Case-Based Review

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CASE: Paranoid and scared

Police bring Mr. C, age 42, to a local crisis center after he is found masturbating in public the same day he was released from jail after serving time for the same behavior. Previously, Mr. C was diagnosed with schizophrenia, paranoid type, and alcohol dependence. He is single, unemployed, and lives with his parents. He has had 3 previous admissions to a psychiatric hospital, but no preexisting medical illness. A judge involuntarily commits Mr. C to our psychiatric facility.

Mr. C looks older than his age and has poor hygiene. He appears bizarre, makes poor eye contact, and speaks slowly but with normal volume. His speech is not coherent, relevant, or goal-directed. He is not able to answer questions properly, chanting “it’s eternity, eternity, eternity.” He shows no tremors, repetitive motor behavior, or muscle rigidity. His affect is flat and he has no suicidal or homicidal ideations. Based on Mr. C’s history, we diagnose him with schizophrenia, paranoid type and alcohol dependence.

Over the next 9 days, Mr. C receives trials of haloperidol, lorazepam, diphenhydramine, ziprasidone, olanzapine, hydroxyzine, trazodone, and benztropine to treat his schizophrenia. From days 1 to 3, all medications are given on an as-needed basis. On day 1, Mr. C receives haloperidol, 20 mg, lorazepam, 9 mg, diphenhydramine, 150 mg, and ziprasidone, 20 mg. On day 2, he receives haloperidol, 15 mg, lorazepam, 10 mg, olanzapine, 20 mg, hydroxyzine, 100 mg, and trazodone, 50 mg. On day 3, he receives haloperidol, 20 mg, lorazepam, 6 mg, and trazodone, 100 mg. On days 4 to 8, in addition to scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d, he receives haloperidol, 5 mg, and lorazepam, 2 mg, as needed. On day 9, he receives the scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d.

During his stay, Mr. C is incoherent and disorganized. On day 9, he eats all of his lunch, none of his dinner, but sips milk and juice and eats snacks. He drinks 2 small cups of water with medication and 2 small cups of water during oral care. His mucosa and tongue are dry. At 11:30 pm, while lying in bed mumbling “scared, scared,” he experiences shortness of breath. His temperature is 99.6°F, blood pressure is 151/93 mm Hg, pulse is 125 beats per minute, respiratory rate is 40 breaths per minute, and oxygen saturation is 91% on ambient air. Twenty minutes later, his blood pressure increases to 180/120 mm Hg. On physical examination, he has “lead pipe” rigidity of both arms. He is awake, confused, and not able to communicate, still mumbling “scared, scared.” Changes in his blood pressure, pulse, and temperature during his stay in the psychiatric hospital are depicted in Figures 1 and 2, respectively.

Figure 1: Mr. C’s blood pressure and pulse changes from day 4 to day 9 in the psychiatric hospital
BP: blood pressure

Figure 2: Mr. C’s temperature changes from day 4 to day 9 in the psychiatric hospital

The authors’ observations

NMS is a life-threatening, iatrogenic neurologic emergency associated with antipsychotic use. Early incidence rate estimates ran as high as 3% of patients treated with antipsychotics; however, more recent data suggest an incidence of 0.01% to 0.02%.¹ This decrease in frequency likely reflects increased awareness of the disorder, more conservative prescribing patterns, and a shift to using atypical antipsychotics.² In the mid 1980s and early 1990s the mortality rate was 25% to 30% if NMS was not promptly recognized and treated³; however, progression to more fulminant, lethal NMS episodes now occurs less often and the mortality rate ranges from 10% to 20%.⁴

If NMS is suspected, immediate transfer to an emergency department (ED) is necessary. Even with early diagnosis, however, complications of NMS are still likely, including:

• rhabdomyolysis
• renal failure
• seizures
• respiratory failure
• aspiration pneumonia
• disseminated intravascular coagulation
• venous thromboembolism.^5-9

Caroff et al reported observing a residual catatonic state after acute NMS symptoms subsided.¹⁰

Although the pathophysiology of NMS is complex—involving a cascade of dysregulation in multiple neurochemical and neuroendocrine systems—dopamine blockade likely plays a pivotal role in triggering the condition.² In addition, evidence supports the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most NMS features.¹¹

TREATMENT: Arrival in the ED

Based on his elevated blood pressure (151/93 mm Hg), “lead pipe” rigidity, and increased body temperature associated with Mr. C’s history of haloperidol use for 9 days, the treatment team suspects NMS. Labile blood pressure, which changed from 151/93 to 180/120 mm Hg in 20 minutes, reinforces the NMS diagnosis. Approximately 30 minutes after Mr. C shows signs of NMS, he is transferred to a local ED. He is awake, alert, and communicative after he arrives in the ED, but becomes confused and noncommunicative the next morning. When he arrives in the ED, he is found to have tachycardia (114 beats per minute), tachypnea (26 breaths per minute), blood pressure of 132/84 mm Hg, and temperature of 102°F. In the ED, he is given IV normal saline, diphenhydramine, 25 mg, and IV lorazepam, 1 mg. His rigidity slightly improves.

Early the next morning, his blood pressure is 182/89 mm Hg, respirations are 30 to 40 breaths per minute, and heart rate is 120 beats per minute. He then receives IV lorazepam, 2 mg, after which his tachypnea, tachycardia, and elevated blood pressure improve.

