Cases That Test Your Skills

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

 

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

With growing abuse of these medications, we aim to encourage detailed history taking about abuse of OTC drugs, especially diphenhydramine in adolescent patients.


Outcome Improvement, discharge
Mr. L is given a dual diagnosis of diphenhydramine-induced psychotic disorder with
hallucinations and diphenhydramine-induced depressive disorder, both with onset during intoxication. He also is given a provisional diagnosis of psychotic disorder not otherwise specified and major depressive disorder. Last, he is given a diagnosis of Cannabis dependence with physiological dependence, MDMA abuse, hydrocodone abuse, and Robitussin abuse.

Mr. L is maintained on fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime and 0.5 mg in the morning. He receives milieu, individual, group, recreational, and medical therapy while in the hospital. Symptoms abate and he is discharged with a plan to follow up with outpatient providers.

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

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

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

 

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

With growing abuse of these medications, we aim to encourage detailed history taking about abuse of OTC drugs, especially diphenhydramine in adolescent patients.


Outcome Improvement, discharge
Mr. L is given a dual diagnosis of diphenhydramine-induced psychotic disorder with
hallucinations and diphenhydramine-induced depressive disorder, both with onset during intoxication. He also is given a provisional diagnosis of psychotic disorder not otherwise specified and major depressive disorder. Last, he is given a diagnosis of Cannabis dependence with physiological dependence, MDMA abuse, hydrocodone abuse, and Robitussin abuse.

Mr. L is maintained on fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime and 0.5 mg in the morning. He receives milieu, individual, group, recreational, and medical therapy while in the hospital. Symptoms abate and he is discharged with a plan to follow up with outpatient providers.

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

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

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

 

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

With growing abuse of these medications, we aim to encourage detailed history taking about abuse of OTC drugs, especially diphenhydramine in adolescent patients.


Outcome Improvement, discharge
Mr. L is given a dual diagnosis of diphenhydramine-induced psychotic disorder with
hallucinations and diphenhydramine-induced depressive disorder, both with onset during intoxication. He also is given a provisional diagnosis of psychotic disorder not otherwise specified and major depressive disorder. Last, he is given a diagnosis of Cannabis dependence with physiological dependence, MDMA abuse, hydrocodone abuse, and Robitussin abuse.

Mr. L is maintained on fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime and 0.5 mg in the morning. He receives milieu, individual, group, recreational, and medical therapy while in the hospital. Symptoms abate and he is discharged with a plan to follow up with outpatient providers.

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

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

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

 

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

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

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

 

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

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

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

 

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

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

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

 

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

 

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Outcome Stability achieved
Mr. C is successfully discharged from the inpa­tient service after 24 days in the hospital on the following regimen: olanzapine, 20 mg/d; duloxetine 60 mg/d; benztropine, 0.5 mg/d; haloperidol, 20 mg/d; metoprolol, 25 mg/d; clonazepam, 0.25 mg/d; quetiapine, 50 mg/d; and chlorpromazine, 50 mg as needed for agi­tation and paranoia. He is given a diagnosis of toxic secondary cardiomyopathy due to clozap­ine, and remains asymptomatic from a cardiac perspective after discontinuing clozapine.

 

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

 

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

 

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Outcome Stability achieved
Mr. C is successfully discharged from the inpa­tient service after 24 days in the hospital on the following regimen: olanzapine, 20 mg/d; duloxetine 60 mg/d; benztropine, 0.5 mg/d; haloperidol, 20 mg/d; metoprolol, 25 mg/d; clonazepam, 0.25 mg/d; quetiapine, 50 mg/d; and chlorpromazine, 50 mg as needed for agi­tation and paranoia. He is given a diagnosis of toxic secondary cardiomyopathy due to clozap­ine, and remains asymptomatic from a cardiac perspective after discontinuing clozapine.

 

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Case Agitated and violent
Mr. C, age 19, presents with anxiety, agitation, isolation, social withdrawal, and paranoia. He is admitted to the inpatient unit after attempting to punch his father and place him in a headlock. Mr. C has no history of mental illness, no signifi­cant medical history, and no significant family history of mental illness.

The treatment team determines that this is Mr. C’s first psychotic break. He is given a diag­nosis of psychosis, not otherwise specified and started on risperidone, titrated to 2 mg/d, later discontinued secondary to tachycardia. He is then started on haloperidol, 5 mg/d titrated to 10 mg/d, and psychotic symptoms abate. Mr. C is discharged with a plan to receive follow-up care at an outpatient mental health center.

One year later, Mr. C is readmitted with a similar presentation: paranoia, agitation, anxi­ety, and isolation. After discharge, he starts an intensive outpatient program (IOP) for long-term treatment of adults who have a diagnosis of a schizophrenia spectrum disorder.

Several medication trials ensue, includ­ing risperidone, escitalopram, citalopram, fluphenazine, lorazepam, quetiapine, and haloperidol. Despite these trials over the course of 2 years, Mr. C continues to display paranoia and agitation, and is unable to resume academic and community activities. Within the IOP, Mr. C is placed in a vocational training program and struggles to remain stable enough to continue his job at a small greenhouse.

Concurrently, Mr. C is noted to be abusing alcohol. After the IOP treatment team expresses concern about his abuse, he reduces alcohol intake and he and his parents are educated on the impact of alcohol use on schizophrenia.

Which treatment option would you choose next?
   a) initiate a trial of clozapine
   b) try a long-acting injectable antipsychotic
   c) recommend inpatient treatment

The authors’ observations
Clozapine is an atypical antipsychotic that is FDA-approved for treatment-resistant schizophrenia; it also helps reduce recur­rent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Clozapine works by blocking D2 recep­tors, thereby reducing positive symptoms. It also blocks serotonin 2A receptors, which enhances dopamine release in certain brain regions, thereby reducing motor side effects. Interactions at 5-HT2C and 5-HT1A recep­tors may address cognitive and affective symptoms. Clozapine can help relieve nega­tive symptoms and can decrease aggression. Because it has a low risk of tardive dyskine­sia, clozapine is useful when treating patients with treatment-resistant schizophrenia.^1-3

Treatment Quick heart rate
Mr. C’s IOP treatment team considers a clo­zapine trial because previous medication tri­als failed. All paperwork for the registry and screening labs are completed and Mr. C is started on clozapine.

Mr. C’s clozapine dosages are:
   • Days 1 to 9: 25 mg/d
   • Days 10 to 16: 50 mg/d
   • Days 17 to 23: 75 mg/d
   • Days 24 to 32: 100 mg/d
   • Days 33 to 37: 125 mg/d
   • Day 38: 150 mg/d.

On Day 45 of the clozapine trial, Mr. C is increasingly paranoid toward his father and thinks that his father is controlling his thoughts. Mr. C tells the attending psychiatrist that he ingested a handful of clonazepam and considered putting a bag over his head with the intent to commit suicide. Mr. C is admitted to the inpatient unit.

Admission vitals recorded a heart rate of 72 beats per minute but, later that day, the rate was recorded in the vital sign book as 137 beats per minute. The treatment team considers dehydration, anxiety, and staff error; Mr. C is observed carefully. Over the next 2 days, heart rate remains between 102 and 119 beats per minute.

Because of persistent tachycardia, the team orders lab studies, a medical consult, and an electrocardiogram (ECG). Thyroid panel, elec­trolytes, and clozapine level are within normal limits; ECG is unremarkable.

Although tachycardia is a known side effect of clozapine,^3,4 we order an echocar­diogram because of Mr. C’s young age and non-diagnostic laboratory workup. The echo study demonstrates reduced left-ventricular ejection fraction (LVEF) of 45%. Tests for HIV infection and Lyme disease are negative. The cardiology team diagnoses cardiomyopathy of unknown origin.

Although Mr. C has a history of alcohol abuse, the cardiology team believes that alco­hol consumption does not adequately explain the cardiomyopathy, given his young age and the limited number of lifetime drinking-years (approximately 4 or 5); the team determines that clozapine is causing secondary cardiomy­opathy and tachycardia, leading to reduced LVEF. Clozapine is stopped because the rec­ommended treatment for toxic secondary cardiomyopathy is to remove the offending agent. At this point, the clozapine dosage is 250 mg/d.

At the medical team’s recommendation, Mr. C is started on metoprolol, a beta blocker, at 25 mg/d.

 

The etiology of secondary cardiomyopathy includes all of the following except:
   a) tachycardia-induced
   b) autoimmune
   c) radiation-induced
   d) infiltrative
   e) endomyocardial

The authors’ observations
Cardiomyopathies are diseases of the heart muscle causing mechanical and electrical dysfunction. This group of diseases has a range of symptoms, causes, and treatments. Disease manifests typically as arrhythmia, systolic dysfunction, or diastolic dysfunc­tion. Classification systems are based on origin, anatomy, physiology, primary treat­ments, method of diagnosis, biopsy, histopa­thology, and symptomatic state.

The American Heart Association Scientific Statement5 distinguishes cardiomyopathies by degree of organ involvement. Diseases confined to the heart are defined as primary cardiomyopathy, which may have a genetic, acquired, or mixed cause. Acquired causes include inflammatory (myocarditis), stress (Takotsubo), peripartum, and tachycardia. Cardiomyopathies that are part of general­ized systemic disorders are defined as sec­ondary cardiomyopathy (Table 1).

