 73 participants in the placebo group.

Continue to: Conclusion

Conclusion

• In patients with TRD who responded to initial treatment with esketamine, continuing esketamine plus an oral antidepressant resulted in clinically meaningful superiority in preventing relapse compared with a placebo nasal spray plus an oral antidepressant.

3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.

Many studies have documented the efficacy of ketamine as a rapid-onset antidepressant. Studies investigating the mechanism of this effect have focused on antagonism of N-methyl-D-aspartate (NMDA) receptors. However, several clinical trials that attempted to replicate this rapid antidepressant effect with other NMDA receptor antagonists had only limited success. Williams et al³ conducted the first human study that presents evidence that opioid receptor activation may be necessary for ketamine’s acute antidepressant effect.

Study design

• This double-blind crossover study evaluated if opioid receptor activation is necessary for ketamine to have an antidepressant effect in patients with TRD.
• Twelve participants completed both sides of the study in a randomized order. Participants received placebo or naltrexone prior to an IV infusion of ketamine.
• Researchers measured patients’ scores on the Hamilton Depression Rating Scale (HAM-D) at baseline and 1 day after infusion. Response was defined as a ≥50% reduction in HAM-D score.

Outcomes

• Reductions in HAM-D scores among participants in the ketamine plus naltrexone group were significantly lower than those of participants in the ketamine plus placebo group.
• Dissociation related to ketamine use did not differ significantly between the naltrexone group and the placebo group.

Continue to: Conclusion

Conclusion

• This small study found a significant decrease in the antidepressant effect of ketamine infusion in patients with TRD when opioid receptors are blocked with naltrexone prior to infusion, which suggests opioid receptor activation is necessary for ketamine to be effective as an antidepressant.
• This appears to be consistent with observations of buprenorphine’s antidepressant effects. Caution is indicated until additional studies can further elucidate the mechanism of action of ketamine’s antidepressant effects (see "Ketamine/esketamine: Putative mechanism of action," page 32).

4. Nidich S, Mills PJ, Rainforth M, et al. Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial. Lancet Psychiatry. 2018;5(12):975-986.

Posttraumatic stress disorder (PTSD) is a common and important public health problem. Evidence-based treatments for PTSD include trauma-focused therapies such as prolonged exposure therapy (PE). However, some patients may not respond to PE, drop out, or elect not to pursue it. Researchers continue to explore treatments that are non-trauma-focused, such as mindfulness meditation and interpersonal psychotherapy. In a 3-group comparative effectiveness trial, Nidich et al⁴ examined the efficacy of a non-trauma-focused intervention, transcendental meditation (TM), in reducing PTSD symptom severity and depression in veterans.

Study design

• Researchers recruited 203 veterans with PTSD from the Department of Veterans Affairs (VA) San Diego Healthcare System between June 2013 and October 2016.
• Participants were randomly assigned to 1 of 3 groups: 68 to TM, 68 to PE, and 67 to PTSD health education (HE).
• Each group received 12 sessions over 12 weeks. In addition to group and individual sessions, all participants received daily practice or assignments.
• The Clinician-Administered PTSD Scale (CAPS) was used to assess symptoms before and after treatment.

Outcomes

• The primary outcome assessed was change in PTSD symptom severity at the end of the study compared with baseline as measured by change in CAPS score.
• Transcendental meditation was found to be significantly non-inferior to PE, with a mean change in CAPS score of −16.1 in the TM group and −11.2 in the PE group.
• Both the TM and PE groups also had significant reductions in CAPS scores compared with the HE group, which had a mean change in CAPS score of −2.5.

Continue to: Conclusion

Conclusion

• Transcendental meditation is significantly not inferior to PE in the treatment of veterans with PTSD.
• The findings from this first comparative effectiveness trial comparing TM with an established psychotherapy for PTSD suggests the feasibility and efficacy of TM as an alternative therapy for veterans with PTSD.
• Because TM is self-administered after an initial expert training, it may offer an easy-to-implement approach that may be more accessible to veterans than other treatments.

5. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Several smaller randomized trials of prazosin involving a total of 283 active-duty service members, veterans, and civilian participants have shown efficacy of prazosin for PTSD-related nightmares, sleep disturbance, and overall clinical functioning. However, in a recent trial, Raskind et al⁵ failed to demonstrate such efficacy.

Study design

• Veterans with chronic PTSD nightmares were recruited from 13 VA medical centers to participate in a 26-week, double-blind, randomized controlled trial.
• A total of 304 participants were randomized to a prazosin treatment group (n = 152) or a placebo control group (n = 152).
• During the first 10 weeks, prazosin or placebo were administered in an escalating fashion up to a maximum dose.
• The CAPS, Pittsburgh Sleep Quality Index (PSQI), and Clinical Global Impressions of Change (CGIC) scores were measured at baseline, after 10 weeks, and after 26 weeks.

Outcomes

• Three primary outcomes measures were assessed: change in score from baseline to 10 weeks on CAPS item B2, the PSQI, and the CGIC.
• A secondary measure was change in score from baseline of the same measures at 26 weeks.
• There was no significant difference between the prazosin group and the placebo group in any of the primary or secondary measures.