The authors’ observations

A case-control study by Keck et al¹² comparing 18 patients with NMS and 36 matched neuroleptic-treated patients with no history of the syndrome identified greater psychomotor agitation, significantly higher doses of neuroleptics, greater rates of dosage increase, and a greater number of IM injections as potential risk factors. Other potential risk factors include use of restraints, pre-existing CNS dopamine activity or receptor function abnormalities, and iron deficiency.² Agitation, dehydration, and exhaustion were found to be the most consistent systemic factors predisposing patients taking antipsychotics to NMS in small case-control studies.^13,14 Well-supported risk factors also include use of high-potency antipsychotics, prior episodes of NMS, age <40, male sex, malnutrition, organic brain syndromes, and lithium use.^3,5,15

There is no way to predict the risk of NMS for an individual patient. Usually, symptoms develop within 4 weeks of starting an antipsychotic, but can occur after taking the same dose for many months. The onset may be within hours, but on average it is 4 to 14 days after initiating therapy. Among patients who develop NMS, 90% do so within 10 days.^3,5

Mr. C’s risk factors include high-potency antipsychotic use, male sex, relatively high dose (haloperidol, 30 to 35 mg/d), agitation, dehydration, and exhaustion.

Managing NMS

The standard approaches for managing patients with NMS include discontinuing suspected triggering drugs and providing supportive care. Beyond supportive care, oral or IV benzodiazepines may relieve symptoms and speed recovery.² Dopaminergic drugs, such as bromocriptine or amantadine, used alone or with other treatments, can reduce parkinsonism and disease duration and mortality.² Dantrolene may be useful only for NMS patients who exhibit extreme temperature elevations, rigidity, and true hypermetabolism.¹⁶ Electroconvulsive therapy may be effective for NMS patients whose symptoms do not respond to supportive care and drug therapy or those with residual catatonic or parkinsonian symptoms.²

OUTCOME: Improvement, discharge

Mr. C is admitted to the hospital with the diagnosis of NMS and transferred to the intensive care unit (ICU) for treatment. After Mr. C is admitted to the ICU, apart from continuing the medication given in the ED, he also receives dantrolene, 2 mg/kg, then 1 mg/kg, 4 times a day, as well as IV lorazepam, 1 mg every 6 hours. His other medications include IV pantoprazole, 40 mg/d, for prophylaxis of stress ulcer. Diphenhydramine administration is changed to as needed. On the second day in the ICU, he has only mild upper extremity rigidity but no lower extremity rigidity. However, he suffers 1 seizure, which is treated with IV fosphenytoin at the loading dose, 18 mg/kg, then a maintaining dose of 5 mg phenytoin equivalent/kg/d.

Figure 3: Mr. C’s creatine kinase level (IU/L) during the first 5 days in the intensive care unit

Figure 4: Mr. C’s blood pressure before and after admission

Figure 5: Mr. C’s temperature before and after admissionMr. C remains in the ICU for 7 days. There he receives valproic acid, titrated to 500 mg in the morning and 1,000 mg at bedtime, for agitation. He also receives olanzapine, 5 mg/d, for psychotic symptoms. He develops deep vein thrombosis in the right cephalic vein, which is treated with subcutaneous enoxaparin, 1 mg/kg, and warfarin, 5 mg/d.

He is discharged from the hospital after 2 weeks and returns to the psychiatric facility. He continues to be treated for paranoid schizophrenia with olanzapine, 5 mg/d.

The authors’ observations

High-potency, typical antipsychotics can cause NMS, as shown in Mr. C’s case. It also can be caused by typical low-potency antipsychotics,³ atypical antipsychotics,¹⁷ antiemetic drugs,¹⁸ and lithium,^19,20 and can occur after the withdrawal of levodopa and similar dopaminergic agents during Parkinson’s disease treatment.²¹ Atypical antipsychotics reported to be associated with NMS include clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and paliperidone.^22-27 Atypical antipsychotic-induced NMS also has been reported in children and adolescents.^22,28-30

With the broad application of atypical antipsychotics, physicians should be aware of atypical NMS presentation. Although NMS diagnosis commonly requires core symptoms of hyperthermia and muscle rigidity (Table 1 and 2),³¹ atypical presentations may not demonstrate temperature changes and/or muscle rigidity or may progress slowly over several days, leading to a delay in diagnosis and treatment.^28,30,32,33 Therefore, clinicians should evaluate any patient taking antipsychotics for features of NMS and not prematurely exclude a NMS diagnosis in cases where severe rigidity or hyperthermia is not initially apparent.³³

Table 1

DSM-IV-TR criteria for neuroleptic malignant syndrome

Table 2

Diagnostic features of neuroleptic malignant syndrome

Related Resource

• Neuroleptic Malignant Syndrome Information Service. www.nmsis.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Diphenhydramine • Benadryl
• Enoxaparin • Lovenox
• Fosphenytoin • Cerebyx
• Haloperidol • Haldol
• Hydroxyzine • Vistaril
• Levodopa • Sinemet
• Lithium • Eskalith, Lithobid, others
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Pantoprazole • Protonix
• Phenytoin • Dilantin
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproic acid • Depakote
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

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

Acknowledgements

The authors are very grateful for the critical reviews by James R. Allen, MD, MPH, professor of Child and Adolescent Psychiatry Fellowship Program at the University of Oklahoma and Lori Hake, DO, director of Psychiatry Residency Training Program at Griffin Memorial Hospital in Norman, OK.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Paranoid and scared

Police bring Mr. C, age 42, to a local crisis center after he is found masturbating in public the same day he was released from jail after serving time for the same behavior. Previously, Mr. C was diagnosed with schizophrenia, paranoid type, and alcohol dependence. He is single, unemployed, and lives with his parents. He has had 3 previous admissions to a psychiatric hospital, but no preexisting medical illness. A judge involuntarily commits Mr. C to our psychiatric facility.

Mr. C looks older than his age and has poor hygiene. He appears bizarre, makes poor eye contact, and speaks slowly but with normal volume. His speech is not coherent, relevant, or goal-directed. He is not able to answer questions properly, chanting “it’s eternity, eternity, eternity.” He shows no tremors, repetitive motor behavior, or muscle rigidity. His affect is flat and he has no suicidal or homicidal ideations. Based on Mr. C’s history, we diagnose him with schizophrenia, paranoid type and alcohol dependence.