Secondary cardiomyopathies have many causes. These include toxicity (medica­tions or alcohol), cancer therapy, infiltra­tive, storage disease, and endomyocardial, inflammatory, autoimmune, endocrine, and neurologic diseases.⁵

Evaluation of suspected cardiomyopathy begins with a history and physical focused on identifying causative factors. Selective testing, based on pretest probabilities, might include lab testing, ECG, and echocardiogra­phy, and can narrow the differential diagno­sis. When toxin-induced cardiomyopathy is suspected, withdrawing the toxin and moni­toring for improvement is recommended. The treatment and prognosis for cardiomy­opathies vary, based on the cause.⁶

Review of the literature
After 23 cases of fatal and non-fatal myo­carditis were found in a study of 8,000 patients starting clozapine,⁷ manufacturers in Australia introduced clinical guidelines. Before initiating clozapine, they recom­mended, clinicians should:
   • screen for cardiac symptoms
   • screen for a family history of heart disease
   • obtain baseline ECG
   • obtain baseline markers of myocardial damage (troponin assay and serum creatinine)
   • obtain baseline echocardiogram
   • repeat cardiac monitoring after the first and second week and then repeat in 6 months
   • maintain a high degree of vigilance for signs and symptoms of cardiac toxicity throughout clozapine treatment.^8,9

After studying 38 cases of clozap­ine-induced myocarditis—3 fatal— Ronaldson et al¹⁰ listed primary diag­nostic features as:  
   • tachycardia (heart rate >100 beats per minute)  
   • heart rate >120 beats per minute  
   • temperature >37°C  
   • chest pain  
   • troponin I/T level >2 ng/mL  
   • C-reactive protein (CRP) > 100 mg/L  
   • erythrocyte sedimentation rate >50 mm/h.

Among non-fatal cases, symptoms abated after clozapine was discontinued. In 36 of the 38 cases, symptoms emerged 14 to 22 days after clozapine was started. For tachycardia to be considered a diagnostic feature, it must persist for at least 24 hours; if the heart rate is ≥120 beats per minute, however, persistence is not a criterion. It was thought that elevated CRP might herald disease onset; the authors suggest that CRP >50 mg/L should warrant increased monitoring with daily ECG and troponin levels.

Authors’ recommendations include:  
   • measuring troponin and CRP and order an ECG at baseline and at 7, 14, 21, and 28 days  
   • examining patient for signs and symp­toms of illness at these same intervals  
   • considering chest pain or fever as an indicator of cardiomyopathy  
   • asking patients to report any illness during this 4-week period  
   • if ECG is abnormal or troponin ele­vated, decreasing clozapine pending further investigation.¹⁰ 

When medications fail
We had to discontinue Mr. C’s clozapine, which meant that the therapeutic relation­ship established between him and the psy­chology fellow became an important and, at times, the only bond between him and the medical team while olanzapine was initiated. The alliance between patient and clinician is an important factor for positive prognosis in mental health treatment.^11-13 Priebe and McCabe¹⁴ asked if the therapeu­tic relationship in psychiatry is “the basis of therapy or therapy itself?” In a review of studies that used an operationalized mea­surement of the therapeutic relationship in treating severe mental illness, the authors concluded that the therapeutic relation­ship is a reliable predictor of outcome.¹⁵

In Mr. C’s case, the psychology fellow, who also works with the Partial Hospitalization Program/Intensive Outpatient Program (PHP/IOP), joined the treatment team on the inpatient unit a few days into hospitalization. Eleven meetings, includ­ing a discharge session, were held between the psychology fellow and the patient during the inpatient hospitaliza­tion. Mr. C also participated in a daily group session, facilitated by the psychol­ogy fellow.

Maintaining recognition of the bound­ary disturbance that characterizes schizo­phrenic psychoses was important for Mr. C. As Auerhahn and Moskowitz¹⁶ wrote, the inpatient therapist can be transformed by the schizophrenia patient into the all-knowing, all-powerful early mother, which could contribute to substantial improvement in the patient’s functioning and report of symptoms, only to have the patient’s symp­toms return after discharge.

 

In an effort to evaluate the duration, fre­quency, and intensity of Mr. C’s symptom experience, a goal of Mr. C’s hospitalization was to attach words to his internal states, including mood and intensity of paranoid ideation. We showed Mr. C directly and indi­rectly that reporting intensification of symp­toms and decreased functioning would not result in abandonment or punishment, and worked to demonstrate through our actions that the treatment team differs from Mr. C’s view of the world as dangerous and others as hostile and omnipotent.


Treatment Developing language
Initially, Mr. C gives a number (from 1 to 10) to describe his mood, 10 being the happiest he has ever felt and 1 being the most depressed. The treatment team discusses how important it is that Mr. C know his feelings and be able to convey to others how he feels.

Over time, Mr. C is encouraged to attach a feeling word to the number, and by discharge, he stops using numbers and responds to inqui­ries about his feelings with a mood word. This practice has been reinforced with the patient in the IOP program, allowing him to continue practicing linking his internal state with feeling words.

During hospitalization, Mr. C becomes more vocal about his level of paranoia and is now more likely to seek support when he first expe­riences a paranoid thought, rather than waiting until after he is paranoid and agitated. Mr. C is encouraged to monitor his thoughts and feel­ings, and to practice coping strategies he has identified as helpful, including deep breathing, meditation, listening to music, and reminding himself that he is safe.

The treatment team responds to Mr. C’s reports of paranoid ideation (eg, “Some of the other patients were talking about me today”) by processing the affect, and hypothesizing other explanations for these events to slow down “jumping to conclusions,” which is a common part of the paranoid experience.¹⁷ Additionally, all meetings with the cardiology team are processed and Mr. C receives psychoeduca­tion about his heart function. Joint sessions with the psychiatry resident and psychology fellow allow Mr. C to ask medical questions and immediately process his reactions, which likely ameliorated his anxiety and allowed him to continue connecting with, identifying, and verbalizing his internal experiences. Given his history of paranoia, sessions also showed that Mr. C is an active participant in his treatment, with the hope of lessening his belief that bad things happen to him and that they are out of his control.

We maintain frequent contact with Mr. C’s parents to update them on their son’s function­ing and to discuss treatment interventions that were helpful and the family could implement when Mr. C returns home. Discharge medica­tions are discussed.

After 24 days in the inpatient unit, Mr. C is discharged to the IOP program. The psychology fellow walks Mr. C to the IOP program, where he transitioned immediately from inpatient to the IOP daily schedule of groups and an appointment with the program psychiatrist. The psychology fellow also arranged for and participated in the family meeting with Mr. C’s parents, sister, and treatment providers in the IOP program after his first day back at the IOP.

Throughout his hospitalization, Mr. C had no symptoms of cardiomyopathy, without exercise intolerance, shortness of breath, fatigue, or fever. He is discharged with follow-up care at his outpatient program at the PHP level of care and a follow-up echocardiogram and cardiology appointment are scheduled for 6 weeks later.

The authors' observations
Throughout Mr. C’s hospitalization, the intersections among psychiatry, psychol­ogy, cardiology, and internal medicine were apparent and necessary for treat­ment. No one specialty was able to com­pletely direct this patient’s care without the expertise of, and input from, others. When it looked like all medications had failed, the relationship between the patient and the psychology fellow and the appli­cation of previously learned coping strate­gies prevented acute decompensation.

Clozapine is FDA-approved for treatment-resistant schizophrenia and often is a last resort to help patients remain sta­ble. When clozapine is chosen, it is impor­tant to be aware of its side-effect profile (Table 2,¹ and Table 3,^1-3) and the need for monitoring. The importance of relying on colleagues from other specialties to assist in the effective monitoring process cannot be overstated. This multidisciplinary team ensured that Mr. C did not experience acute decompensation during this process. Cardiac function improved, with an LVEF of 50% after clozapine was discontinued. Mr. C has not needed hospitalization again.

Outcome Stability achieved
Mr. C is successfully discharged from the inpa­tient service after 24 days in the hospital on the following regimen: olanzapine, 20 mg/d; duloxetine 60 mg/d; benztropine, 0.5 mg/d; haloperidol, 20 mg/d; metoprolol, 25 mg/d; clonazepam, 0.25 mg/d; quetiapine, 50 mg/d; and chlorpromazine, 50 mg as needed for agi­tation and paranoia. He is given a diagnosis of toxic secondary cardiomyopathy due to clozap­ine, and remains asymptomatic from a cardiac perspective after discontinuing clozapine.

 

Follow-up appointment with cardiology and repeat echocardiography were scheduled for 6 weeks after discharge. The follow-up echocardiogram showed improvement (LVEF, 50%). Mr. C continues to do well and remains a client at the IOP program.

Bottom Line
Clozapine often is used as a last resort for patients with treatment-resistant schizophrenia, but its side-effect profile requires careful management and monitoring. If a patient taking clozapine shows tachycardia, consider cardiomyopathy. Evaluation might include lab testing, electrocardiography, and echocardiography. Symptoms often resolve when clozapine is discontinued.

Related Resources
• Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.
• Layland JJ, Liew D, Prior DL. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust. 2009;190(4):190-192.

Drug Brand Names
Benztropine • Cogentin               Fluphenazine • Prolixin
Chlorpromazine • Thorazine        Haloperidol • Haldol
Citalopram • Celexa                    Lorazepam • Ativan
Clonazepam • Klonopin               Metoprolol • Lopressor
Clozapine • Clozaril                    Olanzapine • Zyprexa
Duloxetine • Cymbalta                Quetiapine • Seroquel
Escitalopram • Lexapro               Risperidone • Risperdal

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

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

 

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

 

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

 

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

 

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

 

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

 

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

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

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

 

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

 

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

 

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

 

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Nearly naked
Mr. A, age 68, is found sitting in his car, wear­ing only a jacket, underpants, and boots. He speaks of spreading a message about Osama bin Laden and “taking a census.” Police officers bring him to a hospital emergency depart­ment for evaluation.

The examining clinician determines that Mr. A is a danger to himself and others because of mental illness, leading to admission to our state psychiatric hospital.

Mr. A’s wife describes recent spend­ing sprees with large purchases. She had obtained a restraining order against her hus­band because of his threatening remarks and behaviors. Within days of the order issuance, he got a home equity loan and purchased a $300,000 house.

The medical history is notable for type 2 diabetes mellitus. Although he is not tak­ing medications, his blood sugar is well controlled. Other than an initial resting heart rate of 116 beats per minute, vital signs are stable and within normal lim­its. Physical examination is unremarkable. Screening laboratory studies are notable for mildly elevated hepatic function, which approaches normal range several days after admission.

Mr. A reports a remote history of alcohol abuse but says he had not been drinking recently, and does not detail his pattern of use. Urine toxicology screen is negative for all substances of abuse.

Mental status examination reveals dishev­eled appearance, motor agitation, pressured speech, labile affect, loosening of associa­tions, grandiose delusions, and auditory hal­lucinations. Mr. A’s thought processes are grossly disorganized, such that we could not gather a meaningful history. He believes God is speaking directly to him about plans to build a carousel at Disney World. He makes strange gestures with his hands throughout the inter­view, as if attempting to trace the shapes of letters and numbers. He frequently speaks of seeing an array of colors. Cognitive examina­tion reveals a score of 5 of 30 on the Montreal Cognitive Assessment (Figure 1), indicating a severe impairment in neurocognitive func­tioning. He demonstrates limited insight and markedly impaired judgment, and denies hav­ing a mental illness.

What should be the next step in managing Mr. A?
a) obtain records from other facilities and collateral history
b) start an antipsychotic
c) order a brain MRI
d) start an alcohol withdrawal protocol

The authors’ observations
Mr. A showed elements of mania, psycho­sis, and delirium. We considered a broad differential diagnosis (Table). Mr. A initially could not provide reliable or accurate information. The least invasive next step was to obtain additional history from his wife and other medical records to refine the differential diagnosis.

HISTORY Bizarre behavior
Mr. A allows staff to speak with his wife and obtain records from a psychiatric hospitaliza­tion 3 years earlier. Mrs. A reports significant and rapid changes in her husband’s behav­ior and personality over 3 months, but does not describe a recent alcohol relapse. Mr. A sleeps very little, remaining awake and active throughout the night. He frequently rear­ranges the furniture in their home for no clear reason. Once, he knocked on the door of a young female neighbor asking if she found him attractive.

Mr. A has a significant criminal history. Approximately 30 years ago, he was charged with attempted murder of his ex-wife and he had faced charges of attempted kidnapping and assaulting a police officer. However, he has no recent legal issues.

Mr. A has a history of episodes that are simi­lar to this presentation. Seven years ago, he impulsively purchased a $650,000 house after his fourth wife died. He then had a $90,000 heart-shaped pool installed. He also drove a tractor through his stepdaughter’s car for no apparent reason. Also, 3 years ago, he displayed symptoms similar to his current presentation, including insomnia, irritability, and grandios­ity. He engaged in strange behaviors, such as dressing up and imitating homeless people at his church.

During the hospitalization 3 years ago, cli­nicians gave Mr. A a diagnosis of bipolar dis­order, current episode manic, and delirium of an unclear cause. A medical workup, includ­ing brain MRI, did not uncover a basis for his delirium. Antipsychotics (risperidone and per­phenazine) and mood stabilizers (lithium and valproic acid), stabilized his condition; after 7 weeks, Mr. A was discharged, but he did not pursue outpatient psychiatric care.

What is the most likely DSM-5 diagnosis?
   a) major neurocognitive disorder (dementia)
   b) alcohol use disorder (eg, Wernicke- Korsakoff syndrome)
   c) delirium secondary to mania
   d) psychotic disorder

The authors’ observations
DSM-5¹ suggests a stepwise approach to diagnosis, with consideration of:
   • signs and symptoms
   • substance use
   • general medical condition
   • developmental conflict or stage
   • whether a mental disorder is present.

 

Mr. A’s age and severe cognitive impair­ment raise the possibility of dementia. Rapid onset, history of similar episodes, and apparent inter-episode recovery make dementia unlikely. The history of alcohol abuse and mildly elevated hepatic func­tion tests suggest a substance use disorder such as Wernicke-Korsakoff syndrome or a withdrawal syndrome. However, there is no evidence of excessive alcohol use over the past several months, toxicology studies were negative, and vital signs were stable. General medical causes for Mr. A’s presen­tation, such as hypoglycemia, head trauma, intracranial infection, and metabolic dis­turbance were considered, but physical examination and laboratory studies did not suggest any condition that would explain his condition.

Mr. A’s previous psychiatric hospitaliza­tion is critical in clarifying the more likely diagnosis. A similar presentation yielded the diagnosis of bipolar disorder, manic phase. Our working diagnosis, therefore, was bipolar disorder with features of delir­ious mania.

Delirious mania
Delirious mania was first described by Luther Bell in 1849 and is characterized by an acute and simultaneous onset of mania— severe insomnia, poor judgment, grandios­ity, excitement, emotional lability, bizarre hallucinations, and delusions—and delir­ium—altered consciousness, disorientation, and confusion.^2,3 Although there are no diag­nostic criteria, some authors suggest that delirious mania is characterized by inappro­priate toileting, denudation, profound lack of sleep, and episodic memory impairment that can last hours or days.⁴ Catatonia fre­quently is seen with delirious mania.⁵ Initial case descriptions described a high mortality rate, approaching 75% of patients.⁶ There is little published literature and no classifica­tion of delirious mania in DSM-5.1 Estimates are that delirium is concomitant in 20% to 33% of patients with mania.^7,8

Several theories try to clarify the underly­ing etiology of delirious mania. Jacobowski et al⁹ summarized the etiology and pro­posed that it is:
   • 1 of 3 types of mania, including: acute and delusional manias, as initially pro­posed by Kraeplin
   • a severe form of catatonia
   • a condition akin to, but distinct from, delirium with similar underlying medi­cal causes
   • a primary psychiatric disorder under­lying the cause of delirium.

EVALUATION Brain changes
For several days, Mr. A continues to engage in strange behavior. He tries to take patients’ belongings, is denudative, crawls on floors, licks walls, is unable to feed himself, and exhib­its odd motor movements with purposeless motor activity.

We consult our internal medicine team to iden­tify treatable, medical causes. Results of serum B12, thyroid-stimulating hormone, and rapid plasma reagin studies are within normal limits. Urinalysis is negative. A brain MRI reveals numerous white-matter T2-weighted and FLAIR hyperintensities, indicating small-vessel ischemic changes that are consistent with the findings of an MRI 3 years ago. A sleep-deprived EEG with temporal leads obtained on Day 4 of hospitalization demonstrates a diffusely slow and marginally to poorly organized background, believed to indicate global cerebral dysfunction that is most consistent with nonfocal global encephalopathy. There is no seizure activity. We do not perform a lumbar puncture because of Mr. A’s absence of focal neurologic deficits, lack of fever, and normal white blood cell count.

What is the most appropriate treatment?
   a) electroconvulsive therapy (ECT)
   b) high-dose benzodiazepine
   c) mood stabilizer
   d) antipsychotic

The authors’ observations
We strongly suspect that Mr. A has delirious mania. Symptoms and signs of mania include labile mood, excessive spending, grandios­ity, insomnia, and psychosis together with delirium (marked disorientation, confusion). We ascribed Mr. A’s odd motor behaviors to catatonia, a hallmark of delirious mania. The literature has little description of EEG find­ings in suspected cases of delirious mania; however, abnormal EEG tracings have been reported.¹⁰ We also speculated that Mr. A’s EEG reflected effects produced by his pre­scribed antipsychotic regimen.

Treatment
There is no clear consensus on treating deliri­ous mania. Because catatonia is a key feature of delirious mania—whether etiologically or as a prominent sign of the condition—ECT and benzodiazepines are proposed as pri­mary treatments. In a study of 16 patients with delirious mania, Karmacharya et al4 found ECT to be effective, with patients showing improvement after 1 to 4 treat­ments. Lee et al¹⁰ reported similar findings. Although a high-dose benzodiazepine is not as effective as ECT, a 1-time oral dose of 3 to 4 mg of lorazepam has been used to treat delirious mania.

The efficacy of antipsychotic and mood-stabilizing pharmacotherapy is not clear. Bond³ described 3 cases in which patients were treated effectively with a typical anti­psychotic (haloperidol or chlorpromazine) and lithium. Jung and Lee_¹¹demonstrated the efficacy of atypical antipsychotics, with a marked improvement in symptoms within 1 week. However, other studies do not sup­port these findings. Karmacharya et al⁴ found that typical antipsychotics 1) make the clinical picture worse by increasing extrapy­ramidal symptoms and 2) produce incon­sistent effects. Mood stabilizers sometimes proved beneficial.

Karmacharya et al⁴ further argued that the delay in improvement seen with any antipsychotics and mood stabilizers suggest they should not be considered a first-line treatment. These discordant findings are the result of a small number of studies and a lack of understanding of the exact nature of delirious mania.


TREATMENT Quick Response
Mr. A’s symptoms rapidly resolve with a com­bination of quetiapine, 800 mg/d, haloperidol, 10 mg/d, and lithium, 1,200 mg/d. His mood returns to euthymia and his psychotic symptoms abate. He is able to attend to all activities of daily living. Mental status clears and he is fully oriented and able to hold a logical conversation. He scores 28 out of 30 on a subsequent Montreal Cognitive Assessment, administered 11 days after the ini­tial assessment (Figure 2), indicating normal neurocognitive function. He returns to his baseline level of functioning and is discharged in psychiatrically stable condition. Mr. A has no recollection of the bizarre behaviors he dis­played earlier in his hospitalization.

 

The authors’ observations
We started Mr. A on antipsychotics because of his initial level of agitation. In reviewing pharmacotherapy options for Mr. A’s mania and delirium, we contemplated several options. Quetiapine and lithium were cho­sen after a review of outside hospital records demonstrated a combination of a mood sta­bilizer and an antipsychotic was effective in treating a previous similar episode, which led to remission of Mr. A’s symptoms. We chose quetiapine because of it highly sedat­ing properties, suspecting that it would help treat his insomnia. We thought that the risk that lithium would make delirium worse was mitigated by Mr. A’s previous therapeu­tic response to it. Haloperidol was added for treating delirium, given its more potent D2 antagonism. Mr. A responded quickly to these interventions.

We did not consider ECT at the begin­ning of Mr. A’s admission, and we avoided sedative-hypnotic agents because we were concerned that a benzodiazepine might make his delirium worse. In light of avail­able data suggesting that ECT and ben­zodiazepines are preferred treatments for delirious mania, it is noteworthy that Mr. A responded so robustly and rapidly to an antipsychotic and a mood stabilizer.

Bottom Line
Consider delirious mania in any patient who has a history of bipolar disorder presenting with co-occuring symptoms of mania and delirium. Collateral information is vital to establishing a diagnosis. With suspected delirium, rule out concomitant reversible medical problems. Electroconvulsive therapy, high-dose benzodiazepines, antipsychotics, and mood stabilizers have shown efficacy.

Related Resources
• Nunes AL, Cheniaux E. Delirium and mania with catatonic fea­tures in a Brazilian patient: response to ECT. J Neuropsychiatry Clin Neurosci. 2014;26(1):E1-E3.
• Danivas V, Behere RV, Varambally S, et al. Electroconvulsive ther­apy in the treatment of delirious mania: a report of 2 patients. J ECT. 2010;26(4):278-279.

Drug Brand Names
Chlorpromazine • Thorazine               Perphenazine • Trilafon
Haloperidol • Haldol                           Quetiapine • Seroquel
Lithium • Eskalith                              Risperidone • Risperdal
Lorazepam • Ativan                           Valproic acid • Depakene

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

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Alien thoughts
Mr. C, age 23, is admitted to an intermediate-security facility because of unmanageable aggression. He is not charged with a crime and his legal status is admission by guardian. He is taking haloperidol decanoate, 300 mg IM every 28 days, and divalproex sodium, 1500 mg/d, but he continues to experience auditory hallucina­tions and the delusion that he is an alien.

Mr. C is given a primary diagnosis of chronic undifferentiated schizophrenia. He is started on risperidone tablets, 3 mg/d, and then switched to risperidone orally disintegrating tablets, titrated to 8 mg/d, to ensure compliance. Later, he receives separate trials of high-dose que­tiapine (up to 1200 mg/d) and olanzapine orally disintegrating tablets (up to 30 mg/d). Lithium, 1200 mg/d, sertraline, 100 mg/d, and long-acting propranolol, 120 mg/d, were added at various periods of his treatment.

He continues to experience hallucinations and delusions, is intermittently aggressive, is not engaged in the treatment program, and needs prompting for basic hygiene. Several times, we discuss with Mr. C using clozap­ine, but he refuses, mainly because of weekly blood draws.

How would you proceed with Mr. C’s care?
a) consider electroconvulsive therapy
b) order aripiprazole and an omega-3 fish oil supplement
c) consider involuntary clozapine therapy and lab testing

The author’s observations
Schizophrenia remains a chronic and often refractory illness. Patients suffer from intru­sive hallucinations; social and self-care defi­cits; cognitive impairment; and increased risk of violence, suicide, and premature death from medical causes. Pharmacotherapy is the mainstay of treatment, supplemented by individual and group therapies, psycho­social rehabilitation, housing assistance, and income support. Antipsychotics are funda­mental and clozapine has been established as the most effective antipsychotic in the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study,¹ but it remains underutilized.²

 

In 2008, clozapine accounted for only 4.4% of antipsychotic prescriptions in the United States.³ In our state forensic facility, only 10% of patients on an antipsychotic received clozapine in 2011. Despite the CATIE trial, there were no significant increases in clo­zapine prescribing after the results were published⁴ and patients often experience a substantial delay before clozapine is ini­tiated.⁵ In the last several years, we have looked at methods to increase clozapine use in our hospital and have described some of our experiences. Despite enthusiasm for, and good experi­ence with, clozapine, barriers limit the use of this medication (Table 1). One signifi­cant barrier is patient acceptance. Although most of our patients taking an atypical anti­psychotic will accept a blood draws every 6 months for metabolic monitoring, many will reject clozapine because of the initial weekly blood draw. Other patients will reject a trial of clozapine because of fears of serious adverse reactions.

 

Clinicians may be reluctant to initiate clo­zapine treatment because of increased time demands to obtain and document informed consent, complete initial paperwork, initi­ate a clozapine titration protocol, and order laboratory work. Clinicians also may fear more serious adverse reactions with clozap­ine such as agranulocytosis, acute diabetes, severe constipation, and myocarditis. With close monitoring, however, these outcomes can be avoided, and clozapine therapy can decrease mortality.⁶ With the increasing avail­ability and decreasing cost of genetic analy­sis, in the near future we may be able to better predict clozapine responders and the risk of agranulocytosis before initiating clozapine.^7,8

Overcoming barriers
When initiating clozapine, it is helpful to reduce barriers to treatment. One strategy to improve patient acceptance of blood test­ing is to use fingerstick hematology profiles rather than the typical venipuncture tech­nique. The Micros 60 analyzer can provide a complete blood count and granulocyte count from a blood specimen collected in a mini capillary tube.

National clozapine registries accept results derived from this method of blood analysis. Using preprinted medication and treatment orders can ease the paperwork burden for the psychiatrist. To help ensure safe use of clozapine, clinical pharmacists can help interface with the clozapine reg­istry (see this article at CurrentPsychiatry. com for a list of clozapine registry Web sites), assist with monitoring laboratory and medication orders, and anticipate drug interactions and side effects. Staff mem­bers directly involved in the patient’s care can try to improve the patient’s insight of his (her) illness. Nursing staff can provide medication education.

Many efforts have been made to educate medical staff to reduce adverse effects and improve patients’ experience with clozapine. Employing agents such as polyethylene gly­col, desmopressin, terazosin, and topiramate can help to manage adverse effects of clozap­ine such as constipation, nocturnal enuresis, drooling, and weight gain, respectively. Lithium can help boost a low neutrophil count9; a lithium level >0.4 mEq/L may be needed to achieve this response. Although generally well tolerated, adding lithium can increase the risk of seizures with clozapine. A final hurdle has been the dilemma of an unwilling, but obviously ill and suffering, patient who has failed several medication trials and other therapeutic interventions.

 

TREATMENT Involuntary clozapine
Mr. C continues to believe that he is an alien. He also thinks he is involved in a mission for God. He has physically assaulted staff on occasion. Overall, his mood shows no persis­tent abnormality and his sleep and appetite are normal. Family history reveals that Mr. C’s brother has schizophrenia. Because of Mr. C’s refractory illness, we seek the guardian’s con­sent for a trial of clozapine and ask for per­mission to give backup medication and lab testing involuntarily if necessary.

We obtain informed consent and orders are written. Mr. C refuses the first 2 doses of clozapine (12.5 mg at bedtime) and receives a backup order of IM olanzapine, 5 mg. He initially refuses baseline and 1-week hematology pro­files, which then are obtained involuntarily by manual hold. Subsequently, Mr. C no longer refused medication or lab tests. His clozap­ine dosage is titrated to 400 mg/d, guided by clinical response and plasma level.

The authors’ observations
We work in a public forensic psychiatry facility, where the average length of stay is 680 days. In a public psychiatry facil­ity there may be pressure to reduce the length of stay by moving patients to a less restrictive setting and thereby reducing the overall census. Many patients at our facil­ity likely would benefit from clozapine. In an effort to provide this important therapy to patients who refuse it despite refrac­tory symptoms, chronic hospitalization, and dangerous behaviors, we have devel­oped an option of involuntary clozapine administration. When efforts to convince the patient to agree to clozapine treatment fail, approval for the involuntary adminis­tration of medication and laboratory testing can be requested.

Involuntary clozapine treatment may be an important option for patients who have a guardian (as do approximately one-half of patients at our facility). It also might be an option for patients who have a court order or other legal document approving a trial of involuntary clozapine. When seeking approval from a guardian, explain the ben­efits and risks of treatment. Some guardians are public administrators, such as elected officials who serve as conservators and guardians, and may be familiar with clo­zapine and successes with other patients, and quickly support the request. In other cases, the guardian is a family member and might require more education and time to make a decision.

After obtaining approval from a guard­ian, inform the patient of the plan to initi­ate clozapine, with the goal of gradually reducing some or most of the other psy­chotropics. Describe to your patient why weekly hematology profiles are necessary. In collaboration with the treatment team, a convenient time is scheduled for the baseline lab draw. If lab results meet the baseline requirements, clozapine is initi­ated, usually using the orally disintegrat­ing formulation. The patient is informed about the lab results, medication orders, and potential side effects. If the patient refuses medication, an IM backup of another atypical antipsychotic may be ordered in place of the missed clozapine dose, after obtaining the guardian’s per­mission. Employing physical restraint such as a manual hold to obtain labora­tory testing or to administer medication triggers restraint and seclusion policies.

How do you ensure compliance with clozapine therapy in an unwilling patient?
a) mouth check
b) medication watch (sitting in a public area for 30 minutes after a dose)
c) dissolving clozapine tablets
d) monitoring therapy with clozapine/nor­clozapine plasma levels

 

The authors’ observations
At times we have instituted all of the meth­ods noted in Table 2. We have most often used dissolving tablets and plasma monitoring.

OUTCOME Improvement, transfer
Mr. C gradually improves over 6 months. The voices, delusions, and aggression resolve. He remains mildly disorganized and has poor insight, with unrealistic goals. Approximately 3 years after admission and 1 year after clo­zapine was initiated, Mr. C is transferred to a minimum-security facility.

The authors’ observations
Overall, our experience has been success­ful with the approach we have described. Patients often do not resist the treatment plan once they see our commitment to their well-being. When they do resist, it has been only for 1 to 3 doses of medica­tion, and 1 or 2 blood draws. Of 6 recent cases under this protocol, we have dis­charged 3; 1 is approaching discharge; 1 has had minimal improvement to date; and 1 required discontinuation because of neutropenia. We recommend considering involuntary clozapine therapy for refractory patients who have a poor prognosis.

Bottom Line
Clozapine is an underutilized treatment for refractory schizophrenia, often because of patient refusal. In a case presentation format we review the barriers to clozapine therapy. We discuss clinical and legal issues for administering clozapine to an unwilling patient.

Related Resources
• Hill M, Freundenrich O. Clozapine: key discussion points for pre­scribers. Clin Schizophr Relat Psychoses. 2013;6(4):177-185.
• Nielsen J, Correll C, Manu P, et al. Termination of clozapine treat­ment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613.

Drug Brand Names
Aripiprazole • Abilify                            
Polyethylene glycol • MiraLax
Clozapine • Clozaril, FazaClo                
ropranolol • Inderal LA
Desmopressin • DDAVP                     
Quetiapine • Seroquel
Divalproex sodium • Depakote             
Risperidone • Risperdal
Haloperidol • Haldol                            
Sertraline • Zoloft
Lithium • Eskalith, Lithobid   
Terazosin • Hytrin
Olanzapine • Zyprexa            
Topiramate • Topamax

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

In women, a high prolactin level can cause

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

 

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

In women, a high prolactin level can cause

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

 

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Paranoid and hallucinating
Ms. S, age 30, is an unmarried graduate stu­dent who has been given a diagnosis of schizophrenia, paranoid type, during inpatient hospitalization that was prompted by impair­ment in school functioning (difficulty turning in assignments, poor concentration, making careless mistakes on tests), paranoid delu­sions, and multisensory hallucinations. She says that her roommate and classmates are working together to make her leave school, and recalls seeing them “snare and smirk” as she passes by. Ms. S says that she feels her classmates are calling her names and talking badly about her as soon as she is out of sight.

Ms. S is antipsychotic-naïve and has a base­line body mass index of 17.8 kg/m², indicat­ing that she is underweight. We believe that olanzapine, 20 mg/d, is a good initial treat­ment because of its propensity for weight gain; however, she experiences only marginal improvement. Ms. S does not have health insurance, and cannot afford a brand name medication; therefore, she is cross-tapered to perphenazine, 8 mg, and benzatropine, 0.5 mg, both taken twice daily (olanzapine was not available as a generic at the time).

At discharge, Ms. S does not report any hallucinatory experiences, but is guarded, voices suspicions about the treatment team, and asks “What are they doing with all my blood?”—referring to blood draws for labora­tory testing during hospitalization.

As an outpatient, Ms. S is continued on the same medications until she has to be switched because she cannot afford the out-of-pocket cost of the antipsychotic, perphenazine ($80 a month). Clozapine is recommended, but Ms. S refuses because of the mandatory weekly blood monitoring. She briefly tries fluphen­azine, 2.5 mg/d, but it is discontinued because of malaise and lightheadedness without extrapyramidal symptoms.

Clozapine is again recommended, but Ms. S remains suspicious of the necessary blood draws and refuses. After several trials of antipsychotics, Ms. S starts paliperidone using samples from the clinic, titrated to 6 mg at bedtime. Once tolerance and therapeutic improvement are observed, she is continued on this medication through the manufactur­er’s patient assistance program.

Within 3 months, Ms. S and her fam­ily find that she has improved signifi­cantly. She no longer reports hallucinatory experiences, is less guarded during ses­sions, and has followed through with paid and volunteer job applications and inter­views. She soon finds a job teaching entry-level classes at a community college and is looking forward to a summer trip abroad.

During a follow-up appointment, Ms. S reports that she had missed 2 consecutive menstrual cycles without galactorrhea or fractures. A urine pregnancy test is negative; the prolactin level is 72 μg/L.

Hyperprolactinemia in women is defined as a plasma prolactin level of 

a)>2.5 µg/L
b) >5 µg/L
c) >10 µg/L
d) >20 µg/L
e) >25 µg/L


The authors’ observations
A prolactin level >25 μg/L is considered abnormal.¹ A level of >250 μg/L may identify a prolactinoma; however, levels >200 μg/L have been observed in patients taking an antipsychotic.¹ Given Ms. S’s clinically significant elevation of prolactin, she is referred to her primary care physi­cian. We decide to augment her regimen with aripiprazole, 10 mg/d, because this drug has been noted to help in cases of hyperprolactinemia associated with other antipsychotics.^2,3

Prolactin serves several roles in the body, including but not limited to lacta­tion, sexual gratification, proliferation of oligodendrocyte precursor cells, surfac­tant synthesis of fetal lungs at the end of pregnancy, and neurogenesis in maternal and fetal brains (Figure 1 and Figure 2). A 2004 review reported secondary amenor­rhea, galactorrhea, and osteopenia as com­mon symptoms of hyperprolactinemia.⁵ Hyperprolactinemia has been seen with most antipsychotics, both typical and atypical. Although several studies docu­ment prolactin elevation with risperidone, fewer have examined the active metabolite (9-hydroxyrisperidone) paliperidone.^5-7

In women, a high prolactin level can cause

a) menstrual disturbance
b) galactorrhea
c) breast engorgement
d) sexual dysfunction
e) all of the above


The authors’ observations
Acutely, hyperprolactinemia can cause menstrual abnormalities, decreased libido, breast engorgement, galactorrhea, and sexual dysfunction in women.⁸ In men, the most common symptoms of hyperprolac­tinemia are loss of interest in sex, erectile dysfunction, infertility, and gynecomas­tia. Osteoporosis has been associated with chronic elevation of the prolactin level⁸ (Table).

TREATMENT Adjunctive aripiprazole
After 8 weeks of adjunctive aripiprazole, Ms. S’s prolactin level decreases to 42 μg/L, but menses do not return. Because her family and primary care providers are eager to have the prolactin level return to nor­mal, reducing her risk of complications, we decide to decrease paliperidone to 3 mg at bedtime.
Eight weeks later, Ms. S shows functional improvement. A repeat test of prolactin is 24 μg/L; she reports a 4-day period of spotting 1 week ago. One month later, the prolactin level is 21 μg/L, and she reports having a normal menstrual period. She continues treatment with paliperidone, 3 mg/d, and aripiprazole, 10 mg/d, experiences regular menses, and continues teaching.


Pharmacotherapy of hyperprolactinemia includes

 

a) haloperidol
b) perphenazine
c) bromocriptine
d) olanzapine
e) risperidone

The authors' observations
Our goal in treating Ms. S was to address her schizophrenia symptoms and improve her overall functioning. Often, finding an effective treatment can be challeng­ing, and there is little evidence to support the efficacy of one antipsychotic over another.⁴ In Ms. S’s case, our care was stymied by the cost of medication, chal­lenges related to delusions intrinsic to the illness (she refused clozapine because of required blood draws), and adverse effects. When Ms. S developed amenorrhea while taking paliperidone— the only medication that showed sig­nificant improvement in her psychotic symptoms—our goal was to maintain her functional level without significant long-term adverse effects.

Managing hyperprolactinemia
Management of iatrogenic hyperprolac­tinemia includes decreasing the dosage of the offending agent, using a prolactin-sparing antipsychotic, or initiating a dopa­mine agonist, such as bromocriptine or cabergoline, in addition to an antipsy­chotic.^1,4 Aripiprazole is considered to be a prolactin-sparing agent because of its pro­pensity to increase the prolactin level to less of a degree than what is seen with other antipsychotics; in fact, it has been shown to reduce an elevated prolactin level.^9-11

Most typical and atypical antipsychotics are dopamine—specifically D2—receptor antagonists. These antipsychotics prevent dopamine from binding to the D2 recep­tor and from inhibiting prolactin release, therefore causing hyperprolactinemia. Aripiprazole differs from other antipsychot­ics: It is a partial D2 receptor agonist with high affinity, and therefore suppresses pro­lactin release.⁸ In a randomized controlled trial, aripiprazole had a lower rate of prolac­tin elevation compared with placebo.¹²

Aripiprazole’s ability to reduce an elevated prolactin level caused by other antipsychotics has been demonstrated in several studies with haloperidol,¹³ olan­zapine,^14,15 and risperidone.^15-17 There has been 1 case report,18 but no controlled stud­ies, of aripiprazole being used to decrease the prolactin level in patients treated with paliperidone.

In Ms. S’s case, adding aripiprazole, 10 mg/d, reduced her prolactin level by approximately 50%. Because several stud­ies have shown that adjunctive aripipra­zole with a D2 antagonist normalizes the prolactin level,¹⁹ it is reasonable to con­clude that adding aripiprazole facilitated reduction of her prolactin level and might have continued to do so if given more time. Regrettably, because of patient and fam­ily concerns, paliperidone was reduced before this could be determined. It is unclear whether normalization of Ms. S’s prolactin level and return of her menstrual cycle was caused by adding aripiprazole or by reducing the dosage of paliperidone.

Although additional randomized con­trolled trials should be conducted on the utility of this approach, it is reasonable to consider augmentation with aripiprazole when treating a patient who is stable on an antipsychotic, including paliperidone, but has developed hyperprolactinemia secondary to treatment.

BOTTOM LINE
Hyperprolactinemia is a relatively common, underreported side effect of both typical and atypical antipsychotics. Paliperidone and risperidone have been shown to have the highest risk among the atypical antipsychotics; aripiprazole has the lowest risk. Treatment of an elevated prolactin level should include reduction or discontinuation of the offending agent and augmentation with aripiprazole.

Related Resources
• Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review [published online March 28, 2014]. CNS Drugs. doi: 10.1007/s40263-014-0157-3.
• Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8(8):e70179. doi: 10.1371/journal.pone.0070179.

Drug Brand Names
Aripiprazole • Abilify               Haloperidol • Haldol
Benzatropine • Cogentin         Olanzapine • Zyprexa
Bromocriptine • Parlodel         Paliperidone • Invega
Cabergoline • Dostinex           Perphenazine • Trilafon
Clozapine • Clozaril                Risperidone • Risperdal
Fluphenazine • Prolixin

DisclosureThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

 

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

 

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

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

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

 

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

 

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

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

CASE Self Signing
Mrs. H, a 47-year-old, deaf, African American woman, is brought into the emergency room because she is becoming increasingly withdrawn and is signing to herself. She was hospitalized more than 10 years ago after de­veloping psychotic symptoms and received a diagnosis of psychotic disorder, not otherwise specified. She was treated with olanzapine, 10 mg/d, and valproic acid, 1,000 mg/d, but she has not seen a psychiatrist or taken any psy­chotropics in 8 years. Upon admission to the inpatient psychiatric unit, Mrs. H reports, through an American Sign Language (ASL) interpreter, that she has had “problems with her parents” and with “being fair” and that she is 18 months pregnant. Urine pregnancy test is negative. Mrs. H also reports that her mother is pregnant. She indicates that it is difficult for her to describe what she is try­ing to say and that it is difficult to be deaf. 

She endorses “very strong” racing thoughts, which she first states have been present for 15 years, then reports it has been 20 months. She endorses high-energy levels, feeling like there is “work to do,” and poor sleep. However, when asked, she indicates that she sleeps for 15 hours a day.

Which is critical when conducting a psychiatric assessment for a deaf patient?

   a) rely only on the ASL interpreter
   b) inquire about the patient’s communica­tion preferences
   c) use written language to communicate instead of speech
   d) use a family member as interpreter

The authors’ observations
Mental health assessment of a deaf a patient involves a unique set of challenges and requires a specialized skill set for mental health practitioners—a skill set that is not routinely covered in psychiatric training programs.

a We use the term “deaf” to describe patients who have severe hearing loss. Other terms, such as “hearing impaired,” might be considered pejorative in the Deaf community. The term “Deaf” (capitalized) refers to Deaf culture and community, which deaf patients may or may not identify with.

Deafness history
It is important to assess the cause of deafness,^1,2 if known, and its age of onset (Table 1). A person is considered to be pre­lingually deaf if hearing loss was diagnosed before age 3.² Clinicians should establish the patient’s communication preferences (use of assistive devices or interpreters or preference for lip reading), home commu­nication dynamic,² and language fluency level.^1-3 Ask the patient if she attended a specialized school for the deaf and, if so, if there was an emphasis on oral communica­tion or signing.²

HISTORY Conflicting reports
Mrs. H reports that she has been deaf since age 9, and that she learned sign language in India, where she became the “star king.” Mrs. H states that she then moved to the United States where she went to a school for the deaf. When asked if her family is able to communicate with her in sign language, she nods and indicates that they speak to her in “African and Indian.”

Mrs. H’s husband, who is hearing, says that Mrs. H is congenitally deaf, and was raised in the Midwestern United States where she at­tended a specialized school for the deaf. Mr. H and his 2 adult sons are hearing but commu­nicate with Mrs. H in basic ASL. He states that Mrs. H sometimes uses signs that he and his sons cannot interpret. In addition to increased self-preoccupation and self-signing, Mrs. H has become more impulsive.

What are limitations of the mental status examination when evaluating a deaf patient?

   a) facial expressions have a specific linguis­tic function in ASL
   b) there is no differentiation in the mental status exam of deaf patients from that of hearing patients
   c) the Mini-Mental State Examination (MMSE) is a validated tool to assess cogni­tion in deaf patients
   d) the clinician should not rely on the in­terpreter to assist with the mental status examination

The authors’ observation
Performing a mental status examination of a deaf patient without recognizing some of the challenges inherent to this task can lead to misleading findings. For example, sign­ing and gesturing can give the clinician an impression of psychomotor agitation.² What appears to be socially withdrawn behavior might be a reaction to the patient’s inability to communicate with others.^2,3 Social skills may be affected by language deprivation, if present.³ In ASL, facial expressions have specific linguistic functions in addition to representing emotions,² and can affect the meaning of the sign used. An exaggerated or intense facial expression with the sign “quiet,” for example, usually means “very quiet.”⁴ In assessing cognition, the MMSE is not available in ASL and has not been vali­dated in deaf patients.⁵ Also, deaf people have reduced access to information, and a lack of knowledge does not necessarily cor­relate with low IQ.²

 

The interpreter’s role
An ASL interpreter can aid in assessing a deaf patient’s communication skills. The interpreter can help with a thorough lan­guage evaluation^1,6 and provide information about socio-cultural norms in the Deaf community.⁷ Using an ASL interpreter with special training in mental health^1,3,6,7 is im­portant to accurately diagnose thought dis­orders in deaf patients.¹

EVALUATION Mental status exam
Mrs. H is poorly groomed and is wearing a pink housecoat, with her hair in disarray. She seems to be distracted by something next to the in­terpreter, because her eyes keep roving in this direction. She has moderate psychomotor agi­tation, based on the rapidity of her signing and gesturing. Mrs. H makes indecipherable vocal­izations while signing, often loud and with an urgent quality. Her affect is elevated and ex­pansive. She is not oriented to place or time and when asked where she is, signs, “many times, every day, 6-9-9, 2-5, more trouble…”

The ASL interpreter notes that Mrs. H signs so quickly that only about one-half of her signs are interpretable. Mrs. H’s grammar is not always correct and that her syntax is, at times, inappro­priate. Mrs. H’s letters are difficult to interpret because she often starts and concludes a word with a clear sign, but the intervening letters are rapid and uninterpretable. She also uses several non-alphabet signs that cannot be in­terpreted (approximately 10% to 15% of signs) and repeats signs without clear context, such as “nothing off.” Mrs. H can pause to clarify for the interpreter at the beginning of the interview but is not able to do so by the end of the interview.

How does assessment of psychosis differ when evaluating deaf patients?

   a) language dysfluency must be carefully differentiated from a thought disorder
   b) signing to oneself does not necessarily indicate a response to internal stimuli
   c) norms in Deaf culture might be miscon­strued as delusions
   d) all of the above

The authors’ observations
The prevalence of psychotic disorders among deaf patients is unknown.⁸ Although older studies have reported an increased prevalence of psychotic disorders among deaf patients, these studies suffer from methodological problems.¹ Other studies are at odds with each other, variably reporting a greater,⁹ equivalent,¹⁰ and lesser incidence of psychotic disorders in deaf psychiatric in­patients.¹¹ Deaf patients with psychotic dis­orders experience delusions, hallucinations, and thought disorders,^1,3 and assessing for these symptoms in deaf patients can present a diagnostic challenge (Table 2).

Delusions are thought to present simi­larly in deaf patients with psychotic dis­orders compared with hearing patients.^1,3 Paranoia may be increased in patients who are postlingually deaf, but has not been as­sociated with prelingual deafness. Deficits in theory of mind related to hearing im­pairment have been thought to contribute to delusions in deaf patients.^1,12

Many deaf patients distrust health care systems and providers,^2,3,13 which may be misinterpreted as paranoia. Poor commu­nication between deaf patients and clini­cians and poor health literacy among deaf patients contribute to feelings of mistrust. Deaf patients often report experiencing prejudice within the health care system, and think that providers lack sufficient knowledge of deafness.¹³ Care must be taken to ensure that Deaf cultural norms are not misinterpreted as delusions.

Hallucinations. How deaf patients expe­rience hallucinations, especially in prelingual deafness, likely is different from hallucinatory experiences of hearing patients.^1,14 Deaf people with psychosis have described ”ideas coming into one’s head” and an almost “telepathic” process of “knowing.”¹⁴ Deaf patients with schizo­phrenia are more likely to report visual elements to their hallucinations; however, these may be subvisual precepts rather than true visual hallucinations.^1,15 For ex­ample, hallucination might include the perception of being signed to.¹

Deaf patients’ experience of auditory hallucinations is thought to be closely re­lated to past auditory experiences. It is unlikely that prelingually deaf patients experience true auditory hallucinations.^1,14 An endorsement of hearing a “voice” in ASL does not necessarily translate to an audiological experience.¹⁵ If profoundly prelingually deaf patients endorse hearing voices, generally they cannot assign acous­tic properties (pitch, tone, volume, accent, etc.).^1,14,15 It may not be necessary to fully comprehend the precise modality of how hallucinations are experienced by deaf pa­tients to provide therapy.¹⁴

Self-signing, or signing to oneself, does not necessarily indicate that a deaf person is responding to a hallucinatory experience. Non-verbal patients may gesture to them­selves without clear evidence of psychosis. When considering whether a patient is ex­periencing hallucinations, it is important to look for other evidence of psychosis.³

Possible approaches to evaluating hal­lucinations in deaf patients include ask­ing,, “is someone signing in your head?” or “Is someone who is not in the room trying to communicate with you?”

 

Thought disorders in deaf psychiatric in­patients are difficult to diagnose, in part because of a high rate of language dysflu­ency in deaf patients; in samples of psychi­atric inpatients, 75% are not fluent in ASL, 66% are not fluent in any language).^1,3,11 Commonly, language dysfluency is related to language deprivation because of late or inadequate exposure to ASL, although it may be related to neurologic damage or aphasia.^1,3,6,16 Deaf patients can have addi­tional disabilities, including learning dis­abilities, that might contribute to language dysfluency.² Language dysfluency can be misattributed to a psychotic process^1-3,7 (Table 3).¹

Language dysfluency and thought dis­orders can be difficult to differentiate and may be comorbid. Loose associations and flight of ideas can be hard to assess in pa­tients with language dysfluency. In general, increasing looseness of association between concepts corresponds to an increasing like­lihood that a patient has true loose asso­ciations rather than language dysfluency alone.³ Deaf patients with schizophrenia can be identified by the presence of associ­ated symptoms of psychosis, especially if delusions are present.^1,3

EVALUATION Psychotic symptoms
Mrs. H’s thought process appears disorganized and illogical, with flight of ideas. She might have an underlying language dysfluency. It is likely that Mrs. H is using neologisms to communi­cate because of her family’s lack of familiarity with some of her signs. She also demonstrates perseveration, with use of certain signs repeat­edly without clear context (ie, “nothing off”).

Her thought content includes racial themes—she mentions Russia, Germany, and Vietnam without clear context—and delusions of being the “star king” and of being pregnant. She endorses paranoid feelings that people on the inpatient unit are trying to hurt her, al­though it isn’t clear whether this represents a true paranoid delusion because of the hectic climate of the unit, and she did not show unnecessarily defensive or guarded behaviors.

She is seen signing to herself in the dayroom and endorses feeling as though someone who is not in the room—described as an Indian teacher (and sometimes as a boss or principal) known as “Mr. Smith” or “Mr. Donald”—is trying to communicate with her. She describes this person as being male and female. She men­tions that sometimes she sees an Indian man and another man fighting. It is likely that Mrs. H is experiencing hallucinations from decompen­sated psychosis, because of the constellation and trajectory of her symptoms. Her nonverbal behavior—her eyes rove around the room dur­ing interviews—also supports this conclusion.

Because of evidence of mood and psychotic symptoms, and with a collateral history that suggests significant baseline disorganization, Mrs. H receives a diagnosis of schizoaffective disorder, bipolar type. She is restarted on olan­zapine, 10 mg/d, and valproic acid, 1,000 mg/d.

Mrs. H’s psychomotor acceleration and af­fective elevation gradually improve with phar­macotherapy. After a 2-week hospitalization, despite ongoing disorganization and self-sign­ing, Mrs. H’s husband says that he feels she is improved enough to return home, with plans to continue to take her medications and to re­establish outpatient follow-up.

Bottom Line

Psychiatric assessment of deaf patients presents distinctive challenges related to cultural and language barriers—making it important to engage an ASL interpreter with training in mental health during assessment of a deaf patient. Clinicians must become familiar with these challenges to provide effective care for mentally ill deaf patients.

Related Resources
• Landsberger SA, Diaz DR. Communicating with deaf pa­tients: 10 tips to deliver appropriate care. Current Psychiatry. 2010;9(6):36-37.
• Deaf Wellness Center. University of Rochester School of Medicine. www.urmc.rochester.edu/deaf-wellness-center.
• Gallaudet University Mental Health Center. www.gallaudet.edu/
mental_health_center.html.

Drug Brand Names
Olanzapine • Zyprexa
Valproic acid • Depakote

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

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

 

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

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

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

 

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

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

CASE Paranoid and confused

Mr. P, age 46, presents to the emergency department (ED) with a chief complaint of feeling “very weird.” Although he has seen a number of psychiatrists in the past, he does not recall being given a specific diagnosis. He describes his feelings as “1 minute I am fine and the next minute I am confused.” He endorses feeling paranoid for the past 6 to 12 months and reports a history of passive suicidal ideations. On the day he presents to the ED, however, he has a specific plan to shoot himself. He does not report audiovisual hallucinations, but has noticed that he talks to himself often.

Mr. P reports feeling worthless at times. He has a history of manic symptoms, including decreased need for sleep and hypersexuality. He describes verbal and sexual abuse by his foster parents. Mr. P reports using Cannabis and opioids occasionally and to drinking every “now and then” but not every day. He denies using benzodiazepines. When he is evaluated, he is not taking any medication and has no significant medical problems. Mr. P reports a history of several hospitalizations, but he could not describe the reasons or timing of past admissions.

Mr. P has a 10^th-grade education. He lives with his fiancée, who reports that he has been behaving oddly for some time. She noticed that he has memory problems and describes violent behavior, such as shaking his fist at her, breaking the television, and attempting to cut his throat once when he was “intoxicated.” She says she does not feel safe around him because of his labile mood and history of
aggression. She confirms that Mr. P does not drink daily but binge-drinks at times.

Initial mental status examination of evaluation reveals hyperverbal, rapid speech. Mr. P is circumstantial and tangential in his thought process. He has poor judgment and insight and exhibits suicidal ideations with a plan. Toxicology screening reveals a blood alcohol level of 50 mg/dL and is positive for Cannabis and opiates.

Which condition most likely accounts for Mr. P’s presentation?
    a) bipolar disorder, currently manic
    b) substance-induced mood disorder
    c) cognitive disorder
    d) delirium


TREATMENT Rapid improvement

From the ED, Mr. P was admitted to an inpatient psychiatric unit, where he was found initially to be disoriented to time, place, and person. His thought process remained disorganized and irrational, with significant memory difficulties. He is noted to have an unsteady gait. Nursing staff observes that Mr. P has significant difficulties with activities of daily living and requires assistance. He talks in circles
and uses nonsensical words.

His serum vitamin B₁₂ level, folate level, rapid plasma reagin, magnesium level, and thiamine level are within normal limits; CT scan of the brain is unremarkable. Neuropsychological testing reveals significant and diffuse cognitive deficits suggestive of frontal lobe dysfunction. He is deemed to not have decision-making capacity; because he has no family, his fiancée is appointed as his temporary health care proxy.

Thiamine and lorazepam are prescribed as needed because of Mr. P’s history of alcohol abuse. However, it’s determined that he does not need lorazepam because his vital signs are stable and there is no evidence of alcohol withdrawal symptoms.

During the course of his 10-day hospitalization, Mr. P’s cognitive difficulties resolved. He regains orientation to time, place, and person. He gains skill in all his activities of daily living, to the point of independence, and is discharged with minimal supervision. Vitamin B supplementation is prescribed, with close follow up in an outpatient day program. MRI/SPECT scan is considered to rule out frontotemporal dementia as recommended by the results of his neurocognitive testing profile.

Which condition likely account for Mr. P’s presentation during inpatient hospitalization?
    a) Wernicke’s encephalopathy
    b) Korsakoff’s syndrome
    c) malingering
    d) frontotemporal dementia
    e) a neurodegenerative disease

The author's observations

Mr. P’s fluctuating mental status, gait instability, and confabulation create high suspicion for Wernicke’s encephalopathy; his dramatic improvement with IV thiamine supports that diagnosis. Mr. P attends the outpatient day program once after his discharge, and is then lost to follow-up.

During inpatient stay, Mr. P eventually admits to binge drinking several times a week, and drinking early in the morning, which would continue throughout the day. His significant cognitive deficits revealed by neuropsychological testing suggests consideration of a differential diagnosis of multifactorial cognitive dysfunction because of:
   • long-term substance use
   • Korsakoff’s syndrome
   • frontotemporal dementia
   • a neurodegenerative disease
   • malingering (Table 1).

Wernicke’s encephalopathy
Wernicke’s encephalopathy is a life-threatening neurologic disorder caused by thiamine deficiency. The disease is rare, catastrophic in onset, and clinically complex¹; as in Mr. P’s case, diagnosis often is delayed. In autopsy studies, the reported prevalence of Wernicke’s encephalopathy is 0.4% to 2.8%.1 Wernicke’s encephalopathy was suspected before death in 33% of alcohol-dependent patientsand 6% of nonalcoholics.¹ Other causes of Wernicke’s encephalopathy include cancer, gastrointestinal surgery, hyperemesis gravidarum, a starvation or malnutrition state, GI tract disease, AIDS, parenteral nutrition, repetitive vomiting, and infection.¹

 

Diagnosis. Making the correct diagnosis is challenging because the clinical presentation can be variable. No lab or imaging studies confirm the diagnosis. The triad of signs considered to support the diagnosis include ocular signs such as nystagmus, cerebellar signs, and confusion. These signs occur in only 8% to 10% of patients in whom the diagnosis likely.^1,2

Attempts to increase the likelihood of making an accurate lifetime diagnosis of
Wernicke’s encephalopathy include expanding the focus to 8 clinical domains:
   • dietary deficiency
   • eye signs
   • cerebellar signs
   • seizures
   • frontal lobe dysfunction
   • amnesia
   • mild memory impairment
   • altered mental status.¹

The sensitivity of making a correct diagnosis increases to 85% if at least 2 of 4 features—namely dietary deficiency, eye signs, cerebellar signs, memory impairment, and altered mental status—are present. These criteria can be applied to alcoholic and nonalcoholic patients.¹Table 2_³ lists common and uncommon symptoms of Wernicke’s encephalopathy.

Although CT scan of the brain is not a reliable test for the disorder, MRI can be powerful tool that could support a diagnosis of acute Wernicke’s encephalopathy.¹ We did not consider MRI in Mr. P’s case because the consulting neurologist thought this was unnecessary because of the quick improvement in his cognitive status with IV thiamine—although MRI might have helped to detect the disease earlier. In some studies, brain MRI revealed lesions in two-thirds of Wernicke’s encephalopathy patients.¹ Typically, lesions are symmetrical and seen in the thalamus, mammillary body, and periaqueductal areas.^1,4 Atypical lesions commonly are seen in the cerebellum, dentate nuclei, caudate nucleus, and cerebral cortex.¹

Treatment. Evidence supports use of IV thiamine, 200 mg 3 times a day, when the disease is suspected or established.^1,2 Thiamine has been associated with sporadic anaphylactic reactions, and should be administered when resuscitation facilities are available. Do not delay treatment because resuscitation measures are unavailable because you risk causing irreversible brain damage.¹

In Mr. P’s case, prompt recognition of the need for thiamine likely led to a better outcome. Thiamine supplementation can prevent Wernicke’s encephalopathy in some patients. Prophylactic parenteral administration of thiamine before administration of glucose in the ED is recommended, as well as vitamin B supplementation with thiamine included upon discharge.^1,2 Studies support several treatment regimens for patients with Wernicke’s encephalopathy and those at risk of it.^1,3,5

Neither the optimal dosage of thiamine nor the appropriate duration of treatment have been determined by randomized, double-blind, controlled studies; empirical clinical practice and recommendations by Royal College of Physicians, London, suggest that a more prolonged course of thiamine—administered as long as improvement continues—might be beneficial.⁶

Left untreated, Wernicke’s encephalopathy can lead to irreversible brain damage.²
Mortality has been reported as 17% to 20%; 82% of patients develop Korsakoff’s syndrome, a chronic condition characterized by short-term memory loss. One-quarter of patients who develop Korsakoff’s syndrome require long-term residential care because of permanent brain damage.²

Making a diagnosis of Wernicke’s encephalopathy is a challenge because no specific symptom or diagnostic test can be relied upon to confirm the diagnosis. Also, patients might deny that they have an alcohol problem or give an inaccurate history of their alcohol use,² as Mr. P did. The disorder is substantially underdiagnosed; as a consequence, patients are at risk of brain damage.²

Bottom Line

Not all patients who present with aggressive behavior, mania, and psychiatric
symptoms have a primary psychiatric diagnosis. It is important to consider
nutritional deficiencies caused by chronic alcohol abuse in patients presenting
with acute onset of confusion or altered mental status. Wernicke’s encephalopathy
might be the result of alcohol abuse and can be treated with IV thiamine.

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

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K’s husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone,
6 mg/d. Her psychiatrist started paliperidone 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9ºC (85.8ºF) via bladder probe.

The authors’ observations

Hypothermia is core body temperature <35ºC (95ºF).¹ It often is caused by exposure to low ambient temperature (Table 1),¹ but Ms. K’s husband denied that she had been exposed to cold. Because of Ms. K’s neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions—she believed that her caregivers were trying to harm her—she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes.² These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit.³ Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging.² Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability.⁴

Before her AVM rupture, review of Ms. K’s psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of divalproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 ×10³/μL), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; CO₂, 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia.¹

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia.¹ Head CT and brain MRI show chronic changes after Ms. K’s right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolactinemia of 155.7 ng/mL, a known adverse effect of antipsychotics.⁵

 

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸

 

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature.^7,8 Kudoh et al¹⁹ investigated temperature regulation during anesthesia in patients with chronic (≥7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3).^7-12,15 The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral á-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as “drug intolerance.”

This case also highlights the importance of adequate medication reconciliation at
admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.

Bottom Line

Thermal dysregulation—hyperthermia and hypothermia—can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.

Related Resource

• Espay AJ, et al. Frontal lobe syndromes. http://emedicine.medscape.com/article/1135866-overview. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Aripiprazole • Abilify                    Lamotrigine • Lamictal
Bromocriptine • Parlodel              Lorazepam • Ativan
Chlorpromazine • Thorazine         Paliperidone • Invega
Citalopram • Celexa                    Risperidone • Risperdal
Clozapine • Clozaril                     Sertraline • Zoloft
Divalproex sodium • Depakote     Thioridazine • Mellaril

Disclosure

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

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K’s husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone,
6 mg/d. Her psychiatrist started paliperidone 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9ºC (85.8ºF) via bladder probe.

The authors’ observations

Hypothermia is core body temperature <35ºC (95ºF).¹ It often is caused by exposure to low ambient temperature (Table 1),¹ but Ms. K’s husband denied that she had been exposed to cold. Because of Ms. K’s neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions—she believed that her caregivers were trying to harm her—she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes.² These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit.³ Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging.² Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability.⁴

Before her AVM rupture, review of Ms. K’s psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of divalproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 ×10³/μL), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; CO₂, 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia.¹

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia.¹ Head CT and brain MRI show chronic changes after Ms. K’s right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolactinemia of 155.7 ng/mL, a known adverse effect of antipsychotics.⁵

 

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸

 

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature.^7,8 Kudoh et al¹⁹ investigated temperature regulation during anesthesia in patients with chronic (≥7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3).^7-12,15 The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral á-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as “drug intolerance.”

This case also highlights the importance of adequate medication reconciliation at
admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.

Bottom Line

Thermal dysregulation—hyperthermia and hypothermia—can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.

Related Resource

• Espay AJ, et al. Frontal lobe syndromes. http://emedicine.medscape.com/article/1135866-overview. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Aripiprazole • Abilify                    Lamotrigine • Lamictal
Bromocriptine • Parlodel              Lorazepam • Ativan
Chlorpromazine • Thorazine         Paliperidone • Invega
Citalopram • Celexa                    Risperidone • Risperdal
Clozapine • Clozaril                     Sertraline • Zoloft
Divalproex sodium • Depakote     Thioridazine • Mellaril

Disclosure

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