Continue to: Conclusion

Conclusion

• Compared with placebo, prazosin was not associated with improvement in nightmares or sleep quality for veterans with chronic PTSD nightmares.
• Because psychosocial instability was an exclusion criterion, it is possible that a selection bias resulting from recruitment of patients who were mainly in clinically stable condition accounted for these negative results, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment.

6. Yesavage JA, Fairchild JK, Mi Z, et al. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans: a randomized clinical trial. JAMA Psychiatry. 2018;75(9):884-893.

Treatment-resistant depression in veterans is a major clinical challenge because of these patients’ increased risk of suicide. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results for TRD. In a randomized trial, Yesavage et al⁶ compared rTMS vs sham rTMS in veterans with TRD.

Study design

• Veterans with TRD were recruited from 9 VA medical centers throughout the United States between September 2012 and May 2016.
• Researchers randomized 164 participants into 1 of 2 groups in a double-blind fashion. The treatment group (n = 81) received left prefrontal rTMS, and the control group (n = 83) received sham rTMS.

Outcomes

• In an intention-to-treat analysis, remission rate (defined as a HAM-D score of ≤10) was assessed as the primary outcome measure.
• Remission was seen in both groups, with 40.7% of the treatment group achieving remission and 37.4% of the control group achieving remission. However, the difference between the 2 groups was not significant (P = .67), with an odds ratio of 1.16.

Continue to: Conclusion

Conclusion

• In this study, treatment with rTMS did not show a statistically significant difference in rates of remission from TRD in veterans compared with sham rTMS. This differs from previous rTMS trials in non-veteran patients.
• The findings of this study also differed from those of other rTMS research in terms of the high remission rates that were seen in both the active and sham groups.

Bottom Line

The risk of death might be increased in children and young adults who receive highdose antipsychotics. Continued treatment with intranasal esketamine may help prevent relapse in patients with treatment-resistant depression (TRD) who initially respond to esketamine. The antidepressant effects of ketamine might be associated with opioid receptor activation. Transcendental meditation may be helpful for patients with posttraumatic stress disorder (PTSD), while prazosin might not improve nightmares or sleep quality in patients with PTSD. Repetitive transcranial magnetic stimulation (rTMS) might not be any more effective than sham rTMS for veterans with TRD.

Related Resources

• NEJM Journal Watch. www.jwatch.org.
• F1000 Prime. https://f1000.com/prime/home.
• BMJ Journals Evidence-Based Mental Health. https://ebmh.bmj.com.

Drug Brand Names

Buprenorphine • Subutex
Chlorpromazine • Thorazine
Esketamine nasal spray • Spravato
Ketamine • Ketalar
Naltrexone • Narcan
Prazosin • Minipress

To the readers of Current Psychiatry,

The American Psychiatric Association (APA) informed me on 12-27-19 that my editorial in the December issue about my candidacy for APA President-Elect was unfair to the other candidates because they should have been invited to publish their own statements side-by-side with mine. I was not aware of this because the APA election rules allow a candidate to blog or write on all social media or to send a mass mailing unilaterally. I take full responsibility for my mistake and decided to inform the APA Board of Trustees that I am withdrawing my candidacy for APA President-Elect. I hope the elections will go smoothly and wish the APA well.

Please note that my loyalty to the APA is very strong. That’s why my January 2020 editorial strongly urges all psychiatrists to join (or rejoin) the APA because unity will make it more possible for us to advocate for our patients, increase access to mental health, eliminate stigma, achieve true parity, and raise the profile of psychiatry as a medical discipline.

As you may have read in my campaign statement, one of my major goals as a candidate was to change the name of the APA to the American Psychiatric Physicians Association, or APPA. This name change is critical so that the public knows our medical identity. It also will differentiate us from the other APA (American Psychological Association), which is the first to appear when anyone enters APA on Google or other search engines. I will lobby vigorously with the current APA president, the APA CEO, and whoever becomes President-Elect to get this name change approved by the Board of Trustees. I am very sure that the vast majority of psychiatrists will support such a name change.

Thank you and I hope 2020 will be a happy and healthy year for all of you, and for all our psychiatric patients.

To the readers of Current Psychiatry,

The American Psychiatric Association (APA) informed me on 12-27-19 that my editorial in the December issue about my candidacy for APA President-Elect was unfair to the other candidates because they should have been invited to publish their own statements side-by-side with mine. I was not aware of this because the APA election rules allow a candidate to blog or write on all social media or to send a mass mailing unilaterally. I take full responsibility for my mistake and decided to inform the APA Board of Trustees that I am withdrawing my candidacy for APA President-Elect. I hope the elections will go smoothly and wish the APA well.

Please note that my loyalty to the APA is very strong. That’s why my January 2020 editorial strongly urges all psychiatrists to join (or rejoin) the APA because unity will make it more possible for us to advocate for our patients, increase access to mental health, eliminate stigma, achieve true parity, and raise the profile of psychiatry as a medical discipline.

As you may have read in my campaign statement, one of my major goals as a candidate was to change the name of the APA to the American Psychiatric Physicians Association, or APPA. This name change is critical so that the public knows our medical identity. It also will differentiate us from the other APA (American Psychological Association), which is the first to appear when anyone enters APA on Google or other search engines. I will lobby vigorously with the current APA president, the APA CEO, and whoever becomes President-Elect to get this name change approved by the Board of Trustees. I am very sure that the vast majority of psychiatrists will support such a name change.

Thank you and I hope 2020 will be a happy and healthy year for all of you, and for all our psychiatric patients.

To the readers of Current Psychiatry,

The American Psychiatric Association (APA) informed me on 12-27-19 that my editorial in the December issue about my candidacy for APA President-Elect was unfair to the other candidates because they should have been invited to publish their own statements side-by-side with mine. I was not aware of this because the APA election rules allow a candidate to blog or write on all social media or to send a mass mailing unilaterally. I take full responsibility for my mistake and decided to inform the APA Board of Trustees that I am withdrawing my candidacy for APA President-Elect. I hope the elections will go smoothly and wish the APA well.

Please note that my loyalty to the APA is very strong. That’s why my January 2020 editorial strongly urges all psychiatrists to join (or rejoin) the APA because unity will make it more possible for us to advocate for our patients, increase access to mental health, eliminate stigma, achieve true parity, and raise the profile of psychiatry as a medical discipline.

As you may have read in my campaign statement, one of my major goals as a candidate was to change the name of the APA to the American Psychiatric Physicians Association, or APPA. This name change is critical so that the public knows our medical identity. It also will differentiate us from the other APA (American Psychological Association), which is the first to appear when anyone enters APA on Google or other search engines. I will lobby vigorously with the current APA president, the APA CEO, and whoever becomes President-Elect to get this name change approved by the Board of Trustees. I am very sure that the vast majority of psychiatrists will support such a name change.

Thank you and I hope 2020 will be a happy and healthy year for all of you, and for all our psychiatric patients.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

Advances in neuroimaging over the past 25 years have allowed for an increasingly sophisticated understanding of the structural and functional brain abnormalities associated with psychiatric disease.¹ It has been postulated that a better understanding of aberrant brain circuitry in psychiatric illness will be critical for transforming the diagnosis and treatment of these illnesses.² In fact, in 2008, the National Institute of Mental Health launched the Research Domain Criteria project to reformulate psychiatric diagnosis based on biologic underpinnings.³

In the midst of these scientific advances and the increased availability of neuroimaging, some private clinics have begun to offer routine brain scans as part of a comprehensive psychiatric evaluation.^4-7 These clinics suggest that single-photon emission computed tomography (SPECT) of the brain can provide objective, reliable psychiatric diagnoses. Unfortunately, using SPECT for psychiatric diagnosis lacks empirical support and carries risks, including exposing patients to radioisotopes and detracting from empirically validated treatments.⁸ Nonetheless, given the current diagnostic challenges in psychiatry, it is understandable that patients, parents, and clinicians alike have reported high receptivity to the use of neuroimaging for psychiatric diagnosis and treatment planning.⁹

While neuroimaging is central to the search for improved understanding of the biologic foundations of mental illness, progress in identifying biomarkers has been disappointing. There are currently no neuroimaging biomarkers that can reliably distinguish patients from controls, and no empirical evidence supports the use of neuroimaging in diagnosing psychiatric conditions.¹⁰ The current standard of clinical care is to use neuroimaging to diagnose neurologic diseases that are masquerading as psychiatric disorders. However, given the rapid advances and availability of this technology, determining if and when neuroimaging is clinically indicated will likely soon become increasingly complex. Prior to the widespread availability of this technology, it is worth considering the potential advantages and pitfalls to the adoption of neuroimaging in psychiatry. In this article, we:

• outline arguments that support the use of neuroimaging in psychiatry, and some of the limitations
• discuss special considerations for patients with first-episode psychosis (FEP) and forensic psychiatry
• suggest guidelines for best-practice models based on the current evidence.

Advantages of widespread use of neuroimaging in psychiatry

Currently, neuroimaging is used in psychiatry to rule out neurologic disorders such as seizures, tumors, or infectious illness that might be causing psychiatric symptoms. If neuroimaging were routinely used for this purpose, one theoretical advantage would be increased neurologic diagnostic accuracy. Furthermore, increased adoption of neuroimaging may eventually help broaden the phenotype of neurologic disorders. In other words, psychiatric symptoms may be more common in neurologic disorders than we currently recognize. A second advantage might be that early and definitive exclusion of a structural neurologic disorder may help patients and families more readily accept a psychiatric diagnosis and appropriate treatment.

In the future, if biomarkers of psychiatric illness are discerned, using neuroimaging for diagnosis, assessment, and treatment planning may help increase objectivity and reduce the stigma associated with mental illness. Currently, psychiatric diagnoses are based on emotional and behavioral self-report and clinical observations. It is not uncommon for patients to receive different diagnoses and even conflicting recommendations from different clinicians. Tools that aid objective diagnosis will likely improve the reliability of the diagnosis and help in assessing treatment response. Also, concrete biomarkers that respond to treatment may help align psychiatric disorders with other medical illnesses, thereby decreasing stigma.

Cautions against routine neuroimaging

There are several potential pitfalls to the routine use of neuroimaging in psychiatry. First, clinical psychiatry is centered on clinical acumen and the doctor–patient relationship. Many psychiatric clinicians are not accustomed to using lab measures or tests to support the diagnostic process or treatment planning. Psychiatrists may be resistant to technologies that threaten clinical acumen, the power of the therapeutic relationship, and the value of getting to know patients over time.¹¹ Overreliance on neuroimaging for psychiatric diagnosis also carries the risk of becoming overly reductionistic. This approach may overemphasize the biologic aspects of mental illness, while excluding social and psychological factors that may be responsive to treatment.

Second, the widespread use of neuroimaging is likely to result in many incidental findings. This is especially relevant because abnormality does not establish causality. Incidental findings may cause unnecessary anxiety for patients and families, particularly if there are minimal treatment options.

Continue to: Third, it remains unclear...

Third, it remains unclear whether widespread neuroimaging in psychiatry will be cost-effective. Unless imaging results are tied to effective treatments, neuroimaging is unlikely to result in cost savings. Presently, patients who can afford out-of-pocket care might be able to access neuroimaging. If neuroimaging were shown to improve clinical outcomes but remains costly, this unequal distribution of resources would create an ethical quandary.

Finally, neuroimaging is complex and almost certainly not as objective as one might hope. Interpreting images will require specialized knowledge and skills that are beyond those of currently certified general psychiatrists.¹² Because there is a great deal of overlap in brain anomalies across psychiatric illnesses, it is unclear whether using neuroimaging for diagnostic purposes will eclipse a thorough clinical assessment. For example, the amygdala and insula show activation across a range of anxiety disorders. Abnormal amygdala activation has also been reported in depression, bipolar disorder, schizophrenia, and psychopathy.¹³

In addition, psychiatric comorbidity is common. It is unclear how much neuro­imaging will add diagnostically when a patient presents with multiple psychiatric disorders. Comorbidity of psychiatric and neurologic disorders also is common. A neurologic illness that is detectable by structural neuroimaging does not necessarily exclude the presence of a psychiatric disorder. This poses yet another challenge to developing reliable, valid neuroimaging techniques for clinical use.

Areas of controversy

First-episode psychosis. Current practice guidelines for neuroimaging in patients with FEP are inconsistent. The Canadian Choosing Wisely Guidelines recommend against routinely ordering neuroimaging in first-episode psychoses in the absence of signs or symptoms that suggest intracranial pathology.¹⁴ Similarly, the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia recommends ordering neuroimaging in patients for whom the clinical picture is unclear or when examination reveals abnormal findings.¹⁵ In contrast, the Australian Clinical Guidelines for Early Psychosis recommend that all patients with FEP receive brain MRI.¹⁶ Freudenreich et al¹⁷ describe 2 philosophies regarding the initial medical workup of FEP: (1) a comprehensive medical workup requires extensive testing, and (2) in their natural histories, most illnesses eventually declare themselves.

Despite this inconsistency, the overall evidence does not seem to support routine brain imaging for patients with FEP in the absence of neurologic or cognitive impairment. A systematic review of 16 studies assessing the clinical utility of structural neuroimaging in FEP found that there was “insufficient evidence to suggest that brain imaging should be routinely ordered for patients presenting with first-episode psychosis without associated neurological or cognitive impairment.”¹⁸

Continue to: Forensic psychiatry

Forensic psychiatry. Two academic disciplines—neuroethics and neurolaw—attempt to study how medications and neuroimaging could impact forensic psychiatry.¹⁹ And in this golden age of neuroscience, psychiatrists specializing in forensics may be increasingly asked to opine on brain scans. This requires specific thoughtfulness and attention because forensic psychiatrists must “distinguish neuroscience from neuro-nonsense.”²⁰ These specialists will need to consider the Daubert standard, which resulted from the 1993 case Daubert v Merrell Dow Pharmaceuticals, Inc.²¹ In this case, the US Supreme Court ruled that evidence must be “‘generally accepted’ as reliable in the relevant scientific community” to be admissible. According to the Daubert standard, “evidentiary reliability” is based on scientific validity.²¹

How should we use neuroimaging?

While neuroimaging is a quickly evolving research tool, empirical support for its clinical use remains limited. The hope is that future neuroimaging research will yield biomarker profiles for mental illness, identification of risk factors, and predictors of vulnerability and treatment response, which will allow for more targeted treatments.¹

The current standard of clinical care for using neuroimaging in psychiatry is to diagnose neurologic diseases. Although there are no consensus guidelines for when to order imaging, it is reasonable to consider imaging when a patient has²²:

• abrupt onset of symptoms
• change in level of consciousness
• deficits in neurologic or cognitive examination
• a history of head trauma (with loss of consciousness), whole-brain radiation, neuro­logic comorbidities, or cancer
• late onset of symptoms (age >50)
• atypical presentation of psychiatric illness.

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Although they are rare, in-flight psychiatric emergencies occur because of large numbers of passengers, nonstop flights over longer distances, delayed flights, cramped cabins, and/or alcohol consumption.^1,2 Psychiatric symptoms and substance intoxication/withdrawal each represent up to 3% of all in-flight emergencies, and in most cases (90%), the primary presentation is acute anxiety.^1,2 Common in-flight psychiatric differential diagnoses include depression, psychosis, personality disorders, and somatization.¹

When a passenger requires medical or psychiatric treatment, the flight crew often requests aid from any trained medical professionals who are on board to augment their capabilities and resources (eg, the flight crew’s training, ground-based medical support).¹ In the United States, off-duty medical professionals are not legally required to assist during an in-flight medical emergency.¹ The Aviation Medical Assistance Act of 1998 protects passengers who provide medical assistance from liability, except in cases of gross negligence or willful misconduct.^1,3 Flights outside of the United States are governed by a complex combination of public and private international laws.¹ Here I suggest how to initiate care during in-flight psychiatric emergencies, and offer therapeutic options to employ for a passenger who is exhibiting psychiatric symptoms.

What to do first

Before volunteering to assist in a mental health emergency, consider your capabilities and limitations. Do not volunteer if you are under the influence of alcohol, illicit substances, or any medications (prescription or over-the-counter) that could affect your judgment.

Inform the flight crew that you are a mental health clinician, and outline your current clinical expertise. While the flight crew obtains the medical emergency kit, work to establish rapport with the passenger to identify the psychiatric problem and help de-escalate the situation. Initiate care by¹:

• eliciting a psychiatric history
• inquiring about any use of alcohol, illicit substances, or other mood-altering substances (eg, type, amount, and time of use)
• identifying any use of psychotropic medications (eg, doses, last dose taken, and if these agents are on the aircraft).

The Federal Aviation Administration has minimum requirements for the contents of medical emergency kits aboard US airlines.^1,4 However, they are not required to contain antipsychotics, naloxone, or benzodiazepines.^1,4 Although you may have limited medical resources at your disposal, you can still help passengers in the following ways¹:

Monitor vital signs and mental status changes, identify signs and symptoms of intoxication or withdrawal, and assess for respiratory distress. Provide reassurance to the passenger if appropriate.¹

Administer naloxone (if available) for suspected opioid ingestion.¹ Antiemetics, which are available in these medical kits, can be used if needed. Encourage passengers to remain hydrated and use oxygen as needed.

Continue to: If verbal de-escalation is ineffective...

If verbal de-escalation is ineffective, consider administering a benzodiazepine or antipsychotic (if available).¹ If the passenger is combative, refer to the flight crew for the airline’s security protocols, which may include restraining the passenger or diverting the aircraft. Safety takes priority over attempts at medical management.

If the passenger has respiratory distress, instruct the flight crew to contact ground-based medical support for additional recommendations.¹

A challenging situation

Ultimately, the pilot coordinates with the flight dispatcher to manage all operational decisions for the aircraft and is responsible for decisions regarding flight diversion.¹ In-flight medical volunteers, the flight crew, and ground-based medical experts can offer recommendations for care.¹ Cruising at altitudes of 30,000 to 40,000 feet with limited medical equipment, often hours away from the closest medical facility, will create unfamiliar challenges for any medical professional who volunteers for in-flight psychiatric emergencies.¹

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

Note: Dr. Nasrallah has withdrawn his candidacy for APA President-Elect. For a statement of explanation click here.

I have been informed by the American Psychiatric Association (APA) Nominating Committee that I am a candidate for the position of APA President-Elect. I am honored to be nominated along with 2 other esteemed psychiatrists, David C. Henderson, MD, and Vivian B. Pender, MD.

You have all known me for many years as Editor-in-Chief of this journal, and probably have read many of my 150 editorials in which I frequently discussed and commented on not only the challenges that face psychiatry, but also the great promise and bright future of our evolving clinical neuro­science medical specialty. You can access all of these at MDedge.com/psychiatry/editor.

In this pre-election editorial, I would like to tell you about my qualifications as a candidate for this critical national psychiatry leadership role. Most of you are APA members who will have the opportunity to vote for the candidate of your choice from January 2 to 31, 2020. I hope that you will support my candidacy after learning about my long-standing involvement within the APA governance, as well as my 3 decades of academic leadership experience and productivity. You also know where I stand on the issues from my writings in Current Psychiatry.

APA involvement

• President, Missouri Psychiatric Physicians Association District Branch (2017-2018)
• President, Cincinnati Psychiatric Society (2007-2009)
• President, Ohio Psychiatric Physi­cians Foundation (2008-2013)
• Editor, Ohio Psychiatric Physicians Association (OPPA) Newsletter (Insight Matters) (2003-2008)
• Executive Council, OPPA (2003-2013)
• APA Council on Research (1993-2000)
• APA Committee on Research in Psychiatric Treatments (1992-1995)
• APA Task Force on Schizophrenia (1998-1999)
• President, Ohio Psychiatric Asso­ciation Education and Research Foundation (1987-1994)

Academic track record

• Served as Chief of Psychiatry, VA Medical Center, Iowa City, Iowa for 6 years; Chair, Department of Psychiatry, The Ohio State University for 12 years; Chair, Department of Psychiatry, Saint Louis University for 6 years; and Associate Dean, University of Cincinnati for 4 years
• Published >700 articles, 570 abstracts, and 14 books
• Recruited and developed dozens of faculty members; supervised and mentored hundreds of residents, many of whom became medical directors, department chairs, and/or distinguished clinicians
• Received numerous awards and recognitions for clinical, teaching, and research excellence
• Serve as Editor for 3 journals (Current Psychiatry, Schizophrenia Research, and Biomarkers in Neuro­­­­psychiatry)

Statement of vision and priorities

I am very optimistic about the future of psychiatry. The breakthroughs and advances in neuroscience all bolster the scientific basis of psychiatric disorders, and will lead to many novel treatments in the future. Psychiatry is a medical specialty that is now much more integrated into the “big tent” of medicine. Psychiatrists are physicians, and I believe the name of our association must reflect that. I was successful in changing the names of 2 district branches to include “physicians” (Ohio Psychiatric Physicians Association and Missouri Psychiatric Physicians Association). If elected, I will propose to the Board of Trustees and the APA members that we change our name to the American Psychiatric Physicians Association, which will emphasize our medical identity within mental health. In its 175-year history, the APA has experienced 2 previous name changes.

I believe the strengths of the APA far exceed its weaknesses, and its opportunities outnumber its threats. However, the following perennial challenges must be forcefully addressed by all of us:

1. The pernicious and discriminatory dogma of stigma must be shattered for the sake of patients, their families, their psychiatrists, and the profession.
2. Pre-authorization is essentially the insurance companies practicing medicine without a license when, without ever actually examining the patient, they tell physicians what they should or should not prescribe. That’s felonious!
3. Competent and safe prescribing is the culmination of extensive medical training (approximately 14,000 hours) and psychologists do not qualify.
4. Board certification fees must be reduced, and recertification (Maintenance of Certification) must be simpler and less onerous.
5. Effective parity laws must have teeth, not just words!
6. Patient care, not computer care! Electronic health records must be more user-friendly and less time-consuming.
7. Patients with psychiatric illness who have relapsed must be surrounded by compassionate medical professionals in a hospital setting, not by armed guards in a jail or prison.
8. The shortage of psychiatrists can be remedied if the government funds additional residency slots as it did in the 1960s and 1970s. The number of applicants for psychiatric training is rapidly rising, but the number of residency slots has not changed for decades. Approximately 100 US medical school graduates did not match last year, along with >1,000 international medical graduate applicants.
9. Lawyers have clients; psychiatrists have patients (as do cardiologists, neuro­logists, and oncologists). The term “clients” de-medicalizes psychiatric disorders and does not evoke public support or compassion.
10. Psychotherapy is in fact a neurobiologic treatment that repairs the mind via neuroplasticity and synaptogenesis. It should get the same respect as pharmacotherapy.
11. Untether psychiatric reimbursement from “time”! Psychiatric assessment and treatment are medical procedures. Excising depression, psychosis, panic attacks, or suicidal urges are to the mind what surgery is to the body.
12. Clinical psychiatrists have much to offer for medical advances. Their observations generate hypotheses, and if these are published as a case report or letter to the editor, researchers can conduct hypothesis-testing and discover new treatments thanks to astute clinicians.
13. The FDA should allow clinical trials to investigate treatments of symptoms, not (often heterogenous) DSM diagnoses. This will enable “off-label use” of medication, which often is necessary.

Continue to: Annual dues

Annual dues. The APA is a great organization that should continue to re-invent itself and re-engineer its procedures and business practices to generate additional revenue streams that could help reduce its annual dues. I know many members who complain about the APA dues, and former members who dropped out because of what they consider to be high dues. I try to remind them that the dues are on average a modest .3% to .5% of a psychiatrist’s annual income, and that all of us must unite within our association in order to have the collective power to achieve our goals and solve our challenges.

Public education. The APA must intensify public education across all media platforms. This will help dispel myths, eliminate stigma, enforce parity, and portray psychiatry as a medical and scientific discipline. We have a great story to tell about how neurologic circuitry generates the mind and its mental functions, and the neuro­biologic foundations of psychiatric brain disorders.

The APA should advocate for (and perhaps organize) an annual mental health check-up (online) in children, adolescents, adults, and the elderly for early detection and intervention.

Collaborative care. We should have close relationships with obstetricians to help prevent neurodevelopmental pathology due to perinatal complications as well as to manage depression in women in the pre- and postpartum phases. Collaborative care with pediatricians, family physicians, internists, and neurologists is necessary to integrate physical and mental health care for our patients, many of whom have multiple medical comorbidities and premature mortality.

Lobbying. The APA must intensify its lobbying to address the unacceptably high rate of suicide, addiction-related deaths, posttraumatic stress disorder due to trauma in children and adults, threats to mental health due to climate change and pollution, refugee mental health, stressful political zeitgeist, and the woefully high rate of uninsured or under-insured individuals.

Continue to: Industry

Industry. There are many significant unmet treatment needs in psychiatry. Approximately 82% of DSM disorders do not have any FDA-approved medication. The APA should constructively engage the pharmaceutical industry (the only entity that develops medications for our patients!) to do more research and development of therapies for conditions with no approved treatments, and to explore new mechanisms of action for more effective or tolerable psychiatric medications. Importantly, the APA should urge major pharmaceutical companies not to abandon neuropsychiatric disorders because they afflict tens of millions of US citizens and are the top causes of long-term disabilities.

Journals. The APA should consider rebranding its journals as “JAPA,” similar to JAMA, which will widen its influence and generate revenue to fund various priorities.