Over the next 9 days, Mr. C receives trials of haloperidol, lorazepam, diphenhydramine, ziprasidone, olanzapine, hydroxyzine, trazodone, and benztropine to treat his schizophrenia. From days 1 to 3, all medications are given on an as-needed basis. On day 1, Mr. C receives haloperidol, 20 mg, lorazepam, 9 mg, diphenhydramine, 150 mg, and ziprasidone, 20 mg. On day 2, he receives haloperidol, 15 mg, lorazepam, 10 mg, olanzapine, 20 mg, hydroxyzine, 100 mg, and trazodone, 50 mg. On day 3, he receives haloperidol, 20 mg, lorazepam, 6 mg, and trazodone, 100 mg. On days 4 to 8, in addition to scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d, he receives haloperidol, 5 mg, and lorazepam, 2 mg, as needed. On day 9, he receives the scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d.

During his stay, Mr. C is incoherent and disorganized. On day 9, he eats all of his lunch, none of his dinner, but sips milk and juice and eats snacks. He drinks 2 small cups of water with medication and 2 small cups of water during oral care. His mucosa and tongue are dry. At 11:30 pm, while lying in bed mumbling “scared, scared,” he experiences shortness of breath. His temperature is 99.6°F, blood pressure is 151/93 mm Hg, pulse is 125 beats per minute, respiratory rate is 40 breaths per minute, and oxygen saturation is 91% on ambient air. Twenty minutes later, his blood pressure increases to 180/120 mm Hg. On physical examination, he has “lead pipe” rigidity of both arms. He is awake, confused, and not able to communicate, still mumbling “scared, scared.” Changes in his blood pressure, pulse, and temperature during his stay in the psychiatric hospital are depicted in Figures 1 and 2, respectively.

Figure 1: Mr. C’s blood pressure and pulse changes from day 4 to day 9 in the psychiatric hospital
BP: blood pressure

Figure 2: Mr. C’s temperature changes from day 4 to day 9 in the psychiatric hospital

The authors’ observations

NMS is a life-threatening, iatrogenic neurologic emergency associated with antipsychotic use. Early incidence rate estimates ran as high as 3% of patients treated with antipsychotics; however, more recent data suggest an incidence of 0.01% to 0.02%.¹ This decrease in frequency likely reflects increased awareness of the disorder, more conservative prescribing patterns, and a shift to using atypical antipsychotics.² In the mid 1980s and early 1990s the mortality rate was 25% to 30% if NMS was not promptly recognized and treated³; however, progression to more fulminant, lethal NMS episodes now occurs less often and the mortality rate ranges from 10% to 20%.⁴

If NMS is suspected, immediate transfer to an emergency department (ED) is necessary. Even with early diagnosis, however, complications of NMS are still likely, including:

• rhabdomyolysis
• renal failure
• seizures
• respiratory failure
• aspiration pneumonia
• disseminated intravascular coagulation
• venous thromboembolism.^5-9

Caroff et al reported observing a residual catatonic state after acute NMS symptoms subsided.¹⁰

Although the pathophysiology of NMS is complex—involving a cascade of dysregulation in multiple neurochemical and neuroendocrine systems—dopamine blockade likely plays a pivotal role in triggering the condition.² In addition, evidence supports the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most NMS features.¹¹

TREATMENT: Arrival in the ED

Based on his elevated blood pressure (151/93 mm Hg), “lead pipe” rigidity, and increased body temperature associated with Mr. C’s history of haloperidol use for 9 days, the treatment team suspects NMS. Labile blood pressure, which changed from 151/93 to 180/120 mm Hg in 20 minutes, reinforces the NMS diagnosis. Approximately 30 minutes after Mr. C shows signs of NMS, he is transferred to a local ED. He is awake, alert, and communicative after he arrives in the ED, but becomes confused and noncommunicative the next morning. When he arrives in the ED, he is found to have tachycardia (114 beats per minute), tachypnea (26 breaths per minute), blood pressure of 132/84 mm Hg, and temperature of 102°F. In the ED, he is given IV normal saline, diphenhydramine, 25 mg, and IV lorazepam, 1 mg. His rigidity slightly improves.

Early the next morning, his blood pressure is 182/89 mm Hg, respirations are 30 to 40 breaths per minute, and heart rate is 120 beats per minute. He then receives IV lorazepam, 2 mg, after which his tachypnea, tachycardia, and elevated blood pressure improve.

The authors’ observations

A case-control study by Keck et al¹² comparing 18 patients with NMS and 36 matched neuroleptic-treated patients with no history of the syndrome identified greater psychomotor agitation, significantly higher doses of neuroleptics, greater rates of dosage increase, and a greater number of IM injections as potential risk factors. Other potential risk factors include use of restraints, pre-existing CNS dopamine activity or receptor function abnormalities, and iron deficiency.² Agitation, dehydration, and exhaustion were found to be the most consistent systemic factors predisposing patients taking antipsychotics to NMS in small case-control studies.^13,14 Well-supported risk factors also include use of high-potency antipsychotics, prior episodes of NMS, age <40, male sex, malnutrition, organic brain syndromes, and lithium use.^3,5,15

There is no way to predict the risk of NMS for an individual patient. Usually, symptoms develop within 4 weeks of starting an antipsychotic, but can occur after taking the same dose for many months. The onset may be within hours, but on average it is 4 to 14 days after initiating therapy. Among patients who develop NMS, 90% do so within 10 days.^3,5

Mr. C’s risk factors include high-potency antipsychotic use, male sex, relatively high dose (haloperidol, 30 to 35 mg/d), agitation, dehydration, and exhaustion.

Managing NMS

The standard approaches for managing patients with NMS include discontinuing suspected triggering drugs and providing supportive care. Beyond supportive care, oral or IV benzodiazepines may relieve symptoms and speed recovery.² Dopaminergic drugs, such as bromocriptine or amantadine, used alone or with other treatments, can reduce parkinsonism and disease duration and mortality.² Dantrolene may be useful only for NMS patients who exhibit extreme temperature elevations, rigidity, and true hypermetabolism.¹⁶ Electroconvulsive therapy may be effective for NMS patients whose symptoms do not respond to supportive care and drug therapy or those with residual catatonic or parkinsonian symptoms.²

OUTCOME: Improvement, discharge

Mr. C is admitted to the hospital with the diagnosis of NMS and transferred to the intensive care unit (ICU) for treatment. After Mr. C is admitted to the ICU, apart from continuing the medication given in the ED, he also receives dantrolene, 2 mg/kg, then 1 mg/kg, 4 times a day, as well as IV lorazepam, 1 mg every 6 hours. His other medications include IV pantoprazole, 40 mg/d, for prophylaxis of stress ulcer. Diphenhydramine administration is changed to as needed. On the second day in the ICU, he has only mild upper extremity rigidity but no lower extremity rigidity. However, he suffers 1 seizure, which is treated with IV fosphenytoin at the loading dose, 18 mg/kg, then a maintaining dose of 5 mg phenytoin equivalent/kg/d.

Figure 3: Mr. C’s creatine kinase level (IU/L) during the first 5 days in the intensive care unit

Figure 4: Mr. C’s blood pressure before and after admission

Figure 5: Mr. C’s temperature before and after admissionMr. C remains in the ICU for 7 days. There he receives valproic acid, titrated to 500 mg in the morning and 1,000 mg at bedtime, for agitation. He also receives olanzapine, 5 mg/d, for psychotic symptoms. He develops deep vein thrombosis in the right cephalic vein, which is treated with subcutaneous enoxaparin, 1 mg/kg, and warfarin, 5 mg/d.

He is discharged from the hospital after 2 weeks and returns to the psychiatric facility. He continues to be treated for paranoid schizophrenia with olanzapine, 5 mg/d.

The authors’ observations

High-potency, typical antipsychotics can cause NMS, as shown in Mr. C’s case. It also can be caused by typical low-potency antipsychotics,³ atypical antipsychotics,¹⁷ antiemetic drugs,¹⁸ and lithium,^19,20 and can occur after the withdrawal of levodopa and similar dopaminergic agents during Parkinson’s disease treatment.²¹ Atypical antipsychotics reported to be associated with NMS include clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and paliperidone.^22-27 Atypical antipsychotic-induced NMS also has been reported in children and adolescents.^22,28-30

With the broad application of atypical antipsychotics, physicians should be aware of atypical NMS presentation. Although NMS diagnosis commonly requires core symptoms of hyperthermia and muscle rigidity (Table 1 and 2),³¹ atypical presentations may not demonstrate temperature changes and/or muscle rigidity or may progress slowly over several days, leading to a delay in diagnosis and treatment.^28,30,32,33 Therefore, clinicians should evaluate any patient taking antipsychotics for features of NMS and not prematurely exclude a NMS diagnosis in cases where severe rigidity or hyperthermia is not initially apparent.³³

Table 1

DSM-IV-TR criteria for neuroleptic malignant syndrome

Table 2

Diagnostic features of neuroleptic malignant syndrome

Related Resource

• Neuroleptic Malignant Syndrome Information Service. www.nmsis.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Diphenhydramine • Benadryl
• Enoxaparin • Lovenox
• Fosphenytoin • Cerebyx
• Haloperidol • Haldol
• Hydroxyzine • Vistaril
• Levodopa • Sinemet
• Lithium • Eskalith, Lithobid, others
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Pantoprazole • Protonix
• Phenytoin • Dilantin
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproic acid • Depakote
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

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

Acknowledgements

The authors are very grateful for the critical reviews by James R. Allen, MD, MPH, professor of Child and Adolescent Psychiatry Fellowship Program at the University of Oklahoma and Lori Hake, DO, director of Psychiatry Residency Training Program at Griffin Memorial Hospital in Norman, OK.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Paranoid and scared

Police bring Mr. C, age 42, to a local crisis center after he is found masturbating in public the same day he was released from jail after serving time for the same behavior. Previously, Mr. C was diagnosed with schizophrenia, paranoid type, and alcohol dependence. He is single, unemployed, and lives with his parents. He has had 3 previous admissions to a psychiatric hospital, but no preexisting medical illness. A judge involuntarily commits Mr. C to our psychiatric facility.

Mr. C looks older than his age and has poor hygiene. He appears bizarre, makes poor eye contact, and speaks slowly but with normal volume. His speech is not coherent, relevant, or goal-directed. He is not able to answer questions properly, chanting “it’s eternity, eternity, eternity.” He shows no tremors, repetitive motor behavior, or muscle rigidity. His affect is flat and he has no suicidal or homicidal ideations. Based on Mr. C’s history, we diagnose him with schizophrenia, paranoid type and alcohol dependence.

Over the next 9 days, Mr. C receives trials of haloperidol, lorazepam, diphenhydramine, ziprasidone, olanzapine, hydroxyzine, trazodone, and benztropine to treat his schizophrenia. From days 1 to 3, all medications are given on an as-needed basis. On day 1, Mr. C receives haloperidol, 20 mg, lorazepam, 9 mg, diphenhydramine, 150 mg, and ziprasidone, 20 mg. On day 2, he receives haloperidol, 15 mg, lorazepam, 10 mg, olanzapine, 20 mg, hydroxyzine, 100 mg, and trazodone, 50 mg. On day 3, he receives haloperidol, 20 mg, lorazepam, 6 mg, and trazodone, 100 mg. On days 4 to 8, in addition to scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d, he receives haloperidol, 5 mg, and lorazepam, 2 mg, as needed. On day 9, he receives the scheduled haloperidol, 30 mg/d, benztropine, 1 mg/d, and trazodone, 100 mg/d.

During his stay, Mr. C is incoherent and disorganized. On day 9, he eats all of his lunch, none of his dinner, but sips milk and juice and eats snacks. He drinks 2 small cups of water with medication and 2 small cups of water during oral care. His mucosa and tongue are dry. At 11:30 pm, while lying in bed mumbling “scared, scared,” he experiences shortness of breath. His temperature is 99.6°F, blood pressure is 151/93 mm Hg, pulse is 125 beats per minute, respiratory rate is 40 breaths per minute, and oxygen saturation is 91% on ambient air. Twenty minutes later, his blood pressure increases to 180/120 mm Hg. On physical examination, he has “lead pipe” rigidity of both arms. He is awake, confused, and not able to communicate, still mumbling “scared, scared.” Changes in his blood pressure, pulse, and temperature during his stay in the psychiatric hospital are depicted in Figures 1 and 2, respectively.

Figure 1: Mr. C’s blood pressure and pulse changes from day 4 to day 9 in the psychiatric hospital
BP: blood pressure

Figure 2: Mr. C’s temperature changes from day 4 to day 9 in the psychiatric hospital

The authors’ observations

NMS is a life-threatening, iatrogenic neurologic emergency associated with antipsychotic use. Early incidence rate estimates ran as high as 3% of patients treated with antipsychotics; however, more recent data suggest an incidence of 0.01% to 0.02%.¹ This decrease in frequency likely reflects increased awareness of the disorder, more conservative prescribing patterns, and a shift to using atypical antipsychotics.² In the mid 1980s and early 1990s the mortality rate was 25% to 30% if NMS was not promptly recognized and treated³; however, progression to more fulminant, lethal NMS episodes now occurs less often and the mortality rate ranges from 10% to 20%.⁴

If NMS is suspected, immediate transfer to an emergency department (ED) is necessary. Even with early diagnosis, however, complications of NMS are still likely, including:

• rhabdomyolysis
• renal failure
• seizures
• respiratory failure
• aspiration pneumonia
• disseminated intravascular coagulation
• venous thromboembolism.^5-9

Caroff et al reported observing a residual catatonic state after acute NMS symptoms subsided.¹⁰

Although the pathophysiology of NMS is complex—involving a cascade of dysregulation in multiple neurochemical and neuroendocrine systems—dopamine blockade likely plays a pivotal role in triggering the condition.² In addition, evidence supports the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most NMS features.¹¹

TREATMENT: Arrival in the ED

Based on his elevated blood pressure (151/93 mm Hg), “lead pipe” rigidity, and increased body temperature associated with Mr. C’s history of haloperidol use for 9 days, the treatment team suspects NMS. Labile blood pressure, which changed from 151/93 to 180/120 mm Hg in 20 minutes, reinforces the NMS diagnosis. Approximately 30 minutes after Mr. C shows signs of NMS, he is transferred to a local ED. He is awake, alert, and communicative after he arrives in the ED, but becomes confused and noncommunicative the next morning. When he arrives in the ED, he is found to have tachycardia (114 beats per minute), tachypnea (26 breaths per minute), blood pressure of 132/84 mm Hg, and temperature of 102°F. In the ED, he is given IV normal saline, diphenhydramine, 25 mg, and IV lorazepam, 1 mg. His rigidity slightly improves.

Early the next morning, his blood pressure is 182/89 mm Hg, respirations are 30 to 40 breaths per minute, and heart rate is 120 beats per minute. He then receives IV lorazepam, 2 mg, after which his tachypnea, tachycardia, and elevated blood pressure improve.

The authors’ observations

A case-control study by Keck et al¹² comparing 18 patients with NMS and 36 matched neuroleptic-treated patients with no history of the syndrome identified greater psychomotor agitation, significantly higher doses of neuroleptics, greater rates of dosage increase, and a greater number of IM injections as potential risk factors. Other potential risk factors include use of restraints, pre-existing CNS dopamine activity or receptor function abnormalities, and iron deficiency.² Agitation, dehydration, and exhaustion were found to be the most consistent systemic factors predisposing patients taking antipsychotics to NMS in small case-control studies.^13,14 Well-supported risk factors also include use of high-potency antipsychotics, prior episodes of NMS, age <40, male sex, malnutrition, organic brain syndromes, and lithium use.^3,5,15

There is no way to predict the risk of NMS for an individual patient. Usually, symptoms develop within 4 weeks of starting an antipsychotic, but can occur after taking the same dose for many months. The onset may be within hours, but on average it is 4 to 14 days after initiating therapy. Among patients who develop NMS, 90% do so within 10 days.^3,5

Mr. C’s risk factors include high-potency antipsychotic use, male sex, relatively high dose (haloperidol, 30 to 35 mg/d), agitation, dehydration, and exhaustion.

Managing NMS

The standard approaches for managing patients with NMS include discontinuing suspected triggering drugs and providing supportive care. Beyond supportive care, oral or IV benzodiazepines may relieve symptoms and speed recovery.² Dopaminergic drugs, such as bromocriptine or amantadine, used alone or with other treatments, can reduce parkinsonism and disease duration and mortality.² Dantrolene may be useful only for NMS patients who exhibit extreme temperature elevations, rigidity, and true hypermetabolism.¹⁶ Electroconvulsive therapy may be effective for NMS patients whose symptoms do not respond to supportive care and drug therapy or those with residual catatonic or parkinsonian symptoms.²

OUTCOME: Improvement, discharge

Mr. C is admitted to the hospital with the diagnosis of NMS and transferred to the intensive care unit (ICU) for treatment. After Mr. C is admitted to the ICU, apart from continuing the medication given in the ED, he also receives dantrolene, 2 mg/kg, then 1 mg/kg, 4 times a day, as well as IV lorazepam, 1 mg every 6 hours. His other medications include IV pantoprazole, 40 mg/d, for prophylaxis of stress ulcer. Diphenhydramine administration is changed to as needed. On the second day in the ICU, he has only mild upper extremity rigidity but no lower extremity rigidity. However, he suffers 1 seizure, which is treated with IV fosphenytoin at the loading dose, 18 mg/kg, then a maintaining dose of 5 mg phenytoin equivalent/kg/d.

Figure 3: Mr. C’s creatine kinase level (IU/L) during the first 5 days in the intensive care unit

Figure 4: Mr. C’s blood pressure before and after admission

Figure 5: Mr. C’s temperature before and after admissionMr. C remains in the ICU for 7 days. There he receives valproic acid, titrated to 500 mg in the morning and 1,000 mg at bedtime, for agitation. He also receives olanzapine, 5 mg/d, for psychotic symptoms. He develops deep vein thrombosis in the right cephalic vein, which is treated with subcutaneous enoxaparin, 1 mg/kg, and warfarin, 5 mg/d.

He is discharged from the hospital after 2 weeks and returns to the psychiatric facility. He continues to be treated for paranoid schizophrenia with olanzapine, 5 mg/d.

The authors’ observations

High-potency, typical antipsychotics can cause NMS, as shown in Mr. C’s case. It also can be caused by typical low-potency antipsychotics,³ atypical antipsychotics,¹⁷ antiemetic drugs,¹⁸ and lithium,^19,20 and can occur after the withdrawal of levodopa and similar dopaminergic agents during Parkinson’s disease treatment.²¹ Atypical antipsychotics reported to be associated with NMS include clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and paliperidone.^22-27 Atypical antipsychotic-induced NMS also has been reported in children and adolescents.^22,28-30

With the broad application of atypical antipsychotics, physicians should be aware of atypical NMS presentation. Although NMS diagnosis commonly requires core symptoms of hyperthermia and muscle rigidity (Table 1 and 2),³¹ atypical presentations may not demonstrate temperature changes and/or muscle rigidity or may progress slowly over several days, leading to a delay in diagnosis and treatment.^28,30,32,33 Therefore, clinicians should evaluate any patient taking antipsychotics for features of NMS and not prematurely exclude a NMS diagnosis in cases where severe rigidity or hyperthermia is not initially apparent.³³

Table 1

DSM-IV-TR criteria for neuroleptic malignant syndrome

Table 2

Diagnostic features of neuroleptic malignant syndrome

Related Resource

• Neuroleptic Malignant Syndrome Information Service. www.nmsis.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Diphenhydramine • Benadryl
• Enoxaparin • Lovenox
• Fosphenytoin • Cerebyx
• Haloperidol • Haldol
• Hydroxyzine • Vistaril
• Levodopa • Sinemet
• Lithium • Eskalith, Lithobid, others
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Pantoprazole • Protonix
• Phenytoin • Dilantin
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproic acid • Depakote
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosure

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

Acknowledgements

The authors are very grateful for the critical reviews by James R. Allen, MD, MPH, professor of Child and Adolescent Psychiatry Fellowship Program at the University of Oklahoma and Lori Hake, DO, director of Psychiatry Residency Training Program at Griffin Memorial Hospital in Norman, OK.

Discuss this article at www.facebook.com/CurrentPsychiatry
CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

Schizophrenia-ALS comorbidity

Some investigators have suggested²⁰ the relative rarity of ALS in patients with schizophrenia is attributable to the neuroprotective effects of antipsychotics and antidepressants.²¹ If this is true, it is possible resistance to antipsychotics among some schizophrenia patients may be underpinned by the degree of cell injury and therefore of neurodegeneration, which may be the case with Ms. U.

Controlled, randomized, double-blind studies are needed to confirm our team’s assumptions. Our observation is limited by the lack of standardized scale measurements to assess all schizophrenia domains before starting riluzole and Ms. U’s clinical improvement could be associated with other factors such as passage of time or schizophrenia “burning out.” However, clinical observation and description from family members and hospital staff are important to consider in this case.

The improvement in schizophrenia symptoms observed from a drug with no action on dopamine blockade—a quality observed in all antipsychotics²²—reinforces the possibility that targeting different pathways involved in the genesis of schizophrenia is a reasonable topic for future research. The possible use of riluzole and other glutamate-modulating drugs might influence positive, negative, and cognitive symptoms of schizophrenia.

Related Resources

• Kantrowitz JT, Javitt DC. Glutamate: new hope for schizophrenia treatment. Current Psychiatry. 2011;10(4):68-74.
• Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2011. Epub ahead of print.

Drug Brand Names

• Acamprosate • Campral
• Amantadine • Symmetrel
• Clozapine • Clozaril
• Haloperidol • Haldol
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Loxapine • Loxitane
• Methotrimeprazine • Nozinan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertindole • Serdolect
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Venlafaxine • Effexor

Disclosures

Dr. Millán-González is a consultant to AstraZeneca CAMCAR. Drs. Loizaga-Arniaz and Zúñiga-Montes report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry
CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

Schizophrenia-ALS comorbidity

Some investigators have suggested²⁰ the relative rarity of ALS in patients with schizophrenia is attributable to the neuroprotective effects of antipsychotics and antidepressants.²¹ If this is true, it is possible resistance to antipsychotics among some schizophrenia patients may be underpinned by the degree of cell injury and therefore of neurodegeneration, which may be the case with Ms. U.

Controlled, randomized, double-blind studies are needed to confirm our team’s assumptions. Our observation is limited by the lack of standardized scale measurements to assess all schizophrenia domains before starting riluzole and Ms. U’s clinical improvement could be associated with other factors such as passage of time or schizophrenia “burning out.” However, clinical observation and description from family members and hospital staff are important to consider in this case.

The improvement in schizophrenia symptoms observed from a drug with no action on dopamine blockade—a quality observed in all antipsychotics²²—reinforces the possibility that targeting different pathways involved in the genesis of schizophrenia is a reasonable topic for future research. The possible use of riluzole and other glutamate-modulating drugs might influence positive, negative, and cognitive symptoms of schizophrenia.

Related Resources

• Kantrowitz JT, Javitt DC. Glutamate: new hope for schizophrenia treatment. Current Psychiatry. 2011;10(4):68-74.
• Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2011. Epub ahead of print.

Drug Brand Names

• Acamprosate • Campral
• Amantadine • Symmetrel
• Clozapine • Clozaril
• Haloperidol • Haldol
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Loxapine • Loxitane
• Methotrimeprazine • Nozinan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertindole • Serdolect
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Venlafaxine • Effexor

Disclosures

Dr. Millán-González is a consultant to AstraZeneca CAMCAR. Drs. Loizaga-Arniaz and Zúñiga-Montes report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry
CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

Schizophrenia-ALS comorbidity

Some investigators have suggested²⁰ the relative rarity of ALS in patients with schizophrenia is attributable to the neuroprotective effects of antipsychotics and antidepressants.²¹ If this is true, it is possible resistance to antipsychotics among some schizophrenia patients may be underpinned by the degree of cell injury and therefore of neurodegeneration, which may be the case with Ms. U.

Controlled, randomized, double-blind studies are needed to confirm our team’s assumptions. Our observation is limited by the lack of standardized scale measurements to assess all schizophrenia domains before starting riluzole and Ms. U’s clinical improvement could be associated with other factors such as passage of time or schizophrenia “burning out.” However, clinical observation and description from family members and hospital staff are important to consider in this case.

The improvement in schizophrenia symptoms observed from a drug with no action on dopamine blockade—a quality observed in all antipsychotics²²—reinforces the possibility that targeting different pathways involved in the genesis of schizophrenia is a reasonable topic for future research. The possible use of riluzole and other glutamate-modulating drugs might influence positive, negative, and cognitive symptoms of schizophrenia.

Related Resources

• Kantrowitz JT, Javitt DC. Glutamate: new hope for schizophrenia treatment. Current Psychiatry. 2011;10(4):68-74.
• Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2011. Epub ahead of print.

Drug Brand Names

• Acamprosate • Campral
• Amantadine • Symmetrel
• Clozapine • Clozaril
• Haloperidol • Haldol
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Loxapine • Loxitane
• Methotrimeprazine • Nozinan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertindole • Serdolect
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Venlafaxine • Effexor

Disclosures

Dr. Millán-González is a consultant to AstraZeneca CAMCAR. Drs. Loizaga-Arniaz and Zúñiga-Montes report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

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 paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

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 paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

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 paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

Disclosure

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

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse

Quetiapine

Methods of quetiapine misuse include ingesting pills, inhaling crushed tablets, and injecting a solution of dissolved tablets.^1-7 In case studies, patients report abusing quetiapine for its sedative, anxiolytic, and calming effects.^1,2,4-7 One patient reported snorting crushed quetiapine tablets combined with cocaine for “hallucinogenic” effects.³ Street names for quetiapine include “quell,” “Susie-Q,” and “baby heroin,” and “Q-ball” refers to a combination of cocaine and quetiapine.⁸ Quetiapine tablets have a street value of $3 to $8 for doses ranging from 25 mg to 100 mg.⁹ Although outpatient misuse of quetiapine is common, abuse in correctional settings also is becoming more frequent.¹⁰ Residents of jails and prisons misuse quetiapine for reasons similar to those cited by outpatients: sedation, relief of anxiety, and hallucinogenic effects or “getting high.”^1,2,10 Clinicians must differentiate inmates who have legitimate psychiatric symptoms that require antipsychotic treatment from those who are malingering to obtain the drug. Efforts to treat inmates for substance use disorders may be thwarted by the easy availability of drugs in correctional settings.¹⁰

Other SGAs

The incidence of misuse of olanzapine and other SGAs is more difficult to ascertain. Only 2 case reports describe olanzapine abuse, both in outpatient settings. One describes a patient treated for depression with psychosis who was using increasingly higher doses of olanzapine to obtain euphoric effects.¹¹ Switching to aripiprazole effectively treated her illness and addressed her olanzapine misuse.

In the other case, a patient with bipolar disorder was able to obtain olanzapine, 40 mg/d, by complaining of worsened manic symptoms.¹² He described the experience of misusing olanzapine as getting a “buzz,” feeling “very relaxed,” and blunting the negative jitteriness he felt when he used cocaine.¹² This patient stated that he had observed others abusing olanzapine, both orally and intravenously.

Although the literature lacks reports on the risks of antipsychotic abuse, numerous Web sites purport to sell these drugs without a prescription and some describe the experience of illicit use of drugs such as haloperidol, risperidone, quetiapine, and olanzapine and ways to “enhance” the experience by combining drugs.¹³ Reported experiences with risperidone tend to be negative, citing extrapyramidal side effects and feeling “numb,” whereas olanzapine and quetiapine users describe feeling “drunk without the bad effects of alcohol” and “really happy, calm.” These sites also describe hallucinogenic effects of these agents.¹³

Mechanism of action

The neuropharmacologic reasons for antipsychotics’ abuse potential are difficult to quantify. Quetiapine and olanzapine have been used to treat cocaine and alcohol abuse, and work perhaps by decreasing the dopamine reward system response to substance use.^14,15 Quetiapine’s rapid dissociation from the dopamine receptor has been theorized to contribute to the drug’s abuse potential, possibly through relatively lower potency and decreased residence time at the dopamine receptor.^14-16 This mechanism also contributes to quetiapine’s lower risk of extrapyramidal side effects, which make the drug easier to tolerate.

Although dopamine is a factor in substance abuse and treatment of psychotic disorders, other neuropharmacologic mechanisms must be considered. SGAs are theorized to cause dopamine release in the frontal cortex through effects as 5-HT1A agonists and 5-HT2A antagonists.¹⁶ Antagonism of α-adrenergic and histaminic receptors may account for these agents’ anxiolytic and sedative properties.⁸

Misuse of anticholinergic agents has been reported for >50 years.¹⁷ Psychiatric patients have been reported to increase use of anticholinergics for their movement side effects as well as hallucinogenic effects.¹⁸

Treatment

Regardless of the substance that patients abuse, the treatment goals are the same: to reduce use and achieve recovery. If a patient with psychosis is abusing an SGA, consider switching to an antipsychotic with less abuse potential. Another option is to limit the supply of the abused drug by prescribing smaller quantities or increase the frequency of follow-up visits to ensure compliant use.

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• Galanter M, Kelber HD. The American Psychiatric Publishing textbook of substance abuse treatment. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Diazepam • Valium
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Vicodin
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

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

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse

Quetiapine

Methods of quetiapine misuse include ingesting pills, inhaling crushed tablets, and injecting a solution of dissolved tablets.^1-7 In case studies, patients report abusing quetiapine for its sedative, anxiolytic, and calming effects.^1,2,4-7 One patient reported snorting crushed quetiapine tablets combined with cocaine for “hallucinogenic” effects.³ Street names for quetiapine include “quell,” “Susie-Q,” and “baby heroin,” and “Q-ball” refers to a combination of cocaine and quetiapine.⁸ Quetiapine tablets have a street value of $3 to $8 for doses ranging from 25 mg to 100 mg.⁹ Although outpatient misuse of quetiapine is common, abuse in correctional settings also is becoming more frequent.¹⁰ Residents of jails and prisons misuse quetiapine for reasons similar to those cited by outpatients: sedation, relief of anxiety, and hallucinogenic effects or “getting high.”^1,2,10 Clinicians must differentiate inmates who have legitimate psychiatric symptoms that require antipsychotic treatment from those who are malingering to obtain the drug. Efforts to treat inmates for substance use disorders may be thwarted by the easy availability of drugs in correctional settings.¹⁰

Other SGAs

The incidence of misuse of olanzapine and other SGAs is more difficult to ascertain. Only 2 case reports describe olanzapine abuse, both in outpatient settings. One describes a patient treated for depression with psychosis who was using increasingly higher doses of olanzapine to obtain euphoric effects.¹¹ Switching to aripiprazole effectively treated her illness and addressed her olanzapine misuse.

In the other case, a patient with bipolar disorder was able to obtain olanzapine, 40 mg/d, by complaining of worsened manic symptoms.¹² He described the experience of misusing olanzapine as getting a “buzz,” feeling “very relaxed,” and blunting the negative jitteriness he felt when he used cocaine.¹² This patient stated that he had observed others abusing olanzapine, both orally and intravenously.

Although the literature lacks reports on the risks of antipsychotic abuse, numerous Web sites purport to sell these drugs without a prescription and some describe the experience of illicit use of drugs such as haloperidol, risperidone, quetiapine, and olanzapine and ways to “enhance” the experience by combining drugs.¹³ Reported experiences with risperidone tend to be negative, citing extrapyramidal side effects and feeling “numb,” whereas olanzapine and quetiapine users describe feeling “drunk without the bad effects of alcohol” and “really happy, calm.” These sites also describe hallucinogenic effects of these agents.¹³

Mechanism of action

The neuropharmacologic reasons for antipsychotics’ abuse potential are difficult to quantify. Quetiapine and olanzapine have been used to treat cocaine and alcohol abuse, and work perhaps by decreasing the dopamine reward system response to substance use.^14,15 Quetiapine’s rapid dissociation from the dopamine receptor has been theorized to contribute to the drug’s abuse potential, possibly through relatively lower potency and decreased residence time at the dopamine receptor.^14-16 This mechanism also contributes to quetiapine’s lower risk of extrapyramidal side effects, which make the drug easier to tolerate.

Although dopamine is a factor in substance abuse and treatment of psychotic disorders, other neuropharmacologic mechanisms must be considered. SGAs are theorized to cause dopamine release in the frontal cortex through effects as 5-HT1A agonists and 5-HT2A antagonists.¹⁶ Antagonism of α-adrenergic and histaminic receptors may account for these agents’ anxiolytic and sedative properties.⁸

Misuse of anticholinergic agents has been reported for >50 years.¹⁷ Psychiatric patients have been reported to increase use of anticholinergics for their movement side effects as well as hallucinogenic effects.¹⁸

Treatment

Regardless of the substance that patients abuse, the treatment goals are the same: to reduce use and achieve recovery. If a patient with psychosis is abusing an SGA, consider switching to an antipsychotic with less abuse potential. Another option is to limit the supply of the abused drug by prescribing smaller quantities or increase the frequency of follow-up visits to ensure compliant use.

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• Galanter M, Kelber HD. The American Psychiatric Publishing textbook of substance abuse treatment. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Diazepam • Valium
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Vicodin
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

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

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse