Current Psychiatry

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Seeing friends
Mr. B, age 91, presents to the emergency room (ER) for hip pain. As he is being evalu­ated, he asks a nurse to tell the “other people” around her to leave so that he can have pri­vacy. As clarification, Mr. B reports visual hal­lucinations, which prompts the ER physician to request a psychiatry consult.

Mr. B is alert and oriented to time, place, and person when he is evaluated by the on-call psychiatry resident. He reports that he has been seeing several unusual things for the last 4 to 5 months. Asked to elaborate, Mr. B admits seeing colorful and vivid images of people around him. These people come and go as they like; rarely, they talk to him. He describes the conversations as “a constant chatter” in the background and adds that it is difficult to understand what they are talking about.

Mr. B states that he has been “seeing” a cou­ple of people on a regular basis, and they are “sort of like my friends.” He endorses that these people often sing songs or dance for him. He states that, sometimes, these “friends” bring 3 or 4 friends and, although he could not make out their faces clearly, “they all are around me.” He describes the people he sees as “nice people” and does not report being scared or frightened by them.

Mr. B does not report paranoia, and denies command-type hallucinations. He and his family report no unusual changes in behavior in recent months. The medical history is remarkable for atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease, age-related macular degeneration, and glaucoma.

Mr. B denies having any ongoing mood or anxiety symptoms. He states that he knows these people are “probably not real,” and they do not bother him and just keep him company.

What could be causing Mr. B’s hallucinations?
   a) a stroke
   b) late-onset schizophrenia
   c) dementia
   d) Charles Bonnet syndrome

The authors’ observations
Visual hallucinations among geriatric pa-tients are a common and confusing pre­sentation. In addition to several medical causes for this presentation (Table 1), con­sider Charles Bonnet syndrome in patients with visual loss, presenting as visual hal­lucinations with intact insight and absence of a mental illness. Other conditions to con­sider in the differential diagnosis include Parkinson’s disease, dementia with Lewy bodies, schizophrenia, seizures, migraine, and stroke, including lesions of the thala­mus or brain stem.

Charles Bonnet syndrome was first described by Swiss philosopher Charles Bonnet in the 18th century. He reported vivid visual hallucinations in his visually impaired grandfather (bilateral cataracts).¹

It is important to recognize this syn­drome because patients can present across different specialties, including psychia­try, ophthalmology, neurology, geriat­ric medicine, and family medicine.² As life expectancy increases, this condition might be seen more often. It is prudent to identify, intervene, and refer as appropri­ate, in addition to educating patients and caregivers about the nature and course of the condition. 

EVALUATION Not psychotic
Mr. B reports good sleep and appetite. He denies using alcohol or illicit drugs. He states he slipped in the bathroom the day before coming to the ER, but denies other recent falls or injuries. Other than hip pain, he has no other physical complaints. His medication regimen includes aspirin, lisinopril, lovastatin, and metoprolol.

The ER team diagnoses a hip fracture. Mr. B is transferred to the orthopedic service; the psychiatry consult team continues to fol­low him. Mental status examination is unre­markable other than the visual hallucinations. His speech is clear, non-pressured, with goal-directed thought processing. Mini-Mental State Examination score is 23/30 with Mr. B having difficulty with object drawing and 3-object recall. Brief cognitive examination in the ER is unremarkable.

The orthopedic team decides on conserva­tive management of the hip fracture. There is no evidence of infection. Mr. B is afebrile with clear sensorium; complete blood cell count and normal liver function tests are normal; urinalysis and urine drug screen are negative; and chest radiography is unremarkable. CT and MRI of the head are unremarkable.

After 1 week in the hospital, Mr. B contin­ues to experience vivid visual imagery. No signs of active infection are found. An oph­thalmologist is consulted, who confirms Mr. B’s earlier diagnosis of glaucoma and age-related macular degeneration but does not recommend further treatment. Visual field test by confrontation is normal, with normal visual reflexes.

The authors’ observations
The reported prevalence of Charles Bonnet syndrome among visually impaired peo­ple varies from study to study—from as low as 0.4% to as high as 63%.^3-6 The rea­son for such variation can be attributed to several variables:
   • underdiagnosis
   • misdiagnosis
   • underreporting by patients because of the benign nature of the hallucinations
   • patients’ reluctance to report visual hallucinations because of fear of being labeled “mentally ill.”^7,8

Symptoms
There are no specific diagnostic criteria for Charles Bonnet syndrome (Table 2). However, the following are generally accepted for diagnosis⁹:
   • grossly intact cognition, although mild cognitive impairment may be present in some cases¹⁰
    • underlying visual disorder, usually acquired, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion, and optic neuritis^3,4,11
   • no hallucinations or perceptive difficul­ties in other sensory modalities
   • generally intact insight
   • absence of delusions
   • absence of other neurologic, psychiat­ric, toxic, or metabolic conditions; medical causes of delirium must be ruled out.

Hallucinations might not be disturb­ing to the patient. Hallucinations could be simple (light flashes, lines, or geomet­ric shapes) or complex (faces, figures, or scenes),¹² and perceived as in color or in black and white. Hallucinations mostly are pleasant and rarely have any emotional impact or meaning. Although hallucina­tions are almost exclusively visual, they can be accompanied by noise or auditory hallucinations.^13,14

Other characteristics of Charles Bonnet syndrome include:  
   • typical age of onset is approximately 72 years (range, 70 to 92 years)  
   • no sex distinction has been identified  
   • episodes can last from a few seconds to few hours; the syndrome may last a few days or a few years⁵     
   • it is not uncommon for episodes to occur in clusters, followed by symptom-free intervals and recurrences  
   • symptoms tend to fade away as patients progress to complete loss of sight.¹⁵

The course of Charles Bonnet syndrome is uncertain and unpredictable and the epi­sodic nature can be frustrating for both patient and clinician. The syndrome could be misdiagnosed as a psychiatric condition.

Pathophysiology
The precise mechanism behind simple or complex vivid hallucinations in persons with Charles Bonnet syndrome is unclear. Several theories have been proposed.

Release theory proposes a loss of input to the primary visual areas, which decreases cortical inhibition and further causes disin­hibition of visual association areas, thereby “releasing” visual hallucinations.¹⁶ Research suggests that this might be an attempt by surviving neurons to recover vision. Loss of input somehow causes surviving neurons to adapt by increased sensitivity to residual visual stimuli.

Deafferentation theory. This relatively new theory proposes deafferentation of the visual sensory pathway, which, in turn, causes disinhibition of neurons in the visual cortical regions, thereby caus­ing them to fire spontaneously. This could cause a sensation analogous to phantom limb pain, which would be called “phan­tom vision presence of brain activity in the absence of an actual visual input.” Further, biochemical and molecular changes have been proposed to explain the deafferenta­tion theory.¹⁷

Neurobiological evidence. Limited data are available for a neurobiological basis to visual hallucinations in Charles Bonnet syndrome. A few studies have used func­tional MRI and single-photon emission CT and reported possible association of visual hallucinations to specific visual areas.^18,19

Risk factors
Social or physical isolation, loneliness, low extraversion, and shyness are risk factors for Charles Bonnet syndrome in visually impaired people.²⁰ Sensory deprivation and low level of arousal favor the occur­rence of hallucinations.⁵ Rate of vision loss—not the nature of pathology or sever­ity of visual impairment—has been sug­gested to increase the risk of developing Charles Bonnet syndrome.²¹

What are the treatment options for Charles Bonnet syndrome?
   a) begin an antipsychotic
   b) do nothing; there is no cure
   c) educate the patient about the nature of the hallucinations
   d) refer the patient to an ophthalmologist for evaluation of vision loss

Treatment
There are several modalities to manage visual hallucinations in a patient with Charles Bonnet syndrome (Table 3). After ruling out medical and other psychiat­ric causes of visual hallucinations, treat­ment might not be indicated if the patient is not disturbed by the hallucinations. In most cases, reassurance and educating the patient and family about the benign nature of the visual hallucinations is all that is needed.

For patients who are disturbed by these visions or for whom there is a treatable cause, treatment could include cataract removal, medical therapy to reduce intra­ocular pressure in glaucoma, treatment of diabetic retinopathy, or laser photoco­agulation. These treatments are associ­ated with a reduction in hallucinations.²²

In some cases, hallucinations disappear as visual acuity deteriorates. Psychotropics have been used to treat Charles Bonnet syndrome, including:
   • antipsychotics, including haloperi­dol, risperidone, and olanzapine
   • anticonvulsants, including valproic acid, gabapentin, and carbamazepine
   • antidepressants, including mirtazap­ine and venlafaxine.^23-30

Some experts recommend a conserva­tive approach, which might be justified because some cases of Charles Bonnet syndrome are episodic and remit sponta­neously.³¹ Again, however, consider phar­macotherapy if a patient is disturbed by hallucinations or if hallucinations impair overall functioning.

TREATMENT Education
After discussion with Mr. B and his family, he is started on risperidone, 1 mg at bedtime, and the psychiatric team provides informa­tion about the nature of Charles Bonnet syndrome. Mr. B reportedly takes this medi­cation for a few days and then stops because he does not want the visual hallucinations to go away.

The psychiatry team sees Mr. B before dis­charge. He and his family are educated about the benign nature of the syndrome, the need for continued family support, and the fact that hallucinations will have minimal or no impli­cations for his life.

The authors’ observations
It is important to remember that a visual description of hallucinations in Charles Bonnet syndrome can be quite vivid, and that the patient might not identify his hal­lucinations as such or consider them as a problem. Be careful not to dismiss the patient’s complaints as a primary psychi­atric condition. It also is important to be mindful of the patient’s concerns with a psychiatric diagnosis; detailed discussion with the patient is helpful in most cases. A more comprehensive and empathetic approach to care could go a long way to sustain quality of life for these patients.

Bottom Line
Charles Bonnet syndrome is characterized by visual hallucinations in patients with visual impairment who have intact insight and an absence of mental illness. Taking a thorough history can help rule out medical and psychiatric causes of visual hallucinations. Educate patients and family about the nature of the hallucinations. In some cases, a psychotropic may be indicated.

Related Resources
• Nguyen ND, Osterweil D, Hoffman J. Charles Bonnet syn­drome: treating nonpsychiatric hallucinations. Consult Pharm. 2013;28(3):184-188.
• Lapid MI, Burton MC, Chang MT, et al. Clinical phenomenology and mortality in Charles Bonnet syndrome. J Geriatr Psychiatry Neurol. 2013;26(1):3-9.

Drug Brand Names
Carbamazepine • Tegretol                          Mirtazapine • Remeron
Gabapentin • Neurontin                              Olanzapine • Zyprexa
Haloperidol • Haldol                                   Risperidone • Risperdal
Lisinopril • Prinivil, Zestril                           Valproic acid • Depakene
Lovastatin • Mevacor                                  Venlafaxine • Effexor
Metoprolol • Lopressor

Acknowledgement
The authors acknowledge Barry Liskow, MD, Vice Chair of Psychiatry, Kansas University Medical Center, Kansas City, Kansas, for providing both insight into the topic and useful feedback on the manuscript.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.