Telepsychiatry. And why can’t the APA create a national telepsychiatry network to meet the needs of underserved populations who have very little access to psychiatric care as in many rural areas? Private companies have filled that space, but the APA and its members can do it better, and this can become a benefit of membership.

Brain bank. Finally, the APA should consider establishing a “Brain Bank” of various psychiatric subspecialties to consult and advise the military, college administrators, corporations, and government agencies about strategies and tactics to solve many problems that arise from overt or covert psychiatric illnesses among their employees, staff, students, or constituents.

The APA cannot solve all societal problems, but it has the moral authority and clinical/scientific depth and gravitas to create an agenda of solutions and to partner with many other stakeholders to achieve mutual societal health goals.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) scale is a well-established protocol that attempts to measure the degree of alcohol and benzodiazepine withdrawal. The CIWA-Ar scale measures 10 domains and indexes the severity of withdrawal on a scale from 0 to 67; scores >8 are generally considered to be indicative of at least mild-to-moderate withdrawal, and scores >20 represent significant withdrawal.¹ Despite its common use in many medical settings, the CIWA-Ar scale has been impugned as a less-than-reliable index of true alcohol withdrawal² and has the potential for misuse among ordering physicians.³ In this case report, I describe a malingering patient who intentionally and successfully feigned symptoms of alcohol withdrawal, which demonstrates that the purposeful reproduction of symptoms measured by the CIWA-Ar scale can render the protocol clinically useless.

CASE REPORT

Mr. G, a 63-year-old African-American man, was admitted to the general medical floor with a chief complaint of alcohol withdrawal. He had a history of alcohol use disorder, severe, and unspecified depression. He said he had been drinking a gallon of wine plus “a fifth” of vodka every day for the past 1.5 months. More than 1 year ago, he had been admitted for alcohol withdrawal with subsequent delirium tremens, but he denied having any other psychiatric history.

In the emergency department, Mr. G was given IV lorazepam, 6 mg total, for alcohol withdrawal. He was reported to be “scoring” on the CIWA-Ar scale with apparently uncontrollable tremulousness, visual hallucinations, and confusion. His vitals were within normal limits, his mean corpuscular volume and lipase level were within normal limits, and the rest of his presentation was largely unremarkable.

Once admitted to the general medical floor, he continued to receive benzodiazepines for what was documented as severe alcohol withdrawal. When clinical staff were not in the room, the patient was observed to be resting comfortably without tremulousness. When the patient was seen by the psychiatry consultation service, he produced full body tremulousness with marked shoulder and hip thrusting. His account of how much he had been drinking contradicted the amount he reported to other teams in the hospital. When the consulting psychiatrist appeared unimpressed by his full body jerking, the patient abruptly pointed to the corner of the room and yelled “What is that?” when nothing was there. When the primary medical team suggested to the patient that his vitals were within normal limits and he did not appear to be in true alcohol withdrawal, the patient escalated the degree of his full body jerking.

Over the next few days, the patient routinely would tell clinical staff “I’m having DTs.” He also specifically requested lorazepam. After consultation, the medical and psychiatry teams determined the patient was feigning symptoms of alcohol withdrawal. The lorazepam was discontinued, and the patient was discharged home with outpatient psychiatric follow-up.

Limitations of the CIWA-Ar scale

The CIWA-Ar scale is intended to guide the need for medications, such as benzodiazepines, to help mitigate symptoms of alcohol withdrawal. Symptom-triggered benzodiazepine treatment has been shown to be superior to fixed-schedule dosing.⁴ However, symptom-triggered treatment is problematic in the setting of feigned symptoms.

When psychiatrists and nurses calculate a CIWA-Ar score, they rely on both subjective accounts of a patient’s withdrawal severity as well as objective signs, such as vitals and a physical examination. Many of the elements included in the CIWA-Ar scale can be easily feigned (Table). Feigned alcohol withdrawal may fall into 2 categories: (1) the false reporting of subjective symptoms, and (2) the false portrayal of objective signs.

Continue to: The false reporting...

The false reporting of subjective symptoms can include the reported presence of nausea or vomiting, anxiety, tactile hallucinations, auditory hallucinations, headache or head fullness, and visual hallucinations. The false portrayal of objective signs can include the feigning of tremulousness, agitation, and confusion (eg, incorrectly answering orienting questions). In both categories, the simple presence of these signs or symptoms, whether falsely reported or falsely portrayed, would cause the patient to “score” on the CIWA-Ar scale.

Thus, the need to effectively rule out feigned symptoms is essential because inappropriate dosing of benzodiazepines can be dangerous, costly, and utilize limited hospital resources that could otherwise be diverted to a patient with a true medical or psychiatric illness. In these instances, it is crucial to pay close attention to vital signs because these are more reliable indices of withdrawal. A patient’s ability to purposefully feign symptoms of alcohol withdrawal highlights the limitations of the CIWA-Ar scale as a validated measure of alcohol withdrawal, and renders it effectively useless in the setting of either malingering or factitious disorder.

Resnick⁵ describes malingering as either pure malingering, partial malingering, or false imputation. Pure malingering refers to the feigning of a nonexistent disorder or illness. Partial malingering refers to the exaggeration of symptoms that are present, but to a lesser degree. False imputation refers to the attribution of symptoms from a separate disorder to one the patient knows is unrelated (eg, attributing chronic low back pain from a prior sports injury to a recent motor vehicle accident). In Mr. G’s case, he had multiple prior admissions for true, non-feigned alcohol withdrawal with subsequent delirium tremens. His knowledge of the signs and symptoms of alcohol withdrawal therefore helped him make calculated efforts to manipulate clinical staff in his quest to obtain benzodiazepines. Whether this was pure or partial malingering remained unclear because Mr. G’s true level of withdrawal could not be adequately assessed.

Potentially serious consequences

The CIWA-Ar scale is among the most widely used scales to determine the level of alcohol withdrawal and need for subsequent benzodiazepine treatment. However, its effective use is limited because it relies on subjective symptoms and objective signs that can be easily feigned or manipulated. In the setting of malingering or factitious disorder, when a patient is feigning symptoms of alcohol withdrawal, the CIWA-Ar scale may be rendered clinically useless. This can lead to dangerous iatrogenic adverse effects, lengthy and nontherapeutic hospital stays, and an increasing financial burden on health care systems.

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

• an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
• a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
• the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

Psychotropic medications and black-box warnings

Psychotropic medications have a large number of black-box warnings.¹⁴ Because it is difficult to find black-box warnings for multiple medications in one place, we have provided 2 convenient resources to address this gap: a concise summary guide (Table 3) and a more detailed database (Table 4, Table 5, Table 6, Table 7, and Table 8). In these Tables, the possible risk mitigations, off-label uses, and monitoring are not meant to be formal recommendations or endorsements but are for independent clinician consideration only.

The information in these Tables was drawn from publicly available data, primarily the Micromedex and FDA web sites (see Related Resources). Because this information changes over time, at the end of this article we suggest ways for clinicians to stay updated with black-box warnings and build on the information provided in this article. These tools can be useful for day-to-day clinical practice in addition to studying for professional examinations. The following are selected high-profile black-box warnings.

Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Initially issued in 2005, this warning was extended in 2007 to indicate that depression itself is associated with an increased risk of suicide. This black-box warning is used for an entire class of medications as well as for a specific patient population (age ≤24). Moreover, it indicates that suicide rates in patients age >65 were lower among patients using antidepressants.

Among psychotropic medication black-box warnings, this warning has perhaps been the most controversial. For example, it has been suggested that this black-box warning may have inadvertently increased suicide rates by discouraging clinicians from prescribing antidepressants,¹⁵ although this also has been called into question.¹⁶ This black-box warning illustrates that the consequences of issuing black-box warnings can be very difficult to assess, which makes their clinical effects highly complex and challenging to evaluate.¹⁴

Antipsychotics and dementia-related psychosis. This warning was initially issued in 2005 for second-generation antipsychotics and extended to first-generation antipsychotics in 2008. Anti­psychotics as a class carry a black-box warning for increased risk of death in patients with dementia (major neuro­cognitive disorder). This warning extends to the recently approved antipsychotic pimavanserin, even though this agent’s proposed mechanism of action differs from that of other antipsychotics.¹⁷ However, it specifically allows for use in Parkinson’s disease psychosis, which is pimavanserin’s indication.¹⁸ In light of recent research suggesting pimavanserin is effective in dementia-related psychosis,¹⁹ it bears watching whether this agent becomes the first antipsychotic to have this warning removed.

Continue to: This class warning has...

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

Improving documentation of treatment decisions. Fluent knowledge of black-box warnings may help clinicians improve documentation of their treatment decisions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians accurately document both their awareness of these risks, and how these risks informed their risk-benefit analysis in specific clinical situations.

Despite the clear importance the FDA places on black-box warnings, they are not often a topic of study in training or in postgraduate continuing education, and as a result, not all clinicians may be equally conversant with black-box warnings. While black-box warnings do change over time, many psychotropic medication black-box warnings are long-standing and well-established, and they evolve slowly enough to make mastering these warnings worthwhile in order to make the most informed clinical decisions for patient care.

Keeping up-to-date

There are practical and useful ways for busy clinicians to stay up-to-date with black-box warnings. Although these resources exist in multiple locations, together they provide convenient ways to keep current.

The FDA provides access to black-box warnings via its comprehensive database, DRUGS@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). Detailed information about REMS (and corresponding ETASU and other information related to REMS programs) is available at REMS@FDA (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm). Clinicians can make safety reports that may contribute to FDA decision-making on black-box warnings by contacting MedWatch (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program), the FDA’s adverse events reporting system. MedWatch releases safety information reports, which can be followed on Twitter @FDAMedWatch. Note that FDA information generally is organized by specific drug, and not into categories, such as psychotropic medications.

BlackBoxRx (www.blackboxrx.com) is a subscription-based web service that some clinicians may have access to via facility or academic resources as part of a larger FormWeb software package. Individuals also can subscribe (currently, $89/year).

Continue to: Micromedex

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

• US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
• US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
• BlackBoxRx. www.blackboxrx.com. (Subscription required.)
• Mircromedex. www.micromedex.com. (Subscription required.)
• ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien