Case-Based Review

Case: You’re a ‘freak’

A local mental health agency refers Mr. Z, age 23, to our inpatient psychiatry service because of increasing suicidality and psychosis. He began receiving care from the mental health agency 3 years ago, after a psychiatrist diagnosed paranoid schizophrenia.

At presentation, Mr. Z is delusionally preoccupied with a brief relationship he had with a young woman at college 2 years ago. He feels embarrassed about his conduct toward her during a psychotic episode and her subsequent response. He believes strangers are ridiculing him, and he hears voices calling him a “freak” and making crude references to the encounter. He is also contemplating suicide and endorses a suicide plan.

Mr. Z was hospitalized for 1 month last year with schizophrenia symptoms. He is medically healthy and does not abuse alcohol or drugs.

We admit Mr. Z because of his suicidality. Four weeks later, he remains suicidal and hears voices telling him to “rape” and “kill.” Successive 2-week trials of risperidone, 1 mg/d titrated to 5 mg/d, and quetiapine, 200 mg/d titrated to 700 mg/d, cause intolerable akathisia. We try adding propranolol, 20 mg every 8 hours, to alleviate akathisia, but to no avail. Previous trials of olanzapine, 30 mg/d, and haloperidol, dosage unknown, were unsuccessful or caused akathisia.

The authors’ observations

Substantial evidence supports clozapine’s efficacy in treatment-resistant schizophrenia, and this second-generation antipsychotic (SGA) also might reduce suicidality.^1,2 Clinicians often combine antipsychotics, switch to an antidepressant, or add a mood stabilizer for treatment-resistant schizophrenia,³ but little evidence supports these options.

Mr. Z had failed at least 4 antipsychotic trials. We consider clozapine for patients with severe psychosis who have failed 2 or 3 antipsychotic trials or cannot tolerate these medications. Severity of psychosis and presence of suicidality warrant use of clozapine in treatment-resistant cases.

If Mr. Z had tolerated risperidone or quetiapine, we would have waited as long as 8 weeks before switching to clozapine. In inpatients, improvement should be seen 2 to 4 weeks after starting an antipsychotic.

Thoroughly discuss clozapine’s risks and benefits with the patient and caregiver(s) before prescribing. Clozapine can cause a range of side effects, including sedation, weight gain, sialorrhea, seizures, diabetes, pulmonary emboli, and—most notoriously—agranulocytosis. These effects can occur anytime, but the risk is especially high within 1 year of starting the medication.⁴

Perform blood tests weekly during the first 6 months of clozapine therapy and bi-weekly thereafter to check for abnormally low white blood cell counts that might suggest agranulocytosis.

Box 1

TREATMENT: New regimen

After discussing clozapine’s risks and benefits with Mr. Z and his parents, we start the medication at 25 mg/d to gauge tolerability, then titrate to 300 mg/d over 10 days. Mr. Z tolerates clozapine well, with some sedation and sialorrhea. A blood test taken 7 days after we start clozapine shows a normal white blood cell count.

After 10 days on clozapine, Mr. Z’s delusions and hallucinations are considerably less intense. He is no longer suicidal and visits his former college with his parents without thinking about his past acquaintance. We discharge him on clozapine, 300 mg/d, and refer him to the local mental health agency.

Two days later, Mr. Z’s parents report that since discharge their son has had extreme fatigue, shortness of breath, leg edema, and chest pain. We advise them to immediately take their son to the ER for cardiac workup.

 

The authors’ observations

Mr. Z’s sudden-onset physical symptoms suggest myocarditis, a rare but potentially fatal side effect of clozapine whose specific cause is unclear (Box 1).^5-14 Myocarditis has been reported in 0.02% to 0.18% of patients exposed to clozapine,^15-18 with incidence as high as 1.3% per 235 patients.¹⁹

Affected patients typically have been taking clozapine at therapeutic dosages (100 to 450 mg/d).⁷ Clozapine use is most prevalent among men ages 20 to 40, who tend to have more severe schizophrenia and lower cardiac risk than other populations. Correspondingly, clozapine-induced myocarditis is most prevalent in younger men,²⁰ although what specifically causes this susceptibility is unknown.

Nonspecific symptoms such as dyspnea, tachycardia, chest pain, or fever can signal myocarditis (Table)^7,21 and can surface within 4 to 8 weeks of starting clozapine.²² Haas et al²⁰ reported other symptoms—such as leukocytosis—in young (median age 30), predominantly male patients with clozapine-induced myocarditis. Symptoms that typically occur during clozapine titration—such as fever and tachycardia—can mask “subclinical” myocarditis.²²

Mr. Z’s nonspecific symptoms could signal clozapine-induced agranulocytosis or a viral syndrome, or could be delusional. The patient’s acute, sudden symptom onset strongly suggests a cardiac cause. Also, his delusions subsided, and normal blood readings helped us rule out agranulocytosis.

Coulter et al²³ associated myocarditis and cardiomyopathy, a noninflammatory heart muscle disease, with several antipsychotics—including clozapine, chlorpromazine, fluphenazine, haloperidol, and risperidone—as well as lithium. More research is needed to confirm this association.

Emergency medical intervention is critical because mortality rates for myocarditis induced by clozapine have been estimated at 50%.²⁰ Myocarditis could progress to dilated cardiomyopathy,²⁴ with similarly high mortality rates across 5 years.⁷

Order a cardiology consult and workup including:

• serum electrolytes
  
• complete blood count
  
• ECG²¹
  
• tests for myocardial damage including creatine kinase with MB fractionation (CK-MB) and testing for serum troponin I,²⁵ lactic dehydrogenase, and aspartate transaminase (SGOT)²¹
  
• assessment for immune activation and peripheral eosinophilia.²⁵
  

Findings on ECG are wide-ranging and might include sinus tachycardia, atrial or ventricular arrhythmias, left ventricular hypertrophy, nonspecific ST segment and T-wave abnormalities, and intraventricular conduction defects. Assess cardiac function with echocardiography to monitor for dilated cardiomyopathy. Stop clozapine immediately if findings suggest myocarditis.¹⁹

Table

Symptoms that could signal myocarditis in patients taking clozapine

Chest pain Confusion/mental status changes Dyspnea Edema Fatigue/weakness Fever Prolonged tachycardia
Source: Reference 7

TESTING: ‘Is this necessary?’

We contact the ER physician to request the above-mentioned tests, but he questions the need for such extensive and costly testing in a psychiatric patient with nonspecific symptoms.

After several phone conversations to review our recommendations, the emergency physician suggests sending Mr. Z home on a watch-and-wait protocol. We politely but firmly emphasize that Mr. Z needs a full cardiac workup, after which the physician consents to the tests (Box 2).

FINDINGS: suspicious readings

Mr. Z’s cardiac imaging results suggest a cardiopathy:

• echocardiogram shows mild ventricular enlargement with a decreased ejection fraction of 45% (normal reading, 55% to 60%)
  
• ECG shows normal sinus rhythm with low-voltage diffuse T-wave flattening throughout all leads without ST elevation
  
• creatine phosphokinase (CPK) and CKMB are within normal ranges
  
• troponin I is 0.33 ng/mL, a high-normal reading.
  

Mr. Z had no past cardiac abnormality, but an aunt had died in her 30s of viral myocarditis.

Based on these readings, the cardiology service admits Mr. Z with a presumptive diagnosis of clozapine-induced cardiomyopathy. The attending cardiologist stops clozapine and starts the angiotensin-converting enzyme inhibitor enalapril, 2.5 mg bid, for ventricular remodeling. Medical workup includes cytologic testing to rule out immunologic or viral disease.

Five days later, Mr. Z’s cardiac symptoms have resolved. The cardiology unit discharges him on enalapril, 2.5 mg bid, and schedules a cardiac ultrasound for 2 weeks after discharge to confirm progress.

The authors’ observations

Maintain high clinical suspicion while using clozapine. Similar to other patients with a clozapine-induced cardiopathy,¹⁶ Mr. Z showed rapid symptomatic changes after a benign initial course and experienced fairly vague symptoms that raised limited clinical concern at first.

Before starting clozapine therapy, screen all patients for pre-existing cardiac disease, which contraindicates this medication. Alert patients and caregivers to the risks and symptoms that require close monitoring early in treatment.

Many researchers suggest monitoring for myocarditis during the first month of therapy and ordering ECG at baseline and 2 and 4 weeks after starting clozapine.^21,22 Berk et al²⁶ suggest more aggressive monitoring, including:

• baseline ECG
  
• transthoracic echocardiogram
  
• baseline troponin/CK-MB
  
• ECG and troponin/CK-MB at 7 and 14 days
  
• echocardiogram at 6 and 12 months and then annually.
  

RELAPSE: Return of the ‘freak’

 

Immediately after Mr. Z’s discharge from the cardiology unit, we readmit him to inpatient psychiatry. His parents and case manager say he is again becoming preoccupied with his brief college relationship. He has been off clozapine for 5 days.

The authors’ observations

The American Psychiatric Association²⁷ (see http://www.psych.org/psych_pract/treatg/pg/SchizPG-Complete-Feb04.pdf) recommends maximizing 1 medication for at least 2 to 4 weeks to assess schizophrenia symptom response and urges clinicians to consider adverse effects, medical comorbidities, and patient preference before continuing the medication.

These recommendations highlight the challenges of treating medication-resistant schizophrenia. Relapse is common after a serious reaction to clozapine, and combining 2 or more other antipsychotics could lead to significantly greater side effects. A time-limited trial with an antipsychotic and an adjunctive agent might be attempted while carefully weighing the combination’s risks and benefits.²⁷

Clozapine reduced Mr. Z’s psychosis, but rechallenge would likely cause his potentially fatal cardiomyopathy to re-emerge. His sensitivity to adverse antipsychotic effects discourages polypharmacy and further complicates our decision.

Because our therapeutic options are limited, we consider an agent chemically similar to clozapine with pharmacologic overlap—such as olanzapine,⁶ which had improved Mr. Z’s psychotic symptoms during his hospitalization 1 year ago but caused akathisia. We hope to avoid this adverse effect by limiting the dosage to 30 mg/d and adding the antidepressant bupropion, which Mr. Z says had helped him previously.

Box 2

TREATMENT: Another trial

We start olanzapine, 5 mg/d, and titrate to 20 mg/d over 1 week. We add sustained-release bupropion, 200 mg bid, for associated dysphoria.

Mr. Z’s symptoms and paranoia gradually decline, and he tolerates off-unit passes with friends and family before discharge. Staff works closely with him to develop cognitive-behavioral strategies to manage residual paranoia and hallucinations, such as assessing evidence for his delusional beliefs and developing tools to distract him from remaining “voices.” He reports no cardiac symptoms and continues taking enalapril, 2.5 mg bid.

We discharge Mr. Z after 1 week, at which point he shows no suicidal or homicidal thoughts. Follow-up echocardiogram 2 weeks later shows ejection fraction has improved to 60%, suggesting absence of cardiomyopathy.

When last contacted 3 months ago, Mr. Z was stable and living with his parents. He was continuing outpatient psychiatric care and hoped to find an apartment and transition to independent living.

Related resource

• Clozapine safety information.
  www.clozaril.com/.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril
  
• Enalapril • Vasotec
  
• Fluphenazine • Prolixin, Permitil
  
• Haloperidol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Disclosure

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

Case: You’re a ‘freak’

A local mental health agency refers Mr. Z, age 23, to our inpatient psychiatry service because of increasing suicidality and psychosis. He began receiving care from the mental health agency 3 years ago, after a psychiatrist diagnosed paranoid schizophrenia.

At presentation, Mr. Z is delusionally preoccupied with a brief relationship he had with a young woman at college 2 years ago. He feels embarrassed about his conduct toward her during a psychotic episode and her subsequent response. He believes strangers are ridiculing him, and he hears voices calling him a “freak” and making crude references to the encounter. He is also contemplating suicide and endorses a suicide plan.

Mr. Z was hospitalized for 1 month last year with schizophrenia symptoms. He is medically healthy and does not abuse alcohol or drugs.

We admit Mr. Z because of his suicidality. Four weeks later, he remains suicidal and hears voices telling him to “rape” and “kill.” Successive 2-week trials of risperidone, 1 mg/d titrated to 5 mg/d, and quetiapine, 200 mg/d titrated to 700 mg/d, cause intolerable akathisia. We try adding propranolol, 20 mg every 8 hours, to alleviate akathisia, but to no avail. Previous trials of olanzapine, 30 mg/d, and haloperidol, dosage unknown, were unsuccessful or caused akathisia.

The authors’ observations

Substantial evidence supports clozapine’s efficacy in treatment-resistant schizophrenia, and this second-generation antipsychotic (SGA) also might reduce suicidality.^1,2 Clinicians often combine antipsychotics, switch to an antidepressant, or add a mood stabilizer for treatment-resistant schizophrenia,³ but little evidence supports these options.

Mr. Z had failed at least 4 antipsychotic trials. We consider clozapine for patients with severe psychosis who have failed 2 or 3 antipsychotic trials or cannot tolerate these medications. Severity of psychosis and presence of suicidality warrant use of clozapine in treatment-resistant cases.

If Mr. Z had tolerated risperidone or quetiapine, we would have waited as long as 8 weeks before switching to clozapine. In inpatients, improvement should be seen 2 to 4 weeks after starting an antipsychotic.

Thoroughly discuss clozapine’s risks and benefits with the patient and caregiver(s) before prescribing. Clozapine can cause a range of side effects, including sedation, weight gain, sialorrhea, seizures, diabetes, pulmonary emboli, and—most notoriously—agranulocytosis. These effects can occur anytime, but the risk is especially high within 1 year of starting the medication.⁴

Perform blood tests weekly during the first 6 months of clozapine therapy and bi-weekly thereafter to check for abnormally low white blood cell counts that might suggest agranulocytosis.

Box 1

TREATMENT: New regimen

After discussing clozapine’s risks and benefits with Mr. Z and his parents, we start the medication at 25 mg/d to gauge tolerability, then titrate to 300 mg/d over 10 days. Mr. Z tolerates clozapine well, with some sedation and sialorrhea. A blood test taken 7 days after we start clozapine shows a normal white blood cell count.

After 10 days on clozapine, Mr. Z’s delusions and hallucinations are considerably less intense. He is no longer suicidal and visits his former college with his parents without thinking about his past acquaintance. We discharge him on clozapine, 300 mg/d, and refer him to the local mental health agency.

Two days later, Mr. Z’s parents report that since discharge their son has had extreme fatigue, shortness of breath, leg edema, and chest pain. We advise them to immediately take their son to the ER for cardiac workup.

 

The authors’ observations

Mr. Z’s sudden-onset physical symptoms suggest myocarditis, a rare but potentially fatal side effect of clozapine whose specific cause is unclear (Box 1).^5-14 Myocarditis has been reported in 0.02% to 0.18% of patients exposed to clozapine,^15-18 with incidence as high as 1.3% per 235 patients.¹⁹

Affected patients typically have been taking clozapine at therapeutic dosages (100 to 450 mg/d).⁷ Clozapine use is most prevalent among men ages 20 to 40, who tend to have more severe schizophrenia and lower cardiac risk than other populations. Correspondingly, clozapine-induced myocarditis is most prevalent in younger men,²⁰ although what specifically causes this susceptibility is unknown.

Nonspecific symptoms such as dyspnea, tachycardia, chest pain, or fever can signal myocarditis (Table)^7,21 and can surface within 4 to 8 weeks of starting clozapine.²² Haas et al²⁰ reported other symptoms—such as leukocytosis—in young (median age 30), predominantly male patients with clozapine-induced myocarditis. Symptoms that typically occur during clozapine titration—such as fever and tachycardia—can mask “subclinical” myocarditis.²²

Mr. Z’s nonspecific symptoms could signal clozapine-induced agranulocytosis or a viral syndrome, or could be delusional. The patient’s acute, sudden symptom onset strongly suggests a cardiac cause. Also, his delusions subsided, and normal blood readings helped us rule out agranulocytosis.

Coulter et al²³ associated myocarditis and cardiomyopathy, a noninflammatory heart muscle disease, with several antipsychotics—including clozapine, chlorpromazine, fluphenazine, haloperidol, and risperidone—as well as lithium. More research is needed to confirm this association.

Emergency medical intervention is critical because mortality rates for myocarditis induced by clozapine have been estimated at 50%.²⁰ Myocarditis could progress to dilated cardiomyopathy,²⁴ with similarly high mortality rates across 5 years.⁷

Order a cardiology consult and workup including:

• serum electrolytes
  
• complete blood count
  
• ECG²¹
  
• tests for myocardial damage including creatine kinase with MB fractionation (CK-MB) and testing for serum troponin I,²⁵ lactic dehydrogenase, and aspartate transaminase (SGOT)²¹
  
• assessment for immune activation and peripheral eosinophilia.²⁵
  

Findings on ECG are wide-ranging and might include sinus tachycardia, atrial or ventricular arrhythmias, left ventricular hypertrophy, nonspecific ST segment and T-wave abnormalities, and intraventricular conduction defects. Assess cardiac function with echocardiography to monitor for dilated cardiomyopathy. Stop clozapine immediately if findings suggest myocarditis.¹⁹

Table

Symptoms that could signal myocarditis in patients taking clozapine

Chest pain Confusion/mental status changes Dyspnea Edema Fatigue/weakness Fever Prolonged tachycardia
Source: Reference 7

TESTING: ‘Is this necessary?’

We contact the ER physician to request the above-mentioned tests, but he questions the need for such extensive and costly testing in a psychiatric patient with nonspecific symptoms.

After several phone conversations to review our recommendations, the emergency physician suggests sending Mr. Z home on a watch-and-wait protocol. We politely but firmly emphasize that Mr. Z needs a full cardiac workup, after which the physician consents to the tests (Box 2).

FINDINGS: suspicious readings

Mr. Z’s cardiac imaging results suggest a cardiopathy:

• echocardiogram shows mild ventricular enlargement with a decreased ejection fraction of 45% (normal reading, 55% to 60%)
  
• ECG shows normal sinus rhythm with low-voltage diffuse T-wave flattening throughout all leads without ST elevation
  
• creatine phosphokinase (CPK) and CKMB are within normal ranges
  
• troponin I is 0.33 ng/mL, a high-normal reading.
  

Mr. Z had no past cardiac abnormality, but an aunt had died in her 30s of viral myocarditis.

Based on these readings, the cardiology service admits Mr. Z with a presumptive diagnosis of clozapine-induced cardiomyopathy. The attending cardiologist stops clozapine and starts the angiotensin-converting enzyme inhibitor enalapril, 2.5 mg bid, for ventricular remodeling. Medical workup includes cytologic testing to rule out immunologic or viral disease.

Five days later, Mr. Z’s cardiac symptoms have resolved. The cardiology unit discharges him on enalapril, 2.5 mg bid, and schedules a cardiac ultrasound for 2 weeks after discharge to confirm progress.

The authors’ observations

Maintain high clinical suspicion while using clozapine. Similar to other patients with a clozapine-induced cardiopathy,¹⁶ Mr. Z showed rapid symptomatic changes after a benign initial course and experienced fairly vague symptoms that raised limited clinical concern at first.

Before starting clozapine therapy, screen all patients for pre-existing cardiac disease, which contraindicates this medication. Alert patients and caregivers to the risks and symptoms that require close monitoring early in treatment.

Many researchers suggest monitoring for myocarditis during the first month of therapy and ordering ECG at baseline and 2 and 4 weeks after starting clozapine.^21,22 Berk et al²⁶ suggest more aggressive monitoring, including:

• baseline ECG
  
• transthoracic echocardiogram
  
• baseline troponin/CK-MB
  
• ECG and troponin/CK-MB at 7 and 14 days
  
• echocardiogram at 6 and 12 months and then annually.
  

RELAPSE: Return of the ‘freak’

 

Immediately after Mr. Z’s discharge from the cardiology unit, we readmit him to inpatient psychiatry. His parents and case manager say he is again becoming preoccupied with his brief college relationship. He has been off clozapine for 5 days.

The authors’ observations

The American Psychiatric Association²⁷ (see http://www.psych.org/psych_pract/treatg/pg/SchizPG-Complete-Feb04.pdf) recommends maximizing 1 medication for at least 2 to 4 weeks to assess schizophrenia symptom response and urges clinicians to consider adverse effects, medical comorbidities, and patient preference before continuing the medication.

These recommendations highlight the challenges of treating medication-resistant schizophrenia. Relapse is common after a serious reaction to clozapine, and combining 2 or more other antipsychotics could lead to significantly greater side effects. A time-limited trial with an antipsychotic and an adjunctive agent might be attempted while carefully weighing the combination’s risks and benefits.²⁷

Clozapine reduced Mr. Z’s psychosis, but rechallenge would likely cause his potentially fatal cardiomyopathy to re-emerge. His sensitivity to adverse antipsychotic effects discourages polypharmacy and further complicates our decision.

Because our therapeutic options are limited, we consider an agent chemically similar to clozapine with pharmacologic overlap—such as olanzapine,⁶ which had improved Mr. Z’s psychotic symptoms during his hospitalization 1 year ago but caused akathisia. We hope to avoid this adverse effect by limiting the dosage to 30 mg/d and adding the antidepressant bupropion, which Mr. Z says had helped him previously.

Box 2

TREATMENT: Another trial

We start olanzapine, 5 mg/d, and titrate to 20 mg/d over 1 week. We add sustained-release bupropion, 200 mg bid, for associated dysphoria.

Mr. Z’s symptoms and paranoia gradually decline, and he tolerates off-unit passes with friends and family before discharge. Staff works closely with him to develop cognitive-behavioral strategies to manage residual paranoia and hallucinations, such as assessing evidence for his delusional beliefs and developing tools to distract him from remaining “voices.” He reports no cardiac symptoms and continues taking enalapril, 2.5 mg bid.

We discharge Mr. Z after 1 week, at which point he shows no suicidal or homicidal thoughts. Follow-up echocardiogram 2 weeks later shows ejection fraction has improved to 60%, suggesting absence of cardiomyopathy.

When last contacted 3 months ago, Mr. Z was stable and living with his parents. He was continuing outpatient psychiatric care and hoped to find an apartment and transition to independent living.

Related resource

• Clozapine safety information.
  www.clozaril.com/.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril
  
• Enalapril • Vasotec
  
• Fluphenazine • Prolixin, Permitil
  
• Haloperidol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Disclosure

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

Case: You’re a ‘freak’

A local mental health agency refers Mr. Z, age 23, to our inpatient psychiatry service because of increasing suicidality and psychosis. He began receiving care from the mental health agency 3 years ago, after a psychiatrist diagnosed paranoid schizophrenia.

At presentation, Mr. Z is delusionally preoccupied with a brief relationship he had with a young woman at college 2 years ago. He feels embarrassed about his conduct toward her during a psychotic episode and her subsequent response. He believes strangers are ridiculing him, and he hears voices calling him a “freak” and making crude references to the encounter. He is also contemplating suicide and endorses a suicide plan.

Mr. Z was hospitalized for 1 month last year with schizophrenia symptoms. He is medically healthy and does not abuse alcohol or drugs.

We admit Mr. Z because of his suicidality. Four weeks later, he remains suicidal and hears voices telling him to “rape” and “kill.” Successive 2-week trials of risperidone, 1 mg/d titrated to 5 mg/d, and quetiapine, 200 mg/d titrated to 700 mg/d, cause intolerable akathisia. We try adding propranolol, 20 mg every 8 hours, to alleviate akathisia, but to no avail. Previous trials of olanzapine, 30 mg/d, and haloperidol, dosage unknown, were unsuccessful or caused akathisia.

The authors’ observations

Substantial evidence supports clozapine’s efficacy in treatment-resistant schizophrenia, and this second-generation antipsychotic (SGA) also might reduce suicidality.^1,2 Clinicians often combine antipsychotics, switch to an antidepressant, or add a mood stabilizer for treatment-resistant schizophrenia,³ but little evidence supports these options.

Mr. Z had failed at least 4 antipsychotic trials. We consider clozapine for patients with severe psychosis who have failed 2 or 3 antipsychotic trials or cannot tolerate these medications. Severity of psychosis and presence of suicidality warrant use of clozapine in treatment-resistant cases.

If Mr. Z had tolerated risperidone or quetiapine, we would have waited as long as 8 weeks before switching to clozapine. In inpatients, improvement should be seen 2 to 4 weeks after starting an antipsychotic.

Thoroughly discuss clozapine’s risks and benefits with the patient and caregiver(s) before prescribing. Clozapine can cause a range of side effects, including sedation, weight gain, sialorrhea, seizures, diabetes, pulmonary emboli, and—most notoriously—agranulocytosis. These effects can occur anytime, but the risk is especially high within 1 year of starting the medication.⁴

Perform blood tests weekly during the first 6 months of clozapine therapy and bi-weekly thereafter to check for abnormally low white blood cell counts that might suggest agranulocytosis.

Box 1

TREATMENT: New regimen

After discussing clozapine’s risks and benefits with Mr. Z and his parents, we start the medication at 25 mg/d to gauge tolerability, then titrate to 300 mg/d over 10 days. Mr. Z tolerates clozapine well, with some sedation and sialorrhea. A blood test taken 7 days after we start clozapine shows a normal white blood cell count.

After 10 days on clozapine, Mr. Z’s delusions and hallucinations are considerably less intense. He is no longer suicidal and visits his former college with his parents without thinking about his past acquaintance. We discharge him on clozapine, 300 mg/d, and refer him to the local mental health agency.

Two days later, Mr. Z’s parents report that since discharge their son has had extreme fatigue, shortness of breath, leg edema, and chest pain. We advise them to immediately take their son to the ER for cardiac workup.

 

The authors’ observations

Mr. Z’s sudden-onset physical symptoms suggest myocarditis, a rare but potentially fatal side effect of clozapine whose specific cause is unclear (Box 1).^5-14 Myocarditis has been reported in 0.02% to 0.18% of patients exposed to clozapine,^15-18 with incidence as high as 1.3% per 235 patients.¹⁹

Affected patients typically have been taking clozapine at therapeutic dosages (100 to 450 mg/d).⁷ Clozapine use is most prevalent among men ages 20 to 40, who tend to have more severe schizophrenia and lower cardiac risk than other populations. Correspondingly, clozapine-induced myocarditis is most prevalent in younger men,²⁰ although what specifically causes this susceptibility is unknown.

Nonspecific symptoms such as dyspnea, tachycardia, chest pain, or fever can signal myocarditis (Table)^7,21 and can surface within 4 to 8 weeks of starting clozapine.²² Haas et al²⁰ reported other symptoms—such as leukocytosis—in young (median age 30), predominantly male patients with clozapine-induced myocarditis. Symptoms that typically occur during clozapine titration—such as fever and tachycardia—can mask “subclinical” myocarditis.²²

Mr. Z’s nonspecific symptoms could signal clozapine-induced agranulocytosis or a viral syndrome, or could be delusional. The patient’s acute, sudden symptom onset strongly suggests a cardiac cause. Also, his delusions subsided, and normal blood readings helped us rule out agranulocytosis.

Coulter et al²³ associated myocarditis and cardiomyopathy, a noninflammatory heart muscle disease, with several antipsychotics—including clozapine, chlorpromazine, fluphenazine, haloperidol, and risperidone—as well as lithium. More research is needed to confirm this association.

Emergency medical intervention is critical because mortality rates for myocarditis induced by clozapine have been estimated at 50%.²⁰ Myocarditis could progress to dilated cardiomyopathy,²⁴ with similarly high mortality rates across 5 years.⁷

Order a cardiology consult and workup including:

• serum electrolytes
  
• complete blood count
  
• ECG²¹
  
• tests for myocardial damage including creatine kinase with MB fractionation (CK-MB) and testing for serum troponin I,²⁵ lactic dehydrogenase, and aspartate transaminase (SGOT)²¹
  
• assessment for immune activation and peripheral eosinophilia.²⁵
  

Findings on ECG are wide-ranging and might include sinus tachycardia, atrial or ventricular arrhythmias, left ventricular hypertrophy, nonspecific ST segment and T-wave abnormalities, and intraventricular conduction defects. Assess cardiac function with echocardiography to monitor for dilated cardiomyopathy. Stop clozapine immediately if findings suggest myocarditis.¹⁹

Table

Symptoms that could signal myocarditis in patients taking clozapine

Chest pain Confusion/mental status changes Dyspnea Edema Fatigue/weakness Fever Prolonged tachycardia
Source: Reference 7

TESTING: ‘Is this necessary?’

We contact the ER physician to request the above-mentioned tests, but he questions the need for such extensive and costly testing in a psychiatric patient with nonspecific symptoms.

After several phone conversations to review our recommendations, the emergency physician suggests sending Mr. Z home on a watch-and-wait protocol. We politely but firmly emphasize that Mr. Z needs a full cardiac workup, after which the physician consents to the tests (Box 2).

FINDINGS: suspicious readings

Mr. Z’s cardiac imaging results suggest a cardiopathy:

• echocardiogram shows mild ventricular enlargement with a decreased ejection fraction of 45% (normal reading, 55% to 60%)
  
• ECG shows normal sinus rhythm with low-voltage diffuse T-wave flattening throughout all leads without ST elevation
  
• creatine phosphokinase (CPK) and CKMB are within normal ranges
  
• troponin I is 0.33 ng/mL, a high-normal reading.
  

Mr. Z had no past cardiac abnormality, but an aunt had died in her 30s of viral myocarditis.

Based on these readings, the cardiology service admits Mr. Z with a presumptive diagnosis of clozapine-induced cardiomyopathy. The attending cardiologist stops clozapine and starts the angiotensin-converting enzyme inhibitor enalapril, 2.5 mg bid, for ventricular remodeling. Medical workup includes cytologic testing to rule out immunologic or viral disease.

Five days later, Mr. Z’s cardiac symptoms have resolved. The cardiology unit discharges him on enalapril, 2.5 mg bid, and schedules a cardiac ultrasound for 2 weeks after discharge to confirm progress.

The authors’ observations

Maintain high clinical suspicion while using clozapine. Similar to other patients with a clozapine-induced cardiopathy,¹⁶ Mr. Z showed rapid symptomatic changes after a benign initial course and experienced fairly vague symptoms that raised limited clinical concern at first.

Before starting clozapine therapy, screen all patients for pre-existing cardiac disease, which contraindicates this medication. Alert patients and caregivers to the risks and symptoms that require close monitoring early in treatment.

Many researchers suggest monitoring for myocarditis during the first month of therapy and ordering ECG at baseline and 2 and 4 weeks after starting clozapine.^21,22 Berk et al²⁶ suggest more aggressive monitoring, including:

• baseline ECG
  
• transthoracic echocardiogram
  
• baseline troponin/CK-MB
  
• ECG and troponin/CK-MB at 7 and 14 days
  
• echocardiogram at 6 and 12 months and then annually.
  

RELAPSE: Return of the ‘freak’

 

Immediately after Mr. Z’s discharge from the cardiology unit, we readmit him to inpatient psychiatry. His parents and case manager say he is again becoming preoccupied with his brief college relationship. He has been off clozapine for 5 days.

The authors’ observations

The American Psychiatric Association²⁷ (see http://www.psych.org/psych_pract/treatg/pg/SchizPG-Complete-Feb04.pdf) recommends maximizing 1 medication for at least 2 to 4 weeks to assess schizophrenia symptom response and urges clinicians to consider adverse effects, medical comorbidities, and patient preference before continuing the medication.

These recommendations highlight the challenges of treating medication-resistant schizophrenia. Relapse is common after a serious reaction to clozapine, and combining 2 or more other antipsychotics could lead to significantly greater side effects. A time-limited trial with an antipsychotic and an adjunctive agent might be attempted while carefully weighing the combination’s risks and benefits.²⁷

Clozapine reduced Mr. Z’s psychosis, but rechallenge would likely cause his potentially fatal cardiomyopathy to re-emerge. His sensitivity to adverse antipsychotic effects discourages polypharmacy and further complicates our decision.

Because our therapeutic options are limited, we consider an agent chemically similar to clozapine with pharmacologic overlap—such as olanzapine,⁶ which had improved Mr. Z’s psychotic symptoms during his hospitalization 1 year ago but caused akathisia. We hope to avoid this adverse effect by limiting the dosage to 30 mg/d and adding the antidepressant bupropion, which Mr. Z says had helped him previously.

Box 2

TREATMENT: Another trial

We start olanzapine, 5 mg/d, and titrate to 20 mg/d over 1 week. We add sustained-release bupropion, 200 mg bid, for associated dysphoria.

Mr. Z’s symptoms and paranoia gradually decline, and he tolerates off-unit passes with friends and family before discharge. Staff works closely with him to develop cognitive-behavioral strategies to manage residual paranoia and hallucinations, such as assessing evidence for his delusional beliefs and developing tools to distract him from remaining “voices.” He reports no cardiac symptoms and continues taking enalapril, 2.5 mg bid.

We discharge Mr. Z after 1 week, at which point he shows no suicidal or homicidal thoughts. Follow-up echocardiogram 2 weeks later shows ejection fraction has improved to 60%, suggesting absence of cardiomyopathy.

When last contacted 3 months ago, Mr. Z was stable and living with his parents. He was continuing outpatient psychiatric care and hoped to find an apartment and transition to independent living.

Related resource

• Clozapine safety information.
  www.clozaril.com/.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril
  
• Enalapril • Vasotec
  
• Fluphenazine • Prolixin, Permitil
  
• Haloperidol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Propranolol • Inderal
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  

Disclosure

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

CASE: Near-fatal combination

Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.

Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.

Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.

Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.

By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.

HISTORY: Depression and drugs

Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.

Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.

Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.

At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.

HISTORY: Family problems

Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.

The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.

The authors’ observations

Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.

Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.¹ Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.² According to Gold et al,³ long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.

Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.

 

As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.⁴ “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.

Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.

TREATMENT: Medication change

We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.

Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.

After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.

The authors’ observations

Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.^5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:

• work with the mesolimbic dopaminergic system to mediate pleasure and reward
  
• modulate the mesolimbic system
  
• or have the same attenuating effect on both psychic and physical pain.
  

The endogenous opioid system includes several classes of opioid peptides and receptors, including mu and kappa receptors.⁸ Mu receptors mediate opioid effects such as euphoria, respiratory depression, miosis, constipation, and physical withdrawal. Because buprenorphine is a partial mu agonist, it has no additional opioid effect beyond the patient’s maximum tolerable dosage.⁹ Buprenorphine thus has a lower abuse potential, causes less severe physical withdrawal, and is much safer in overdose than the full mu receptor agonists heroin or methadone.^9,10

Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.¹¹ Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.

Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.

The authors’ observations

Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.

Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.

Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.

Box 1

Buprenorphine risks

Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.

Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.

Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.

 

When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.

TREATMENT: An opioid option

After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.

Six months after presentation, Mr. B has not considered suicide, abused alcohol or drugs, or required psychiatric hospitalization. His depression is much improved, though intermittent depressed mood and affect and low self-esteem persist.

We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.

Box 2

The authors’ observations

Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.

Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.

Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.^2,12

FOLLOW-UP: ‘Bup’ stigma

Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”

Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.

During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.

The authors’ observations

Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.

Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.

Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.

 

Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.

Related resources

• U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
  

Drug brand names

• Acamprosate • Campral
  
• Alprazolam • Xanax
  
• Aripiprazole • Abilify
  
• Buprenorphine • Subutex
  
• Buprenorphine/naloxone • Suboxone
  
• Bupropion • Wellbutrin
  
• Diphenoxylate/atropine • Lomotil
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin, Concerta
  
• Mirtazapine • Remeron
  
• Naltrexone • ReVia, Vivitrol
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Roth is a speaker for Reckitt Benckiser.

Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Near-fatal combination

Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.

Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.

Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.

Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.

By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.

HISTORY: Depression and drugs

Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.

Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.

Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.

At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.

HISTORY: Family problems

Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.

The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.

The authors’ observations

Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.

Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.¹ Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.² According to Gold et al,³ long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.

Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.

 

As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.⁴ “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.

Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.

TREATMENT: Medication change

We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.

Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.

After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.

The authors’ observations

Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.^5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:

• work with the mesolimbic dopaminergic system to mediate pleasure and reward
  
• modulate the mesolimbic system
  
• or have the same attenuating effect on both psychic and physical pain.
  

The endogenous opioid system includes several classes of opioid peptides and receptors, including mu and kappa receptors.⁸ Mu receptors mediate opioid effects such as euphoria, respiratory depression, miosis, constipation, and physical withdrawal. Because buprenorphine is a partial mu agonist, it has no additional opioid effect beyond the patient’s maximum tolerable dosage.⁹ Buprenorphine thus has a lower abuse potential, causes less severe physical withdrawal, and is much safer in overdose than the full mu receptor agonists heroin or methadone.^9,10

Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.¹¹ Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.

Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.

The authors’ observations

Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.

Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.

Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.

Box 1

Buprenorphine risks

Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.

Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.

Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.

 

When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.

TREATMENT: An opioid option

After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.

Six months after presentation, Mr. B has not considered suicide, abused alcohol or drugs, or required psychiatric hospitalization. His depression is much improved, though intermittent depressed mood and affect and low self-esteem persist.

We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.

Box 2

The authors’ observations

Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.

Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.

Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.^2,12

FOLLOW-UP: ‘Bup’ stigma

Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”

Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.

During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.

The authors’ observations

Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.

Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.

Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.

 

Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.

Related resources

• U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
  

Drug brand names

• Acamprosate • Campral
  
• Alprazolam • Xanax
  
• Aripiprazole • Abilify
  
• Buprenorphine • Subutex
  
• Buprenorphine/naloxone • Suboxone
  
• Bupropion • Wellbutrin
  
• Diphenoxylate/atropine • Lomotil
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin, Concerta
  
• Mirtazapine • Remeron
  
• Naltrexone • ReVia, Vivitrol
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Roth is a speaker for Reckitt Benckiser.

Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Near-fatal combination

Inpatient psychiatry refers Mr. B, age 50, to our outpatient psychiatry clinic. Two weeks earlier, he tried to kill himself by sitting on a stepladder, tying a noose around his neck, and consuming large amounts of quetiapine, trazodone, and vodka. His wife found him unconscious on the floor with facial abrasions, empty pill bottles, and the noose lying next to him.

Emergency medical personnel brought Mr. B to the ER. His total Glasgow Coma Scale score of 3 indicated he was comatose. Pulse was 65 bpm (low-normal), and blood alcohol level was 106 mg/dL, suggesting he had ingested hazardous amounts of vodka. Quetiapine and trazodone blood levels were not measured.

Gastric lavage was unsuccessful because the orogastric tube became curled in the distal esophagus. Mr. B was successfully intubated and admitted to the intensive care unit. After 2 days, he was medically stable and regained consciousness, though he was delirious. He was transferred to inpatient psychiatry, where the attending psychiatrist diagnosed major depression and alcohol abuse disorder.

Before presentation, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist had added methylphenidate, 40 mg/d, to augment the antidepressants—which were not alleviating his depression—and the attending continued all 3 medications. Prior trials of sertraline, bupropion, trazodone, quetiapine, and aripiprazole were ineffective.

By the time Mr. B is transferred to us, his suicidal thoughts have remitted but he is still notably depressed. He is anergic, feels hopeless about the future, has markedly diminished self-worth, feels excessively guilty over past actions, is socially withdrawn, and shows a blunted, depressed affect. He also complains of insomnia despite taking mirtazapine at bedtime.

HISTORY: Depression and drugs

Mr. B says he has felt depressed on and off since his teens, and his current episode has been continuously severe for 1½ years. He began abusing alcohol and benzodiazepines during this episode but says he has been clean and sober for 2 weeks. He tried to kill himself 2 other times over 6 months by overdosing on alprazolam and was hospitalized after both attempts. He has no history of mania or psychosis.

Mr. B also abused opioids. In college, he was prescribed codeine for back pain after a sports injury. He experienced profound relief from depression after his first dose and soon began abusing codeine and other opioids for mood effects, including diphenoxylate/atropine and “cough syrup.” He says he has never used heroin.

Twenty years of illicit opioid use destroyed Mr. B’s occupational and social functioning, leaving him unable to work in his chosen field. During that period, he was frequently unemployed, socially isolated, and unable to sustain romantic relationships.

At age 40, Mr. B entered a methadone program, began working steadily, and got married. Five years later, he tapered off methadone and to our knowledge remained continuously opioid-free until presentation. Mr. B’s depression persisted while using opioids and worsened after stopping methadone. He also completed an 8-week residential substance abuse treatment program several months before presentation.

HISTORY: Family problems

Mr. B says he was emotionally abused as a child and described his father as excessively rageful. He says he entered a highly skilled profession to please his father but did not enjoy it and has not worked in the field since his early 30s. He has been unemployed for 1 year because his depression makes him feel “unworthy” to work.

The patient’s marriage of 10 years has been riddled with conflict. His depression, substance abuse, suicidality, and unemployment have fueled his wife’s resentment and anger.

The authors’ observations

Mr. B’s depression is challenging because of its severity and many possible causes and perpetuating factors. In addition to acute psychological stress and recent alcohol and benzodiazepine abuse, he has endured long-term opioid addiction. Although he had stayed opioid-free for 5 years, his past addiction contributed to his depression.

Whether Mr. B’s depression or opioid dependence came first is unclear. Either way, past opioid dependence can worsen depression prognosis.¹ Opioid dependence might cause a withdrawal state that lasts years after acute withdrawal has subsided, although some researchers dispute this concept.² According to Gold et al,³ long-term opioid use can cause endogenous opioid system derangements and depression after exogenous opioid use has ceased.

Depression is difficult to diagnose unambiguously in patients who have been using alcohol or anxiolytics because these CNS depressants’ effects might mimic depression. Patients whose symptoms suggest dual disorders commonly alternate between traditional psychiatric interventions and chemical dependence treatment.

 

As with Mr. B, a patient who abstains from 1 substance might start abusing another. This “replacement” is part of an “addiction interaction” theory that recognizes multiple substance and/or behavioral addictions in a patient.⁴ “Replacement” addiction indicates that substance abuse therapy is not adequately addressing some issues.

Coordinating concurrent depression and substance abuse treatment is critical. Although Mr. B’s ongoing psychosocial stress was addressed to varying degrees, endogenous opioid system derangements and/or prolonged opioid withdrawal may have been missed.

TREATMENT: Medication change

We discontinue methylphenidate because it is causing anxiety while leaving Mr. B’s depression unabated. Also, methylphenidate can be addictive.

Over several weeks, we titrate venlafaxine to 300 mg/d and continue mirtazapine, 30 mg at bedtime. We start weekly individual psychotherapy and encourage Mr. B to regularly attend Alcoholics Anonymous (AA) meetings, which he had been attending intermittently for years.

After 1 month, Mr. B’s depression improves marginally, but his depressed mood, anergia, and flat affect persist. He has not relapsed into alcohol or benzodiazepine dependence but reports occasional cravings for opioids and longs for the profound antidepressant effect they once gave him.

The authors’ observations

Sublingual buprenorphine is not FDA-approved to treat depression, although several small studies have described its antidepressant efficacy.^5-7 How exogenous opioids reduce depressive symptoms is unknown, although some researchers believe that endogenous opioids:

• work with the mesolimbic dopaminergic system to mediate pleasure and reward
  
• modulate the mesolimbic system
  
• or have the same attenuating effect on both psychic and physical pain.
  

The endogenous opioid system includes several classes of opioid peptides and receptors, including mu and kappa receptors.⁸ Mu receptors mediate opioid effects such as euphoria, respiratory depression, miosis, constipation, and physical withdrawal. Because buprenorphine is a partial mu agonist, it has no additional opioid effect beyond the patient’s maximum tolerable dosage.⁹ Buprenorphine thus has a lower abuse potential, causes less severe physical withdrawal, and is much safer in overdose than the full mu receptor agonists heroin or methadone.^9,10

Buprenorphine also is a kappa receptor antagonist, which might explain its antidepressant efficacy.¹¹ Whereas full mu agonism mediates euphoria, kappa receptor agonism results in dysphoria. By contrast, kappa receptor antagonism might cause a more stable, noneuphoric antidepressant effect.

Based on Mr. B’s clinical status, we ask him to consider sublingual buprenorphine/naloxone to treat depression and prevent relapse to opioid addiction.

The authors’ observations

Mr. B’s opioid addiction history and type of depression support buprenorphine augmentation. Whereas switching antidepressants or starting ECT would address only his persistent depression, buprenorphine also would target his opioid craving.

Numerous conventional psychotropics have not alleviated Mr. B’s depression, and changing antidepressants might nullify his small gains over the past month. We might consider ECT if buprenorphine does not reduce his depression.

Doctors need to obtain a waiver from the Drug Enforcement Administration (DEA) before using buprenorphine to treat opioid dependence—its approved indication (Box 1). This waiver is not necessary for off-label buprenorphine use. We needed the DEA waiver for Mr. B because we were using buprenorphine to treat opioid relapse prevention as well as depression. To prescribe buprenorphine without a DEA waiver, document that you are using the drug only for the off-label purpose.

Box 1

Buprenorphine risks

Overdose. Buprenorphine can be abused by grinding and dissolving tablets, then injecting them intravenously. Doing this while under the influence of benzodiazepines or other sedatives can cause respiratory depression, leading to coma or death.

Combination buprenorphine/naloxone carries a much lower risk of IV overdose than buprenorphine alone because naloxone blocks mu opioid receptors. This formulation was created specifically to prevent buprenorphine misuse. Because naloxone is metabolized hepatically, it is not pharmacologically active when taken orally and will not block buprenorphine’s effect when buprenorphine/naloxone is taken as prescribed.

Physical dependence and withdrawal. Long-term buprenorphine use can cause physical dependence. Abrupt discontinuation or excessively high doses can precipitate withdrawal. How withdrawal is precipitated is unclear, although some believe the drug displaces itself from mu receptors when doses are too high. Myalgia, headache, abdominal discomfort, rhinorrhea, anxiety, and irritability are common buprenorphine withdrawal symptoms. The dosage at which the drug precipitates withdrawal varies with each patient’s tolerance for opioids.

 

When stopping buprenorphine therapy, taper the medication gradually to minimize withdrawal discomfort and relapse risk. Start tapering by 2 mg per month, then taper more rapidly or slowly based on the patient’s subjective experience.

TREATMENT: An opioid option

After discussing the risks and benefits with Mr. B and his wife, we add buprenorphine/naloxone, 8 mg/d, then increase it to 16 mg/d the next day. He tolerates the medication, and within 1 week his anergia disappears and he feels more motivated and productive. He reports no euphoria from buprenorphine but says it decreases his craving for alcohol, benzodiazepines, and opioids.

Six months after presentation, Mr. B has not considered suicide, abused alcohol or drugs, or required psychiatric hospitalization. His depression is much improved, though intermittent depressed mood and affect and low self-esteem persist.

We continue buprenorphine/naloxone, 16 mg/d, and mirtazapine, 30 mg at bedtime, and reduce venlafaxine to 225 mg/d to mitigate sexual side effects. During weekly individual psychotherapy, we target Mr. B’s marital conflict and low self-esteem, and instruct him on overcoming life obstacles such as unemployment. He is looking for work and attends AA approximately 5 times a week.

Box 2

The authors’ observations

Considering the tumultuousness of Mr. B’s life, his willingness to enter psychotherapy and address underlying issues is significant. Adding buprenorphine to his antidepressant regimen helped stabilize his mood and make psychotherapy possible.

Psychotropics have not induced total remission of Mr. B’s depression, which is multifactorial and requires multimodal treatment. Still, we consider buprenorphine therapy at least partially successful—he has gone 6 months without attempting suicide or requiring psychiatric hospitalization.

Some clinicians consider buprenorphine’s potential for physical dependence a drawback to depression therapy. Physical dependence on a psychotropic does not necessarily outweigh its benefit in severe depression. Indeed, patients with depression can experience discontinuation symptoms from selective serotonin reuptake inhibitors and withdrawal from benzodiazepines.^2,12

FOLLOW-UP: ‘Bup’ stigma

Mr. B feels stigmatized about buprenorphine use, partly because his wife shames him for his history of addiction and views buprenorphine as a constant reminder of his “failures.”

Mrs. B’s dysfunctional attitude leaves Mr. B too ashamed to tell his fellow AA members that he takes buprenorphine. His inability to share these feelings also diminishes his sense of belonging in the 12-step fellowship. Even so, he feels that buprenorphine has helped him tremendously and wants to continue taking it.

During psychotherapy, we address Mr. B’s buprenorphine-related stigma and pervasive shame stemming from his history of mental illness, addiction, inability to work in his chosen field, and past employment failures. We encourage him to overcome his shame by pointing out his strengths—such as the skills he can offer potential employers—and by emphasizing that he did not choose to become depressed and addicted.

The authors’ observations

Most patients addicted to opiates feel much less stigmatized by buprenorphine therapy than by methadone. Patients who feel shame while taking buprenorphine usually are reacting to past opioid addiction rather than current therapy. Mr. B’s buprenorphine-related shame stems from his personality structure.

Shame, however, could create negative expectations of buprenorphine therapy, and can lower some patients’ self-esteem to the point that they feel they do not deserve to get better. Some patients stop buprenorphine prematurely because they believe they have beaten the addiction, but this often leads to relapse to the previous opioid of choice.

Help patients work through the shame of past addiction and encourage them to view buprenorphine therapy as a positive step toward recovery (Box 2). As mental health professionals, we must not collude with society to shame people with past chemical addiction. Creatively yet responsibly broadening our perspective toward psychiatric intervention can help patients such as Mr. B receive optimal treatment.

 

Although members of a 12-step group might harbor an idiosyncratic position on medications or treatment, cooperation with professionals is the program’s mainstream stance. Ideally, combination pharmacotherapy, psychotherapy, and guidance for optimal use of support groups can provide a stable foundation for recovery from both psychiatric and addictive disorders.

Related resources

• U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment Knowledge Application Program, Treatment Improvement Protocol Series. www.kap.samhsa.gov/products/manuals/tips/index.htm.
  

Drug brand names

• Acamprosate • Campral
  
• Alprazolam • Xanax
  
• Aripiprazole • Abilify
  
• Buprenorphine • Subutex
  
• Buprenorphine/naloxone • Suboxone
  
• Bupropion • Wellbutrin
  
• Diphenoxylate/atropine • Lomotil
  
• Methadone • Dolophine
  
• Methylphenidate • Ritalin, Concerta
  
• Mirtazapine • Remeron
  
• Naltrexone • ReVia, Vivitrol
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Roth is a speaker for Reckitt Benckiser.

Drs. Eiger and Tan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: The big freeze

Mr. Q, age 34, is afraid to cross the street. As he steps off the curb, his legs “cramp up.” As the cramping intensifies and his feet stiffen, his heart races, he begins to sweat, and he turns back for fear his legs will buckle in the street. While on the sidewalk, he stays within reach of a building or car in case he falls.

Six months before presentation, Mr. Q walked to church during a blizzard, only to find the church closed because of the storm. He returned home and shoveled snow for 1 hour, during which he repeatedly leaned forward and backward to dump the snow.

The following Sunday, Mr. Q’s legs started to “hurt” as he crossed the street. Thinking he had severely injured himself while shoveling, he began to fear street crossings. At work, he asked coworkers to help him cross over to the subway. By spring, he had become so humiliated by his dependence that he stopped working. His phobia intensified until he presented to us at his family’s urging.

During evaluation, Mr. Q says he can cross only side streets and holds on to his father while crossing. His father, who is retired, spends much of his day helping his son get around.

Complete physical exam by Mr. Q’s primary care physician reveals a possible pulled muscle in his right leg but no other medical problems. Neurologic exam results are normal, ruling out nerve damage.

Later in the evaluation, Mr. Q mentions that at age 10 he was struck by a car. The impact fractured the left side of his skull and left leg, and he temporarily lost consciousness.

Shortly after the accident, Mr. Q developed mild memory and concentration impairments and a moderate stutter. He also experienced nightmares, but they disappeared within days. He says he never received speech therapy or other psychiatric treatment because his family did not have medical insurance.

Mr. Q did not lose function after the accident, but in college his stuttering led to difficulty speaking in class and interacting socially. He suffered panic attacks while on the telephone or during job interviews. He now mostly stays home, where he lives with his parents and a nephew. He interacts only with family members.

During the evaluation, Mr. Q effortlessly walks around the therapist’s office and reports no trouble walking at home. He says the cramps almost never surface at home because he feels “calm” with walls close by. When trying to cross the street, he manages to turn back without falling despite the cramps.

Upon considering this conflict, Mr. Q seems to realize that his fear of street crossings protects him from social situations. His stuttering, however, confounds the evaluation because he has trouble communicating his symptoms.

Mr. Q’s affect is constricted as he describes his anxiety and fear. He says he feels limited and at times depressed by his inability to cross streets, yet shows little dysphoric affect or mourning and seems unusually calm when discussing the problem. He appears relaxed knowing that he can keep avoiding social situations.

The authors’ observations

Mr. Q’s history of fearing interviews and telephone conversations suggests social anxiety, and his fear and avoidance of street crossings suggest a specific phobia. Panic disorder with agoraphobia is not present because the patient never experienced spontaneous panic attacks.

Anxiety is more prevalent among persons who stutter than in fl uent speakers.^1,2

Persons who stutter:

• more commonly report speech anxiety³
  
• are significantly more uneasy in social situations and tend to avoid them^4,5
  
• might not be motivated to eliminate barriers that thwart social interaction.
  

Mr. Q’s stuttering has contributed to his isolation and enabled his phobia. Stuttering has caused significant social discomfort throughout his life, and staying home protects him from that hardship. His fear of street crossings gives him a reason to stay home.

Worse, his stuttering makes it difficult to ascertain his symptoms or plan treatment because it takes him so long to finish a sentence.

EVALUATION: Flashing back

Later in the evaluation, Mr. Q says that whenever he considers or tries crossing a street, he recalls his childhood vehicular injury and fears he will be struck again. He has nightmares of being run over, and these nightmares and flashbacks have been occurring twice weekly since the snowstorm.

During the mental status examination, Mr. Q is well related with fair to poor eye contact, probably because of his stutter; he looks away from the speaker when his stuttering intensifies. His nightmares and flashbacks suggest comorbid posttraumatic stress disorder (PTSD), although he has no persistent symptoms of increased arousal. He also shows no evidence of acute mood disorder, psychosis, or cognitive disturbance.

 

The authors’ observations

PTSD symptoms can develop months to years after a precipitating incident,^6,7 and repeated trauma can make patients more susceptible.

Interestingly, Mr. Q briefly suffered PTSD symptoms after the childhood accident but had no full-blown symptoms until adulthood. In addition to triggering avoidance behaviors, the muscle pull apparently reignited long-dormant PTSD symptoms (fl ashbacks, nightmares).

Mr. Q suffered no other PTSD symptoms. His stuttering might have signaled a psychogenic anxiety disorder, rather than being an incidental finding that developed after acute brain trauma at age 10.

Stuttering also might have contained Mr. Q’s PTSD symptoms for 24 years, until his snow-shoveling injury shattered that containment. Further, while shoveling in the street amid slippery conditions, he might have subconsciously feared he would have trouble eluding an oncoming vehicle.

The authors’ observations

We must address Mr. Q’s stuttering, phobia, and PTSD simultaneously to restore function. If we were to target his street-crossing phobia alone, we would face considerable resistance while exposing the underlying social phobia.

Supportive psychotherapy and exposure therapy—which would involve taking Mr. Q to an intersection and guiding him across—could help him overcome his fear of being run over. Cognitive-behavioral therapy (CBT) alone or with medications also could help.^8,9

Mr. Q’s anxiety, however, is severe enough to keep him from trying exposure therapy. Because staying home is his shield from social contact, he is not motivated to leave his apartment. Although he presented voluntarily, like many patients he is ambivalent toward exposure therapy.

Also, Mr. Q’s stutter makes it difficult to engage him in conversation. His stuttering is so severe that we have trouble doing an adequate CBT case formulation. At times his speech is almost incomprehensible.

Improving Mr. Q’s speech is crucial to completing an assessment, decreasing his social anxiety, and motivating him to conquer his fear of crossing streets. By addressing his stuttering and phobia simultaneously, we can treat his anxiety on 2 fronts:

• the stuttering that stemmed from his car accident at age 10
  
• the street-crossing phobia that developed after he pulled a leg muscle as an adult.
  

Box 1

TREATMENT: 5-step approach

Negative medical results convince Mr. Q that anxiety is holding him back. This allows us to target his anxiety with CBT, in vivo exposure, deep breathing/relaxation, speech therapy, and pharmacotherapy, all of which we start immediately.

CBT. We plan therapy by having Mr. Q list 10 street crossings and rank them from least fearful (side streets) to most fearful (busy intersections). During cognitive interventions, we encourage him to recognize that his fears might be protecting him from social situations, thereby prompting him to catastrophize his muscle cramps.

As part of Mr. Q’s psychoeducation, we reiterate his negative physical examination results and point out that his childhood vehicular injuries might be perpetuating his fears. We work on getting him to recognize that leg tightness does not predict falling and getting hit by a car.

Box 2

In vivo exposure. During our first session, we walk Mr. Q to a 1-way street and—after much coaxing and guidance—lead him into taking 1 step off the curb. The following week, we guide him through a second step. For homework, we have him practice crossing streets daily, at first with family members and then alone.

 

When his legs cramp up while trying to cross, we have him say out loud, “I can do it. I feel calm;” this helps him proceed across the street. We also teach self-empowerment by having him purposely cramp up his legs, then release them to stop the cramping.

Week by week, Mr. Q steps further into the crossing until—after 5 months of painstaking in vivo therapy—he crosses the street both ways on his own. Two weeks later, he crosses busier streets near his church with minimal anxiety (Box 1).

Deep breathing/relaxation. We teach Mr. Q progressive muscle relaxation and slow rhythmic breathing exercises, which he does before crossing streets to reduce his anxiety. For homework, he practices these exercises and soaks his legs in warm water for 10 minutes twice daily to relax his muscles and prevent cramping.

Speech therapy. The primary therapist devotes 20 minutes of each session to speech therapy. She employs relaxation training and therapy techniques such as Easy Onset,¹⁰ in which the patient stretches each sound, syllable, or word for up to 2 seconds, allowing him to speak at a smooth, slow rate. Mr. Q also practices these speech exercises at home.

After 6 weeks, Mr. Q’s stutter improves slightly but he still has trouble communicating. We refer him to a consulting speech therapist, who sees him twice weekly and leads Easy Onset and relaxation exercises. This gives us more time for supportive psychotherapy.

As his speech becomes more fluent, Mr. Q’s social anxiety and fear of street crossings decreases.

Pharmacotherapy. We instruct Mr. Q to take paroxetine, 20 mg/d, and clonazepam, 0.25 mg bid, 30 minutes before in vivo work to manage his anxiety. We titrate clonazepam to 0.5 mg bid over 1 month. He responds well to this regimen but fears he will become dependent on it.

During therapy, Mr. Q and the therapist rank the above interventions from most to least therapeutic (Box 2) so that we can effectively treat him should he relapse.

The authors’ observations

Although Mr. Q’s case is unusual, we feel our diagnostic and treatment methods can be applied to similar cases. His stutter, however, prevented us from conducting a structured diagnostic interview—which would have uncovered his symptoms more quickly—or performing standard manualized therapy.

Some data¹¹ suggest that combination psychotropics and relaxation therapy can compromise long-term exposure therapy outcomes, as the patient’s fear could return once medication is stopped. Mr. Q’s anxiety was crippling, however, and had to be addressed before we could consider exposure therapy.

More research is needed on overcoming patient communication barriers that can hamper treatment. Rapport with patients often makes or breaks psychiatric treatment, and communication problems can prevent that connection. As clinicians, we must watch for linguistic, cognitive, and cultural impediments to treatment.

FOLLOW-UP: ‘I can cross’

Six months after presentation, Mr. Q crosses all types of streets—from 1-way streets to 6-lane intersections—with minimal anxiety. He has resumed his previous level of functioning and is searching for work. His stutter, though greatly improved, is still audible.

We see Mr. Q monthly. We stop paroxetine after 8 months but continue clonazepam to address his many underlying social anxieties. By November—approximately 1½ years after presentation—we have reduced clonazepam to 0.5 mg each morning. We try reducing the morning dose to 0.25 mg, but Mr. Q’s debilitating anxiety resurfaces.

In December, we increase clonazepam to 0.5 mg bid, then reduce it to 0.5 mg each morning 2 months later. In April, we cut clonazepam to 0.25 mg each morning. So far, Mr. Q is functioning well.

The authors’ observations

Patients who begin antistuttering intervention as adults have a poorer speech improvement prognosis than those who start speech therapy in childhood.¹² In leaving his stuttering untreated for 24 years, Mr. Q likely sacrificed quality of life. Speech intervention at an earlier age might have improved his speech and prognosis early on.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Beck AT, Emery G, Greenberg RL. Anxiety disorders and phobias: a cognitive perspective. New York: Basic Books; 1985.
  
• Leahy RL, Holland SJ. Treatment plans and interventions for depression and anxiety disorders. New York: Guilford Press; 2000.
  

Drug brand names

• Clonazepam • Klonopin
  
• Paroxetine • Paxil
  

Disclosure

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

 

Acknowledgment

The authors thank Michael Garret, MD, for his assistance in preparing this article.

CASE: The big freeze

Mr. Q, age 34, is afraid to cross the street. As he steps off the curb, his legs “cramp up.” As the cramping intensifies and his feet stiffen, his heart races, he begins to sweat, and he turns back for fear his legs will buckle in the street. While on the sidewalk, he stays within reach of a building or car in case he falls.

Six months before presentation, Mr. Q walked to church during a blizzard, only to find the church closed because of the storm. He returned home and shoveled snow for 1 hour, during which he repeatedly leaned forward and backward to dump the snow.

The following Sunday, Mr. Q’s legs started to “hurt” as he crossed the street. Thinking he had severely injured himself while shoveling, he began to fear street crossings. At work, he asked coworkers to help him cross over to the subway. By spring, he had become so humiliated by his dependence that he stopped working. His phobia intensified until he presented to us at his family’s urging.

During evaluation, Mr. Q says he can cross only side streets and holds on to his father while crossing. His father, who is retired, spends much of his day helping his son get around.

Complete physical exam by Mr. Q’s primary care physician reveals a possible pulled muscle in his right leg but no other medical problems. Neurologic exam results are normal, ruling out nerve damage.

Later in the evaluation, Mr. Q mentions that at age 10 he was struck by a car. The impact fractured the left side of his skull and left leg, and he temporarily lost consciousness.

Shortly after the accident, Mr. Q developed mild memory and concentration impairments and a moderate stutter. He also experienced nightmares, but they disappeared within days. He says he never received speech therapy or other psychiatric treatment because his family did not have medical insurance.

Mr. Q did not lose function after the accident, but in college his stuttering led to difficulty speaking in class and interacting socially. He suffered panic attacks while on the telephone or during job interviews. He now mostly stays home, where he lives with his parents and a nephew. He interacts only with family members.

During the evaluation, Mr. Q effortlessly walks around the therapist’s office and reports no trouble walking at home. He says the cramps almost never surface at home because he feels “calm” with walls close by. When trying to cross the street, he manages to turn back without falling despite the cramps.

Upon considering this conflict, Mr. Q seems to realize that his fear of street crossings protects him from social situations. His stuttering, however, confounds the evaluation because he has trouble communicating his symptoms.

Mr. Q’s affect is constricted as he describes his anxiety and fear. He says he feels limited and at times depressed by his inability to cross streets, yet shows little dysphoric affect or mourning and seems unusually calm when discussing the problem. He appears relaxed knowing that he can keep avoiding social situations.

The authors’ observations

Mr. Q’s history of fearing interviews and telephone conversations suggests social anxiety, and his fear and avoidance of street crossings suggest a specific phobia. Panic disorder with agoraphobia is not present because the patient never experienced spontaneous panic attacks.

Anxiety is more prevalent among persons who stutter than in fl uent speakers.^1,2

Persons who stutter:

• more commonly report speech anxiety³
  
• are significantly more uneasy in social situations and tend to avoid them^4,5
  
• might not be motivated to eliminate barriers that thwart social interaction.
  

Mr. Q’s stuttering has contributed to his isolation and enabled his phobia. Stuttering has caused significant social discomfort throughout his life, and staying home protects him from that hardship. His fear of street crossings gives him a reason to stay home.

Worse, his stuttering makes it difficult to ascertain his symptoms or plan treatment because it takes him so long to finish a sentence.

EVALUATION: Flashing back

Later in the evaluation, Mr. Q says that whenever he considers or tries crossing a street, he recalls his childhood vehicular injury and fears he will be struck again. He has nightmares of being run over, and these nightmares and flashbacks have been occurring twice weekly since the snowstorm.

During the mental status examination, Mr. Q is well related with fair to poor eye contact, probably because of his stutter; he looks away from the speaker when his stuttering intensifies. His nightmares and flashbacks suggest comorbid posttraumatic stress disorder (PTSD), although he has no persistent symptoms of increased arousal. He also shows no evidence of acute mood disorder, psychosis, or cognitive disturbance.

 

The authors’ observations

PTSD symptoms can develop months to years after a precipitating incident,^6,7 and repeated trauma can make patients more susceptible.

Interestingly, Mr. Q briefly suffered PTSD symptoms after the childhood accident but had no full-blown symptoms until adulthood. In addition to triggering avoidance behaviors, the muscle pull apparently reignited long-dormant PTSD symptoms (fl ashbacks, nightmares).

Mr. Q suffered no other PTSD symptoms. His stuttering might have signaled a psychogenic anxiety disorder, rather than being an incidental finding that developed after acute brain trauma at age 10.

Stuttering also might have contained Mr. Q’s PTSD symptoms for 24 years, until his snow-shoveling injury shattered that containment. Further, while shoveling in the street amid slippery conditions, he might have subconsciously feared he would have trouble eluding an oncoming vehicle.

The authors’ observations

We must address Mr. Q’s stuttering, phobia, and PTSD simultaneously to restore function. If we were to target his street-crossing phobia alone, we would face considerable resistance while exposing the underlying social phobia.

Supportive psychotherapy and exposure therapy—which would involve taking Mr. Q to an intersection and guiding him across—could help him overcome his fear of being run over. Cognitive-behavioral therapy (CBT) alone or with medications also could help.^8,9

Mr. Q’s anxiety, however, is severe enough to keep him from trying exposure therapy. Because staying home is his shield from social contact, he is not motivated to leave his apartment. Although he presented voluntarily, like many patients he is ambivalent toward exposure therapy.

Also, Mr. Q’s stutter makes it difficult to engage him in conversation. His stuttering is so severe that we have trouble doing an adequate CBT case formulation. At times his speech is almost incomprehensible.

Improving Mr. Q’s speech is crucial to completing an assessment, decreasing his social anxiety, and motivating him to conquer his fear of crossing streets. By addressing his stuttering and phobia simultaneously, we can treat his anxiety on 2 fronts:

• the stuttering that stemmed from his car accident at age 10
  
• the street-crossing phobia that developed after he pulled a leg muscle as an adult.
  

Box 1

TREATMENT: 5-step approach

Negative medical results convince Mr. Q that anxiety is holding him back. This allows us to target his anxiety with CBT, in vivo exposure, deep breathing/relaxation, speech therapy, and pharmacotherapy, all of which we start immediately.

CBT. We plan therapy by having Mr. Q list 10 street crossings and rank them from least fearful (side streets) to most fearful (busy intersections). During cognitive interventions, we encourage him to recognize that his fears might be protecting him from social situations, thereby prompting him to catastrophize his muscle cramps.

As part of Mr. Q’s psychoeducation, we reiterate his negative physical examination results and point out that his childhood vehicular injuries might be perpetuating his fears. We work on getting him to recognize that leg tightness does not predict falling and getting hit by a car.

Box 2

In vivo exposure. During our first session, we walk Mr. Q to a 1-way street and—after much coaxing and guidance—lead him into taking 1 step off the curb. The following week, we guide him through a second step. For homework, we have him practice crossing streets daily, at first with family members and then alone.

 

When his legs cramp up while trying to cross, we have him say out loud, “I can do it. I feel calm;” this helps him proceed across the street. We also teach self-empowerment by having him purposely cramp up his legs, then release them to stop the cramping.

Week by week, Mr. Q steps further into the crossing until—after 5 months of painstaking in vivo therapy—he crosses the street both ways on his own. Two weeks later, he crosses busier streets near his church with minimal anxiety (Box 1).

Deep breathing/relaxation. We teach Mr. Q progressive muscle relaxation and slow rhythmic breathing exercises, which he does before crossing streets to reduce his anxiety. For homework, he practices these exercises and soaks his legs in warm water for 10 minutes twice daily to relax his muscles and prevent cramping.

Speech therapy. The primary therapist devotes 20 minutes of each session to speech therapy. She employs relaxation training and therapy techniques such as Easy Onset,¹⁰ in which the patient stretches each sound, syllable, or word for up to 2 seconds, allowing him to speak at a smooth, slow rate. Mr. Q also practices these speech exercises at home.

After 6 weeks, Mr. Q’s stutter improves slightly but he still has trouble communicating. We refer him to a consulting speech therapist, who sees him twice weekly and leads Easy Onset and relaxation exercises. This gives us more time for supportive psychotherapy.

As his speech becomes more fluent, Mr. Q’s social anxiety and fear of street crossings decreases.

Pharmacotherapy. We instruct Mr. Q to take paroxetine, 20 mg/d, and clonazepam, 0.25 mg bid, 30 minutes before in vivo work to manage his anxiety. We titrate clonazepam to 0.5 mg bid over 1 month. He responds well to this regimen but fears he will become dependent on it.

During therapy, Mr. Q and the therapist rank the above interventions from most to least therapeutic (Box 2) so that we can effectively treat him should he relapse.

The authors’ observations

Although Mr. Q’s case is unusual, we feel our diagnostic and treatment methods can be applied to similar cases. His stutter, however, prevented us from conducting a structured diagnostic interview—which would have uncovered his symptoms more quickly—or performing standard manualized therapy.

Some data¹¹ suggest that combination psychotropics and relaxation therapy can compromise long-term exposure therapy outcomes, as the patient’s fear could return once medication is stopped. Mr. Q’s anxiety was crippling, however, and had to be addressed before we could consider exposure therapy.

More research is needed on overcoming patient communication barriers that can hamper treatment. Rapport with patients often makes or breaks psychiatric treatment, and communication problems can prevent that connection. As clinicians, we must watch for linguistic, cognitive, and cultural impediments to treatment.

FOLLOW-UP: ‘I can cross’

Six months after presentation, Mr. Q crosses all types of streets—from 1-way streets to 6-lane intersections—with minimal anxiety. He has resumed his previous level of functioning and is searching for work. His stutter, though greatly improved, is still audible.

We see Mr. Q monthly. We stop paroxetine after 8 months but continue clonazepam to address his many underlying social anxieties. By November—approximately 1½ years after presentation—we have reduced clonazepam to 0.5 mg each morning. We try reducing the morning dose to 0.25 mg, but Mr. Q’s debilitating anxiety resurfaces.

In December, we increase clonazepam to 0.5 mg bid, then reduce it to 0.5 mg each morning 2 months later. In April, we cut clonazepam to 0.25 mg each morning. So far, Mr. Q is functioning well.

The authors’ observations

Patients who begin antistuttering intervention as adults have a poorer speech improvement prognosis than those who start speech therapy in childhood.¹² In leaving his stuttering untreated for 24 years, Mr. Q likely sacrificed quality of life. Speech intervention at an earlier age might have improved his speech and prognosis early on.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Beck AT, Emery G, Greenberg RL. Anxiety disorders and phobias: a cognitive perspective. New York: Basic Books; 1985.
  
• Leahy RL, Holland SJ. Treatment plans and interventions for depression and anxiety disorders. New York: Guilford Press; 2000.
  

Drug brand names

• Clonazepam • Klonopin
  
• Paroxetine • Paxil
  

Disclosure

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

 

Acknowledgment

The authors thank Michael Garret, MD, for his assistance in preparing this article.

CASE: The big freeze

Mr. Q, age 34, is afraid to cross the street. As he steps off the curb, his legs “cramp up.” As the cramping intensifies and his feet stiffen, his heart races, he begins to sweat, and he turns back for fear his legs will buckle in the street. While on the sidewalk, he stays within reach of a building or car in case he falls.

Six months before presentation, Mr. Q walked to church during a blizzard, only to find the church closed because of the storm. He returned home and shoveled snow for 1 hour, during which he repeatedly leaned forward and backward to dump the snow.

The following Sunday, Mr. Q’s legs started to “hurt” as he crossed the street. Thinking he had severely injured himself while shoveling, he began to fear street crossings. At work, he asked coworkers to help him cross over to the subway. By spring, he had become so humiliated by his dependence that he stopped working. His phobia intensified until he presented to us at his family’s urging.

During evaluation, Mr. Q says he can cross only side streets and holds on to his father while crossing. His father, who is retired, spends much of his day helping his son get around.

Complete physical exam by Mr. Q’s primary care physician reveals a possible pulled muscle in his right leg but no other medical problems. Neurologic exam results are normal, ruling out nerve damage.

Later in the evaluation, Mr. Q mentions that at age 10 he was struck by a car. The impact fractured the left side of his skull and left leg, and he temporarily lost consciousness.

Shortly after the accident, Mr. Q developed mild memory and concentration impairments and a moderate stutter. He also experienced nightmares, but they disappeared within days. He says he never received speech therapy or other psychiatric treatment because his family did not have medical insurance.

Mr. Q did not lose function after the accident, but in college his stuttering led to difficulty speaking in class and interacting socially. He suffered panic attacks while on the telephone or during job interviews. He now mostly stays home, where he lives with his parents and a nephew. He interacts only with family members.

During the evaluation, Mr. Q effortlessly walks around the therapist’s office and reports no trouble walking at home. He says the cramps almost never surface at home because he feels “calm” with walls close by. When trying to cross the street, he manages to turn back without falling despite the cramps.

Upon considering this conflict, Mr. Q seems to realize that his fear of street crossings protects him from social situations. His stuttering, however, confounds the evaluation because he has trouble communicating his symptoms.

Mr. Q’s affect is constricted as he describes his anxiety and fear. He says he feels limited and at times depressed by his inability to cross streets, yet shows little dysphoric affect or mourning and seems unusually calm when discussing the problem. He appears relaxed knowing that he can keep avoiding social situations.

The authors’ observations

Mr. Q’s history of fearing interviews and telephone conversations suggests social anxiety, and his fear and avoidance of street crossings suggest a specific phobia. Panic disorder with agoraphobia is not present because the patient never experienced spontaneous panic attacks.

Anxiety is more prevalent among persons who stutter than in fl uent speakers.^1,2

Persons who stutter:

• more commonly report speech anxiety³
  
• are significantly more uneasy in social situations and tend to avoid them^4,5
  
• might not be motivated to eliminate barriers that thwart social interaction.
  

Mr. Q’s stuttering has contributed to his isolation and enabled his phobia. Stuttering has caused significant social discomfort throughout his life, and staying home protects him from that hardship. His fear of street crossings gives him a reason to stay home.

Worse, his stuttering makes it difficult to ascertain his symptoms or plan treatment because it takes him so long to finish a sentence.

EVALUATION: Flashing back

Later in the evaluation, Mr. Q says that whenever he considers or tries crossing a street, he recalls his childhood vehicular injury and fears he will be struck again. He has nightmares of being run over, and these nightmares and flashbacks have been occurring twice weekly since the snowstorm.

During the mental status examination, Mr. Q is well related with fair to poor eye contact, probably because of his stutter; he looks away from the speaker when his stuttering intensifies. His nightmares and flashbacks suggest comorbid posttraumatic stress disorder (PTSD), although he has no persistent symptoms of increased arousal. He also shows no evidence of acute mood disorder, psychosis, or cognitive disturbance.

 

The authors’ observations

PTSD symptoms can develop months to years after a precipitating incident,^6,7 and repeated trauma can make patients more susceptible.

Interestingly, Mr. Q briefly suffered PTSD symptoms after the childhood accident but had no full-blown symptoms until adulthood. In addition to triggering avoidance behaviors, the muscle pull apparently reignited long-dormant PTSD symptoms (fl ashbacks, nightmares).

Mr. Q suffered no other PTSD symptoms. His stuttering might have signaled a psychogenic anxiety disorder, rather than being an incidental finding that developed after acute brain trauma at age 10.

Stuttering also might have contained Mr. Q’s PTSD symptoms for 24 years, until his snow-shoveling injury shattered that containment. Further, while shoveling in the street amid slippery conditions, he might have subconsciously feared he would have trouble eluding an oncoming vehicle.

The authors’ observations

We must address Mr. Q’s stuttering, phobia, and PTSD simultaneously to restore function. If we were to target his street-crossing phobia alone, we would face considerable resistance while exposing the underlying social phobia.

Supportive psychotherapy and exposure therapy—which would involve taking Mr. Q to an intersection and guiding him across—could help him overcome his fear of being run over. Cognitive-behavioral therapy (CBT) alone or with medications also could help.^8,9

Mr. Q’s anxiety, however, is severe enough to keep him from trying exposure therapy. Because staying home is his shield from social contact, he is not motivated to leave his apartment. Although he presented voluntarily, like many patients he is ambivalent toward exposure therapy.

Also, Mr. Q’s stutter makes it difficult to engage him in conversation. His stuttering is so severe that we have trouble doing an adequate CBT case formulation. At times his speech is almost incomprehensible.

Improving Mr. Q’s speech is crucial to completing an assessment, decreasing his social anxiety, and motivating him to conquer his fear of crossing streets. By addressing his stuttering and phobia simultaneously, we can treat his anxiety on 2 fronts:

• the stuttering that stemmed from his car accident at age 10
  
• the street-crossing phobia that developed after he pulled a leg muscle as an adult.
  

Box 1

TREATMENT: 5-step approach

Negative medical results convince Mr. Q that anxiety is holding him back. This allows us to target his anxiety with CBT, in vivo exposure, deep breathing/relaxation, speech therapy, and pharmacotherapy, all of which we start immediately.

CBT. We plan therapy by having Mr. Q list 10 street crossings and rank them from least fearful (side streets) to most fearful (busy intersections). During cognitive interventions, we encourage him to recognize that his fears might be protecting him from social situations, thereby prompting him to catastrophize his muscle cramps.

As part of Mr. Q’s psychoeducation, we reiterate his negative physical examination results and point out that his childhood vehicular injuries might be perpetuating his fears. We work on getting him to recognize that leg tightness does not predict falling and getting hit by a car.

Box 2

In vivo exposure. During our first session, we walk Mr. Q to a 1-way street and—after much coaxing and guidance—lead him into taking 1 step off the curb. The following week, we guide him through a second step. For homework, we have him practice crossing streets daily, at first with family members and then alone.

 

When his legs cramp up while trying to cross, we have him say out loud, “I can do it. I feel calm;” this helps him proceed across the street. We also teach self-empowerment by having him purposely cramp up his legs, then release them to stop the cramping.

Week by week, Mr. Q steps further into the crossing until—after 5 months of painstaking in vivo therapy—he crosses the street both ways on his own. Two weeks later, he crosses busier streets near his church with minimal anxiety (Box 1).

Deep breathing/relaxation. We teach Mr. Q progressive muscle relaxation and slow rhythmic breathing exercises, which he does before crossing streets to reduce his anxiety. For homework, he practices these exercises and soaks his legs in warm water for 10 minutes twice daily to relax his muscles and prevent cramping.

Speech therapy. The primary therapist devotes 20 minutes of each session to speech therapy. She employs relaxation training and therapy techniques such as Easy Onset,¹⁰ in which the patient stretches each sound, syllable, or word for up to 2 seconds, allowing him to speak at a smooth, slow rate. Mr. Q also practices these speech exercises at home.

After 6 weeks, Mr. Q’s stutter improves slightly but he still has trouble communicating. We refer him to a consulting speech therapist, who sees him twice weekly and leads Easy Onset and relaxation exercises. This gives us more time for supportive psychotherapy.

As his speech becomes more fluent, Mr. Q’s social anxiety and fear of street crossings decreases.

Pharmacotherapy. We instruct Mr. Q to take paroxetine, 20 mg/d, and clonazepam, 0.25 mg bid, 30 minutes before in vivo work to manage his anxiety. We titrate clonazepam to 0.5 mg bid over 1 month. He responds well to this regimen but fears he will become dependent on it.

During therapy, Mr. Q and the therapist rank the above interventions from most to least therapeutic (Box 2) so that we can effectively treat him should he relapse.

The authors’ observations

Although Mr. Q’s case is unusual, we feel our diagnostic and treatment methods can be applied to similar cases. His stutter, however, prevented us from conducting a structured diagnostic interview—which would have uncovered his symptoms more quickly—or performing standard manualized therapy.

Some data¹¹ suggest that combination psychotropics and relaxation therapy can compromise long-term exposure therapy outcomes, as the patient’s fear could return once medication is stopped. Mr. Q’s anxiety was crippling, however, and had to be addressed before we could consider exposure therapy.

More research is needed on overcoming patient communication barriers that can hamper treatment. Rapport with patients often makes or breaks psychiatric treatment, and communication problems can prevent that connection. As clinicians, we must watch for linguistic, cognitive, and cultural impediments to treatment.

FOLLOW-UP: ‘I can cross’

Six months after presentation, Mr. Q crosses all types of streets—from 1-way streets to 6-lane intersections—with minimal anxiety. He has resumed his previous level of functioning and is searching for work. His stutter, though greatly improved, is still audible.

We see Mr. Q monthly. We stop paroxetine after 8 months but continue clonazepam to address his many underlying social anxieties. By November—approximately 1½ years after presentation—we have reduced clonazepam to 0.5 mg each morning. We try reducing the morning dose to 0.25 mg, but Mr. Q’s debilitating anxiety resurfaces.

In December, we increase clonazepam to 0.5 mg bid, then reduce it to 0.5 mg each morning 2 months later. In April, we cut clonazepam to 0.25 mg each morning. So far, Mr. Q is functioning well.

The authors’ observations

Patients who begin antistuttering intervention as adults have a poorer speech improvement prognosis than those who start speech therapy in childhood.¹² In leaving his stuttering untreated for 24 years, Mr. Q likely sacrificed quality of life. Speech intervention at an earlier age might have improved his speech and prognosis early on.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
  
• Beck AT, Emery G, Greenberg RL. Anxiety disorders and phobias: a cognitive perspective. New York: Basic Books; 1985.
  
• Leahy RL, Holland SJ. Treatment plans and interventions for depression and anxiety disorders. New York: Guilford Press; 2000.
  

Drug brand names

• Clonazepam • Klonopin
  
• Paroxetine • Paxil
  

Disclosure

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

 

Acknowledgment

The authors thank Michael Garret, MD, for his assistance in preparing this article.

CASE: ‘Like a sledgehammer’

Mr. J, age 54, is admitted to the cardiac critical care unit after repeated tachycardia episodes over 3 years. He also has depressive symptoms including social isolation, passive suicidal thoughts, lack of interest in sex, weight loss, difficulty sleeping, sadness, and decreased appetite, energy, and ability to concentrate. The psychiatry consult team subsequently evaluates him.

Shortly after retiring as a police officer, Mr. J started having 10-second episodes of loss of consciousness and suffered 30 episodes within 1 year. After diagnosing chronic idiopathic ventricular tachycardia, a cardiologist ablated an aberrant left ventricular pathway and inserted a single-lead implantable cardioverter-defibrillator (ICD). He also prescribed the antiarrhythmic amiodarone, but Mr. J could not tolerate the medication’s side effects.

Mr. J’s tachycardia persisted, and repeated episodes triggered an estimated 13 electrical shocks from the ICD over 5 months. At this point, the cardiologist performed a second ablation, removed the single-lead ICD, and implanted a two-lead ICD, which he hoped would more accurately discern between lethal and nonlethal fast heart rhythms.

In addition, the cardiologist prescribed the antiarrhythmic sotalol—which did not suppress the arrhythmia—before switching to flecainide, 100 mg bid, which did. However, Mr. J still suffered fatigue, exercise intolerance, near-syncope, and chest heaviness.

One week after receiving the first ICD, Mr. J recalls, he felt his first shock while out for a walk. He said the shock lasted 5 to 10 seconds and “felt like somebody took a sledgehammer to my chest.” Another time, he suffered 6 successive shocks that threw him to the ground. Motorists pulled over to assist him, which made him feel ashamed.

Before long, Mr. J became increasingly afraid of repeat discharges. As soon as he began a task, he would feel a “thumping” in the back of his neck and start panicking, fearful that a heart rate increase would trigger another shock.

The stress forced Mr. J to abandon his favorite retirement hobbies—remodeling houses and yard work—and to spend his days lying around watching television. Fearing another discharge in public, he has stopped seeing friends and going to church. He has also stopped driving and depends on his female partner of 14 years for daily visits, grocery shopping, and rides to medical appointments. She feels frustrated by his debility.

The authors’ observations

By delivering electrical shocks when ventricles beat too quickly, an ICD shocks the heart back into a normal rhythm. Based on our observation, Mr. J probably had both anxiety-induced tachycardia and recurrent atrial fibrillation.

Although ICDs have prolonged survival for patients with potentially fatal ventricular arrhythmias,^1,2 painful discharges can occur without warning. Patients liken the discharge to an electric shock or to being kicked or punched in the chest.³

Depending on the patient’s activity level, cardiologists routinely program ICDs to discharge at approximately 10 beats per minute above expected heart rates during typical activities. Because ICD leads cannot differentiate between ventricular and supraventricular rhythm disturbances, a rapid supraventricular rhythm might precipitate a discharge intended to treat a more serious ventricular rhythm disturbance.

Frequent ICD discharges could indicate:

• the patient needs a more effective antiarrhythmic
  
• the device needs to be set at a higher rate to avoid discharge during periods of anxiety/exertion
  
• or the device is defective.
  

Between 50% and 70% of patients with a ICD receive multiple shocks within 2 years of implantation, whereas about one-third never experience discharge.⁴

ICD-induced psychopathology

Depression or tachycardia could have caused Mr. J’s fatigue. Either way, he showed numerous other depressive symptoms.

Fear of implant discharge or malfunction often induces psychiatric disorders, particularly in patients who have experienced discharge. As many as 87% of ICD patients suffer anxiety, depression, or other psychiatric symptoms after implantation,⁵ and 13% to 38% meet DSM-IV-TR criteria for an anxiety spectrum disorder.⁶

Multiple psychological theories explain iatrogenic anxiety disorders resulting from ICD firing. Behaviorally, ICD discharge represents an initially unconditioned stimulus that the patient associates with the activity he was engaging in when shocked. The shock discourages the patient from that activity—however benign—for fear it triggered the discharge and could cause future shocks.

ICD recipients often fear the device will malfunction or discharge while they are in public, driving, or operating machinery—leading some to become homebound and cease activities of daily living. The discharge’s unpredictability shatters a patient’s perception of control over his or her life and might induce a learned helplessness⁷ that can strain relationships, as it did with Mr. J and his partner. The patient also could develop anticipatory anxiety, mistaking benign body symptoms or increasing shock frequency for signs of a potentially fatal heart problem.⁸

 

Whether quality of life diminishes as ICD firings become more frequent is uncertain.⁹ The Canadian Implantable Defibrillator Study (N=317) found greater quality of life improvements with ICD therapy than with amiodarone—200 to 400 mg/d maintenance therapy—but the improvements were lost in patients who experienced ≥5 shocks over 12 months.¹⁰ Pauli et al⁷ found misinterpretation of the reason for increasing shocks to be more emotionally destructive than shock frequency, however.

Detecting ICD maladjustment

Patients with ICD maladjustment typically show anticipatory anxiety and negative cognitive attributions, and many engage in fruitless maneuvers to prevent device firing.⁵ Nervousness, dizziness, weakness, and fear are common responses to shock by ICD.¹¹

Most patients with new-onset, post-ICD anxiety disorders have no pre-implant psychiatric history.¹² Only one trial assessing state and trait anxiety before and after ICD placement reported increased trait anxiety in some patients before implantation.¹³

HISTORY: Nights in the cornfield

During psychiatric evaluation, Mr. J reveals that his parents physically and emotionally abused him as a child. He says his father frequently beat him with farm tools, and sometimes the beatings were so severe that his parents kept him home from school to prevent teachers from noticing his bruises. He never received medical treatment for his injuries.

The physical torture continued until high school when, Mr. J recalls, he became fast enough to escape his father’s grasp. “Some nights, I’d sleep in the cornfield,” he said.

For Mr. J, the inescapable threat of painful, unannounced ICD discharges has brought back the anticipatory terror and helplessness of his childhood. Just as he feared his father’s sudden rages, the specter of repeat ICD shocks now haunts him. He says he’d rather have the ICD removed and risk death from tachycardia than live another minute in fear.

The authors’ observations

Mr. J meets DSM-IV-TR criteria for PTSD. He associates ICD discharge with childhood abuse and experiences new-onset flashbacks, hyperarousal, and avoidance behavior.

To our knowledge, ICD shock-induced flashbacks to pre-implant trauma have not been reported, although some data associate ICDs with posttraumatic stress related to heart disease and treatment.^14-16 In one case series,¹⁴ patients showed:

• cluster B re-experiencing symptoms (cognitive preoccupation with trauma or psychophysiologic reactivity to reminders of the ICD and heart disease)
  
• cluster C avoidance symptoms (avoiding activities they thought might activate the ICD)
  
• cluster D hyperarousal symptoms (insomnia, decreased concentration, hypervigilance, and irritability).
  

The authors’ observations

Treating comorbid anxiety or depression in ICD recipients is critical. A number of psychiatric interventions might alleviate behavioral and psychological effects of body-device interactions.

CBT. In a retrospective study¹⁷ of 36 ICD recipients, those who received 9 months of CBT reported decreased depression, anxiety, distress, and sexual problems compared with those who did not. Interestingly, more CBT-group patients (11 of 18) suffered ICD shocks than did controls (6 of 18).

Peer support groups. Out of 58 ICD recipients who answered a post-implant questionnaire, 23 (39%) attended a peer support group.¹⁸ Of these, 22 (96%) found the group helpful and were happier, less hostile, and more sociable after participating. Peer group participants also were more likely to return to work than nonparticipants.

Box

Psychotropics and psychotherapy. A small case series

 

¹² attributes reduction of ICD-induced anxiety to combination individual psychotherapy and unspecified dosages of benzodiazepines. Two patients also received adjunctive fluoxetine or paroxetine, dosages unspecified.

In a double-blind, placebo-controlled crossover study, implantable atrial defibrillator recipients reported decreased pain and anxiety while taking the short-acting benzodiazepine triazolam, 0.375 mg, before patient-activated shock.¹⁹

We recommend trying a combination regimen that acts acutely and subacutely. A long-acting benzodiazepine such as clonazepam can calm acute, overwhelming anxiety, and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine can help manage chronic depressive and generalized anxiety symptoms.

SSRIs are relatively benign but more research on their cardiac safety is needed.^20,21 Tricyclic antidepressants, which prolong cardiac conduction, should be avoided.

In addition to psychotropics, concomitant psychotherapy can reduce chronic symptoms.

The authors’ observations

Requests for ICD removal because of intolerability pose an ethical dilemma (Box).²² Is increased life expectancy resulting from heart-implant technology worth the diminished quality of life stemming from iatrogenic psychopathology? Mr. J felt it was not, but we wanted to try to resolve his crippling anxiety before making a recommendation.

Preparing patients for ICD problems. Anxiety after an ICD shock and the dread of repeat shocks are normal; the goal is to prevent that anxiety from destroying quality of life.

As with Mr. J, many ICD recipients are emotionally unprepared for device-related complications. Most cardiologists do not screen patients for pre-existing anxiety before ICD placement, nor do many adequately address ICD-induced anxiety once the device has been placed.

Psychological screening before implantation can help detect and manage preexisting anxiety disorders. Small-scale evaluations have used anxiety scales to continuously measure anxiety before and after ICD placement.^13,23

Increased patient education on how ICDs work can help patients decide whether to proceed with implantation and tolerate discharges should they occur. Psychological screening and brief, routine communication between providers and patients about psychosocial issues can help patients adjust and identify those who need extended psychological services.⁴

To cope with ICD discharges, encourage patients to:

• develop a plan for how a shock would be handled
  
• perform relaxation exercises immediately after the shock
  
• resume activities they were involved with when the shock occurred to prevent avoidance.²⁴
  

Large, randomized, prospective studies using validated, structured interview tools could help clarify the nature of psychopathology induced by ICD and other technological innovations and evaluate interventions.

TREATMENT: Third attempt

The cardiology team discontinues flecainide and performs a third radioablation, which eradicates ectopic ventricular activity.

Acting on the psychiatry consult team’s advice, Mr. J is transferred to the inpatient mood disorders unit to aggressively treat his PTSD. He undergoes 4 days of intensive CBT designed to explore the connection between his response to the discharges and his father’s abuse. We prescribe clonazepam, 0.5 mg bid, to reduce Mr. J’s agitation and anxiety, and recommend outpatient counseling to help manage his stress—particularly his anxious response to stimuli that remind him of the ICD discharge.

Mr. J is discharged after 12 days in the cardiac and psychiatric units. He has no suicidal thoughts, his sadness has decreased, and his energy, concentration, sleep, and outlook on his future have improved. He also is resolving relationship issues with his partner.

As Mr. J’s anxiety declines and he is increasingly reassured that his arrhythmias are under control, he decides to keep the ICD. His function gradually improves with continued cardiac rehabilitation, although he does not continue psychotherapy.

Related resources

• Stutts LA, Cross NJ, Conti JB, Sears SF. Examination of research trends on patient factors in patients with implantable cardioverter defibrillators. Clin Cardiol 2007;30:64-8.
  
• Sears SF, Shea JB, Conti JB. How to respond to an implantable cardioverter-defibrillator shock. Circulation 2005;111;380-2. http://circ.ahajournals.org/cgi/reprint/111/23/e380.
  
• Pauli P, Wiedemann G, Dengler W, et al. Anxiety in patients with an automatic implantable cardioverter defibrillator: what differentiates them from panic patients? Psychosom Med 1999;61:69-76. www.psychosomaticmedicine.org/cgi/reprint/61/1/69.
  

Drug brand names

• Amiodarone • Cordarone
  
• Clonazepam • Klonopin
  
• Flecainide • Tambocor
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sotalol • Betapace
  
• Triazolam • Halcion, others
  

Disclosure

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

CASE: ‘Like a sledgehammer’

Mr. J, age 54, is admitted to the cardiac critical care unit after repeated tachycardia episodes over 3 years. He also has depressive symptoms including social isolation, passive suicidal thoughts, lack of interest in sex, weight loss, difficulty sleeping, sadness, and decreased appetite, energy, and ability to concentrate. The psychiatry consult team subsequently evaluates him.

Shortly after retiring as a police officer, Mr. J started having 10-second episodes of loss of consciousness and suffered 30 episodes within 1 year. After diagnosing chronic idiopathic ventricular tachycardia, a cardiologist ablated an aberrant left ventricular pathway and inserted a single-lead implantable cardioverter-defibrillator (ICD). He also prescribed the antiarrhythmic amiodarone, but Mr. J could not tolerate the medication’s side effects.

Mr. J’s tachycardia persisted, and repeated episodes triggered an estimated 13 electrical shocks from the ICD over 5 months. At this point, the cardiologist performed a second ablation, removed the single-lead ICD, and implanted a two-lead ICD, which he hoped would more accurately discern between lethal and nonlethal fast heart rhythms.

In addition, the cardiologist prescribed the antiarrhythmic sotalol—which did not suppress the arrhythmia—before switching to flecainide, 100 mg bid, which did. However, Mr. J still suffered fatigue, exercise intolerance, near-syncope, and chest heaviness.

One week after receiving the first ICD, Mr. J recalls, he felt his first shock while out for a walk. He said the shock lasted 5 to 10 seconds and “felt like somebody took a sledgehammer to my chest.” Another time, he suffered 6 successive shocks that threw him to the ground. Motorists pulled over to assist him, which made him feel ashamed.

Before long, Mr. J became increasingly afraid of repeat discharges. As soon as he began a task, he would feel a “thumping” in the back of his neck and start panicking, fearful that a heart rate increase would trigger another shock.

The stress forced Mr. J to abandon his favorite retirement hobbies—remodeling houses and yard work—and to spend his days lying around watching television. Fearing another discharge in public, he has stopped seeing friends and going to church. He has also stopped driving and depends on his female partner of 14 years for daily visits, grocery shopping, and rides to medical appointments. She feels frustrated by his debility.

The authors’ observations

By delivering electrical shocks when ventricles beat too quickly, an ICD shocks the heart back into a normal rhythm. Based on our observation, Mr. J probably had both anxiety-induced tachycardia and recurrent atrial fibrillation.

Although ICDs have prolonged survival for patients with potentially fatal ventricular arrhythmias,^1,2 painful discharges can occur without warning. Patients liken the discharge to an electric shock or to being kicked or punched in the chest.³

Depending on the patient’s activity level, cardiologists routinely program ICDs to discharge at approximately 10 beats per minute above expected heart rates during typical activities. Because ICD leads cannot differentiate between ventricular and supraventricular rhythm disturbances, a rapid supraventricular rhythm might precipitate a discharge intended to treat a more serious ventricular rhythm disturbance.

Frequent ICD discharges could indicate:

• the patient needs a more effective antiarrhythmic
  
• the device needs to be set at a higher rate to avoid discharge during periods of anxiety/exertion
  
• or the device is defective.
  

Between 50% and 70% of patients with a ICD receive multiple shocks within 2 years of implantation, whereas about one-third never experience discharge.⁴

ICD-induced psychopathology

Depression or tachycardia could have caused Mr. J’s fatigue. Either way, he showed numerous other depressive symptoms.

Fear of implant discharge or malfunction often induces psychiatric disorders, particularly in patients who have experienced discharge. As many as 87% of ICD patients suffer anxiety, depression, or other psychiatric symptoms after implantation,⁵ and 13% to 38% meet DSM-IV-TR criteria for an anxiety spectrum disorder.⁶

Multiple psychological theories explain iatrogenic anxiety disorders resulting from ICD firing. Behaviorally, ICD discharge represents an initially unconditioned stimulus that the patient associates with the activity he was engaging in when shocked. The shock discourages the patient from that activity—however benign—for fear it triggered the discharge and could cause future shocks.

ICD recipients often fear the device will malfunction or discharge while they are in public, driving, or operating machinery—leading some to become homebound and cease activities of daily living. The discharge’s unpredictability shatters a patient’s perception of control over his or her life and might induce a learned helplessness⁷ that can strain relationships, as it did with Mr. J and his partner. The patient also could develop anticipatory anxiety, mistaking benign body symptoms or increasing shock frequency for signs of a potentially fatal heart problem.⁸

 

Whether quality of life diminishes as ICD firings become more frequent is uncertain.⁹ The Canadian Implantable Defibrillator Study (N=317) found greater quality of life improvements with ICD therapy than with amiodarone—200 to 400 mg/d maintenance therapy—but the improvements were lost in patients who experienced ≥5 shocks over 12 months.¹⁰ Pauli et al⁷ found misinterpretation of the reason for increasing shocks to be more emotionally destructive than shock frequency, however.

Detecting ICD maladjustment

Patients with ICD maladjustment typically show anticipatory anxiety and negative cognitive attributions, and many engage in fruitless maneuvers to prevent device firing.⁵ Nervousness, dizziness, weakness, and fear are common responses to shock by ICD.¹¹

Most patients with new-onset, post-ICD anxiety disorders have no pre-implant psychiatric history.¹² Only one trial assessing state and trait anxiety before and after ICD placement reported increased trait anxiety in some patients before implantation.¹³

HISTORY: Nights in the cornfield

During psychiatric evaluation, Mr. J reveals that his parents physically and emotionally abused him as a child. He says his father frequently beat him with farm tools, and sometimes the beatings were so severe that his parents kept him home from school to prevent teachers from noticing his bruises. He never received medical treatment for his injuries.

The physical torture continued until high school when, Mr. J recalls, he became fast enough to escape his father’s grasp. “Some nights, I’d sleep in the cornfield,” he said.

For Mr. J, the inescapable threat of painful, unannounced ICD discharges has brought back the anticipatory terror and helplessness of his childhood. Just as he feared his father’s sudden rages, the specter of repeat ICD shocks now haunts him. He says he’d rather have the ICD removed and risk death from tachycardia than live another minute in fear.

The authors’ observations

Mr. J meets DSM-IV-TR criteria for PTSD. He associates ICD discharge with childhood abuse and experiences new-onset flashbacks, hyperarousal, and avoidance behavior.

To our knowledge, ICD shock-induced flashbacks to pre-implant trauma have not been reported, although some data associate ICDs with posttraumatic stress related to heart disease and treatment.^14-16 In one case series,¹⁴ patients showed:

• cluster B re-experiencing symptoms (cognitive preoccupation with trauma or psychophysiologic reactivity to reminders of the ICD and heart disease)
  
• cluster C avoidance symptoms (avoiding activities they thought might activate the ICD)
  
• cluster D hyperarousal symptoms (insomnia, decreased concentration, hypervigilance, and irritability).
  

The authors’ observations

Treating comorbid anxiety or depression in ICD recipients is critical. A number of psychiatric interventions might alleviate behavioral and psychological effects of body-device interactions.

CBT. In a retrospective study¹⁷ of 36 ICD recipients, those who received 9 months of CBT reported decreased depression, anxiety, distress, and sexual problems compared with those who did not. Interestingly, more CBT-group patients (11 of 18) suffered ICD shocks than did controls (6 of 18).

Peer support groups. Out of 58 ICD recipients who answered a post-implant questionnaire, 23 (39%) attended a peer support group.¹⁸ Of these, 22 (96%) found the group helpful and were happier, less hostile, and more sociable after participating. Peer group participants also were more likely to return to work than nonparticipants.

Box

Psychotropics and psychotherapy. A small case series

 

¹² attributes reduction of ICD-induced anxiety to combination individual psychotherapy and unspecified dosages of benzodiazepines. Two patients also received adjunctive fluoxetine or paroxetine, dosages unspecified.

In a double-blind, placebo-controlled crossover study, implantable atrial defibrillator recipients reported decreased pain and anxiety while taking the short-acting benzodiazepine triazolam, 0.375 mg, before patient-activated shock.¹⁹

We recommend trying a combination regimen that acts acutely and subacutely. A long-acting benzodiazepine such as clonazepam can calm acute, overwhelming anxiety, and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine can help manage chronic depressive and generalized anxiety symptoms.

SSRIs are relatively benign but more research on their cardiac safety is needed.^20,21 Tricyclic antidepressants, which prolong cardiac conduction, should be avoided.

In addition to psychotropics, concomitant psychotherapy can reduce chronic symptoms.

The authors’ observations

Requests for ICD removal because of intolerability pose an ethical dilemma (Box).²² Is increased life expectancy resulting from heart-implant technology worth the diminished quality of life stemming from iatrogenic psychopathology? Mr. J felt it was not, but we wanted to try to resolve his crippling anxiety before making a recommendation.

Preparing patients for ICD problems. Anxiety after an ICD shock and the dread of repeat shocks are normal; the goal is to prevent that anxiety from destroying quality of life.

As with Mr. J, many ICD recipients are emotionally unprepared for device-related complications. Most cardiologists do not screen patients for pre-existing anxiety before ICD placement, nor do many adequately address ICD-induced anxiety once the device has been placed.

Psychological screening before implantation can help detect and manage preexisting anxiety disorders. Small-scale evaluations have used anxiety scales to continuously measure anxiety before and after ICD placement.^13,23

Increased patient education on how ICDs work can help patients decide whether to proceed with implantation and tolerate discharges should they occur. Psychological screening and brief, routine communication between providers and patients about psychosocial issues can help patients adjust and identify those who need extended psychological services.⁴

To cope with ICD discharges, encourage patients to:

• develop a plan for how a shock would be handled
  
• perform relaxation exercises immediately after the shock
  
• resume activities they were involved with when the shock occurred to prevent avoidance.²⁴
  

Large, randomized, prospective studies using validated, structured interview tools could help clarify the nature of psychopathology induced by ICD and other technological innovations and evaluate interventions.

TREATMENT: Third attempt

The cardiology team discontinues flecainide and performs a third radioablation, which eradicates ectopic ventricular activity.

Acting on the psychiatry consult team’s advice, Mr. J is transferred to the inpatient mood disorders unit to aggressively treat his PTSD. He undergoes 4 days of intensive CBT designed to explore the connection between his response to the discharges and his father’s abuse. We prescribe clonazepam, 0.5 mg bid, to reduce Mr. J’s agitation and anxiety, and recommend outpatient counseling to help manage his stress—particularly his anxious response to stimuli that remind him of the ICD discharge.

Mr. J is discharged after 12 days in the cardiac and psychiatric units. He has no suicidal thoughts, his sadness has decreased, and his energy, concentration, sleep, and outlook on his future have improved. He also is resolving relationship issues with his partner.

As Mr. J’s anxiety declines and he is increasingly reassured that his arrhythmias are under control, he decides to keep the ICD. His function gradually improves with continued cardiac rehabilitation, although he does not continue psychotherapy.

Related resources

• Stutts LA, Cross NJ, Conti JB, Sears SF. Examination of research trends on patient factors in patients with implantable cardioverter defibrillators. Clin Cardiol 2007;30:64-8.
  
• Sears SF, Shea JB, Conti JB. How to respond to an implantable cardioverter-defibrillator shock. Circulation 2005;111;380-2. http://circ.ahajournals.org/cgi/reprint/111/23/e380.
  
• Pauli P, Wiedemann G, Dengler W, et al. Anxiety in patients with an automatic implantable cardioverter defibrillator: what differentiates them from panic patients? Psychosom Med 1999;61:69-76. www.psychosomaticmedicine.org/cgi/reprint/61/1/69.
  

Drug brand names

• Amiodarone • Cordarone
  
• Clonazepam • Klonopin
  
• Flecainide • Tambocor
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sotalol • Betapace
  
• Triazolam • Halcion, others
  

Disclosure

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

CASE: ‘Like a sledgehammer’

Mr. J, age 54, is admitted to the cardiac critical care unit after repeated tachycardia episodes over 3 years. He also has depressive symptoms including social isolation, passive suicidal thoughts, lack of interest in sex, weight loss, difficulty sleeping, sadness, and decreased appetite, energy, and ability to concentrate. The psychiatry consult team subsequently evaluates him.

Shortly after retiring as a police officer, Mr. J started having 10-second episodes of loss of consciousness and suffered 30 episodes within 1 year. After diagnosing chronic idiopathic ventricular tachycardia, a cardiologist ablated an aberrant left ventricular pathway and inserted a single-lead implantable cardioverter-defibrillator (ICD). He also prescribed the antiarrhythmic amiodarone, but Mr. J could not tolerate the medication’s side effects.

Mr. J’s tachycardia persisted, and repeated episodes triggered an estimated 13 electrical shocks from the ICD over 5 months. At this point, the cardiologist performed a second ablation, removed the single-lead ICD, and implanted a two-lead ICD, which he hoped would more accurately discern between lethal and nonlethal fast heart rhythms.

In addition, the cardiologist prescribed the antiarrhythmic sotalol—which did not suppress the arrhythmia—before switching to flecainide, 100 mg bid, which did. However, Mr. J still suffered fatigue, exercise intolerance, near-syncope, and chest heaviness.

One week after receiving the first ICD, Mr. J recalls, he felt his first shock while out for a walk. He said the shock lasted 5 to 10 seconds and “felt like somebody took a sledgehammer to my chest.” Another time, he suffered 6 successive shocks that threw him to the ground. Motorists pulled over to assist him, which made him feel ashamed.

Before long, Mr. J became increasingly afraid of repeat discharges. As soon as he began a task, he would feel a “thumping” in the back of his neck and start panicking, fearful that a heart rate increase would trigger another shock.

The stress forced Mr. J to abandon his favorite retirement hobbies—remodeling houses and yard work—and to spend his days lying around watching television. Fearing another discharge in public, he has stopped seeing friends and going to church. He has also stopped driving and depends on his female partner of 14 years for daily visits, grocery shopping, and rides to medical appointments. She feels frustrated by his debility.

The authors’ observations

By delivering electrical shocks when ventricles beat too quickly, an ICD shocks the heart back into a normal rhythm. Based on our observation, Mr. J probably had both anxiety-induced tachycardia and recurrent atrial fibrillation.

Although ICDs have prolonged survival for patients with potentially fatal ventricular arrhythmias,^1,2 painful discharges can occur without warning. Patients liken the discharge to an electric shock or to being kicked or punched in the chest.³

Depending on the patient’s activity level, cardiologists routinely program ICDs to discharge at approximately 10 beats per minute above expected heart rates during typical activities. Because ICD leads cannot differentiate between ventricular and supraventricular rhythm disturbances, a rapid supraventricular rhythm might precipitate a discharge intended to treat a more serious ventricular rhythm disturbance.

Frequent ICD discharges could indicate:

• the patient needs a more effective antiarrhythmic
  
• the device needs to be set at a higher rate to avoid discharge during periods of anxiety/exertion
  
• or the device is defective.
  

Between 50% and 70% of patients with a ICD receive multiple shocks within 2 years of implantation, whereas about one-third never experience discharge.⁴

ICD-induced psychopathology

Depression or tachycardia could have caused Mr. J’s fatigue. Either way, he showed numerous other depressive symptoms.

Fear of implant discharge or malfunction often induces psychiatric disorders, particularly in patients who have experienced discharge. As many as 87% of ICD patients suffer anxiety, depression, or other psychiatric symptoms after implantation,⁵ and 13% to 38% meet DSM-IV-TR criteria for an anxiety spectrum disorder.⁶

Multiple psychological theories explain iatrogenic anxiety disorders resulting from ICD firing. Behaviorally, ICD discharge represents an initially unconditioned stimulus that the patient associates with the activity he was engaging in when shocked. The shock discourages the patient from that activity—however benign—for fear it triggered the discharge and could cause future shocks.

ICD recipients often fear the device will malfunction or discharge while they are in public, driving, or operating machinery—leading some to become homebound and cease activities of daily living. The discharge’s unpredictability shatters a patient’s perception of control over his or her life and might induce a learned helplessness⁷ that can strain relationships, as it did with Mr. J and his partner. The patient also could develop anticipatory anxiety, mistaking benign body symptoms or increasing shock frequency for signs of a potentially fatal heart problem.⁸

 

Whether quality of life diminishes as ICD firings become more frequent is uncertain.⁹ The Canadian Implantable Defibrillator Study (N=317) found greater quality of life improvements with ICD therapy than with amiodarone—200 to 400 mg/d maintenance therapy—but the improvements were lost in patients who experienced ≥5 shocks over 12 months.¹⁰ Pauli et al⁷ found misinterpretation of the reason for increasing shocks to be more emotionally destructive than shock frequency, however.

Detecting ICD maladjustment

Patients with ICD maladjustment typically show anticipatory anxiety and negative cognitive attributions, and many engage in fruitless maneuvers to prevent device firing.⁵ Nervousness, dizziness, weakness, and fear are common responses to shock by ICD.¹¹

Most patients with new-onset, post-ICD anxiety disorders have no pre-implant psychiatric history.¹² Only one trial assessing state and trait anxiety before and after ICD placement reported increased trait anxiety in some patients before implantation.¹³

HISTORY: Nights in the cornfield

During psychiatric evaluation, Mr. J reveals that his parents physically and emotionally abused him as a child. He says his father frequently beat him with farm tools, and sometimes the beatings were so severe that his parents kept him home from school to prevent teachers from noticing his bruises. He never received medical treatment for his injuries.

The physical torture continued until high school when, Mr. J recalls, he became fast enough to escape his father’s grasp. “Some nights, I’d sleep in the cornfield,” he said.

For Mr. J, the inescapable threat of painful, unannounced ICD discharges has brought back the anticipatory terror and helplessness of his childhood. Just as he feared his father’s sudden rages, the specter of repeat ICD shocks now haunts him. He says he’d rather have the ICD removed and risk death from tachycardia than live another minute in fear.

The authors’ observations

Mr. J meets DSM-IV-TR criteria for PTSD. He associates ICD discharge with childhood abuse and experiences new-onset flashbacks, hyperarousal, and avoidance behavior.

To our knowledge, ICD shock-induced flashbacks to pre-implant trauma have not been reported, although some data associate ICDs with posttraumatic stress related to heart disease and treatment.^14-16 In one case series,¹⁴ patients showed:

• cluster B re-experiencing symptoms (cognitive preoccupation with trauma or psychophysiologic reactivity to reminders of the ICD and heart disease)
  
• cluster C avoidance symptoms (avoiding activities they thought might activate the ICD)
  
• cluster D hyperarousal symptoms (insomnia, decreased concentration, hypervigilance, and irritability).
  

The authors’ observations

Treating comorbid anxiety or depression in ICD recipients is critical. A number of psychiatric interventions might alleviate behavioral and psychological effects of body-device interactions.

CBT. In a retrospective study¹⁷ of 36 ICD recipients, those who received 9 months of CBT reported decreased depression, anxiety, distress, and sexual problems compared with those who did not. Interestingly, more CBT-group patients (11 of 18) suffered ICD shocks than did controls (6 of 18).

Peer support groups. Out of 58 ICD recipients who answered a post-implant questionnaire, 23 (39%) attended a peer support group.¹⁸ Of these, 22 (96%) found the group helpful and were happier, less hostile, and more sociable after participating. Peer group participants also were more likely to return to work than nonparticipants.

Box

Psychotropics and psychotherapy. A small case series

 

¹² attributes reduction of ICD-induced anxiety to combination individual psychotherapy and unspecified dosages of benzodiazepines. Two patients also received adjunctive fluoxetine or paroxetine, dosages unspecified.

In a double-blind, placebo-controlled crossover study, implantable atrial defibrillator recipients reported decreased pain and anxiety while taking the short-acting benzodiazepine triazolam, 0.375 mg, before patient-activated shock.¹⁹

We recommend trying a combination regimen that acts acutely and subacutely. A long-acting benzodiazepine such as clonazepam can calm acute, overwhelming anxiety, and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine can help manage chronic depressive and generalized anxiety symptoms.

SSRIs are relatively benign but more research on their cardiac safety is needed.^20,21 Tricyclic antidepressants, which prolong cardiac conduction, should be avoided.

In addition to psychotropics, concomitant psychotherapy can reduce chronic symptoms.

The authors’ observations

Requests for ICD removal because of intolerability pose an ethical dilemma (Box).²² Is increased life expectancy resulting from heart-implant technology worth the diminished quality of life stemming from iatrogenic psychopathology? Mr. J felt it was not, but we wanted to try to resolve his crippling anxiety before making a recommendation.

Preparing patients for ICD problems. Anxiety after an ICD shock and the dread of repeat shocks are normal; the goal is to prevent that anxiety from destroying quality of life.

As with Mr. J, many ICD recipients are emotionally unprepared for device-related complications. Most cardiologists do not screen patients for pre-existing anxiety before ICD placement, nor do many adequately address ICD-induced anxiety once the device has been placed.

Psychological screening before implantation can help detect and manage preexisting anxiety disorders. Small-scale evaluations have used anxiety scales to continuously measure anxiety before and after ICD placement.^13,23

Increased patient education on how ICDs work can help patients decide whether to proceed with implantation and tolerate discharges should they occur. Psychological screening and brief, routine communication between providers and patients about psychosocial issues can help patients adjust and identify those who need extended psychological services.⁴

To cope with ICD discharges, encourage patients to:

• develop a plan for how a shock would be handled
  
• perform relaxation exercises immediately after the shock
  
• resume activities they were involved with when the shock occurred to prevent avoidance.²⁴
  

Large, randomized, prospective studies using validated, structured interview tools could help clarify the nature of psychopathology induced by ICD and other technological innovations and evaluate interventions.

TREATMENT: Third attempt

The cardiology team discontinues flecainide and performs a third radioablation, which eradicates ectopic ventricular activity.

Acting on the psychiatry consult team’s advice, Mr. J is transferred to the inpatient mood disorders unit to aggressively treat his PTSD. He undergoes 4 days of intensive CBT designed to explore the connection between his response to the discharges and his father’s abuse. We prescribe clonazepam, 0.5 mg bid, to reduce Mr. J’s agitation and anxiety, and recommend outpatient counseling to help manage his stress—particularly his anxious response to stimuli that remind him of the ICD discharge.

Mr. J is discharged after 12 days in the cardiac and psychiatric units. He has no suicidal thoughts, his sadness has decreased, and his energy, concentration, sleep, and outlook on his future have improved. He also is resolving relationship issues with his partner.

As Mr. J’s anxiety declines and he is increasingly reassured that his arrhythmias are under control, he decides to keep the ICD. His function gradually improves with continued cardiac rehabilitation, although he does not continue psychotherapy.

Related resources

• Stutts LA, Cross NJ, Conti JB, Sears SF. Examination of research trends on patient factors in patients with implantable cardioverter defibrillators. Clin Cardiol 2007;30:64-8.
  
• Sears SF, Shea JB, Conti JB. How to respond to an implantable cardioverter-defibrillator shock. Circulation 2005;111;380-2. http://circ.ahajournals.org/cgi/reprint/111/23/e380.
  
• Pauli P, Wiedemann G, Dengler W, et al. Anxiety in patients with an automatic implantable cardioverter defibrillator: what differentiates them from panic patients? Psychosom Med 1999;61:69-76. www.psychosomaticmedicine.org/cgi/reprint/61/1/69.
  

Drug brand names

• Amiodarone • Cordarone
  
• Clonazepam • Klonopin
  
• Flecainide • Tambocor
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sotalol • Betapace
  
• Triazolam • Halcion, others
  

Disclosure

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

History: ‘They want to kill me’

Police and security agents arrest Ms. A, age 64, at a metropolitan airport. She is extremely agitated and behaving bizarrely, yelling that “the Mafia” is trying to kill her. She has spent 3 days hiding in area hotels, fleeing her “assailants.”

Police arrange Ms. A’s return home; under court order, she is hospitalized in a psychiatric facility. She is diagnosed with paranoid schizophrenia and receives IM haloperidol, 2 mg bid, but shows minimal improvement after 2½ weeks. Her psychotic symptoms improve slightly after the psychiatrist switches her to risperidone, 2 mg bid, but she still cannot function normally. Three weeks after admission, she is transferred to a nursing home for long-term care. She continues risperidone but remains paranoid and delusional.

Three months later, Ms. A is rehospitalized. She is anxious, delusional, confused, and hallucinating at admission. The patient is verbally and physically combative, fearful that medical staff will harm her. She is too violent to be examined, but staff notice that her skin appears thickened, her eyes puffy, and her hair coarse. Her voice sounds low and raspy.

I speak with Ms. A’s son, who reports that before his mother’s arrest he found her in the kitchen wielding a knife, exclaiming she wanted to kill herself. He says she heard a “whoosh” or “ringing” in her right ear while a male voice in her left ear told her, “End it, end it.”

Ms. A is severely obese (weight 325 lbs, body mass index 49 kg/m²). Blood pressure is 140/90 mm Hg, and she is taking captopril, 50 mg bid, for hypertension. Pulse rate and temperature are normal.

Dr. Lachover’s observations

Ms. A’s hallucinatory experiences are atypical, and her psychotic symptoms show little response after 2 months of aggressive inpatient treatment. Three months after discharge, she is rehospitalized in a florid paranoid psychotic state.

The patient’s weight poses an additional obstacle. I avoided second-generation antipsychotics (SGAs) that can cause weight gain, such as clozapine or olanzapine. I tried the SGA risperidone after IM haloperidol, a first-generation antipsychotic, produced minimal response.

Ms. A’s physical symptoms (thickened skin, coarse hair, puffiness under her eyes, and vocal raspiness) suggest an underlying organic process that might be causing her psychosis.

TESTING: Telling results

I order laboratory and other tests to check for an underlying organic disorder:

• Brain MRI is normal, as are CBC, renal and liver function, and serum copper, ceruloplasmin, vitamin B12, and heavy metal levels.
  
• Slit lamp eye exam reveals no Kayser-Fleischer ring, which would have indicated Wilson’s disease.
  
• EEG shows a diffuse, nonspecific, abnormal pattern of slowing and decreased amplitude, suggesting diffuse cerebral dysfunction.
  
• ECG shows sinus bradycardia and a significantly prolonged corrected QT (QTc) interval, indicating delayed ventricular repolarization.
  
• Thyroid panel is abnormal with markedly elevated thyrotropin (31.07 mIU/L).
  

I consult an internist, who diagnoses hypothyroidism based on Ms. A’s thyroid panel (Table 1). An endocrinologist also is consulted. Ms. A is started on levothyroxine, 0.025 mg/d, and continues risperidone, 2 mg bid, to address her paranoia and delusions.

Across 3 weeks, Ms. A’s delusional perceptions and hallucination intensity decrease, and her reality testing and socialization skills improve. She is discharged, after which the internist and I see her weekly to monitor thyroid function and psychiatric symptoms, respectively. Thyroid function gradually returns to normal over 4 to 6 months, and she is maintained on levothyroxine, 0.025 mg/d. Her weight gradually decreases over 12 months to 229 lbs.

Six months after discharge, Ms. A is notably more adept at activities of daily living. Mental status exam shows progressively improved reality testing and decreased paranoia. She is more active, and her mood and affect have brightened. Risperidone is stopped 10 months after discharge, and she has not been rehospitalized for psychiatric problems.

Table 1

Ms. A’s thyroid panel values

Component	Ms. A’s readings	Normal values
Serum cholesterol	310 mg/dL	100 to 199 mg/dL
TSH (thyrotropin)	31.07 mIU/L	0.25 to 4.30 mIU/L
Free T4	0.34 ng/dL	0.80 to 1.80 ng/dL
Total T4 (serum thyroxine)	1.5 µg/dL	4.6 to 12 µg/dL
Total T3 (serum triiodothyronine)	67 ng/dL	70 to 180 ng/dL

Dr. Lachover’s observations

Erroneously diagnosed with paranoid schizophrenia, Ms. A endured 2 extended hospitalizations. Her psychosis and mental state—both of which improved with thyroid replacement therapy—appear to have been a psychiatric manifestation of severe hypothyroidism, or “myxedema madness” (Box).^1-3

Myxedema prevalence in the general public has been reported at 0.5% to 18%. It is roughly 10 times more common in women than in men,⁴ and 5% to 15% of patients with myxedema might develop signs of psychosis.⁴ Myxedema-induced psychosis usually occurs during middle age but has been reported between ages 18 and 73. Prevalence increases with age.⁴

 

Recognizing ‘myxedema madness’

Detecting and treating myxedema in patients with treatment-resistant psychosis can resolve psychiatric and medical symptoms and restore quality of life. Left untreated, it can impair cognitive function and cause lethargy, dysarthria, myopathy, neuropathy, status epilepticus, and coma.^5-7

Psychiatric manifestationsof severe hypothyroidism vary greatly, and a pre-existing psychotic disorder can worsen the presentation. Confusion, disorientation, persecutory delusions, hallucinations, and violent episodes are common symptoms.⁸ The patient may resist medical examination, fearing her life is in danger or the physician is conspiring to harm her.

Myxedema can impair perception and intellectual functioning,⁹ and acute mania has been reported in some cases.¹⁰ Increasing delirium reduces integration of perceptual input, leading to misidentification and disorientation. Cognitive functioning may be impaired, and abnormal thyroid hormone levels might delay event-related brain potential.¹¹

Physical signs also can be telling. The patient might show general psychomotor retardation and slowed speech. The tongue might be swollen, the voice hoarse and croaking. Hair is often coarse and brittle, with hair loss along the sides of the eyebrows. Body temperature often dips below normal.⁴

Patients with hypothyroidism usually gain weight, leading to subcutaneous depositions of fat that frequently appear as a “buffalo-hump” or periorbital edema known as “myxedema facies.”¹² Because myxedema increases risk of heart disease, elevated cholesterol, and hypertension, immediate treatment is mandatory for severely obese patients such as Ms. A.

Dr. Lachover’s observations

Detecting Ms. A’s hypothyroidism early could have prevented needless hospitalizations and failed treatment. Order a baseline thyroid panel for every patient who presents with psychotic symptoms or depression, which is the primary affective disturbance seen in myxedema.

Box

Serum cholesterol >200 mg/dL, anemia and hypertension, basal metabolic rate≤20% of normal levels, triiodothyronine (T3) 4.5 mIU/L suggest myxedema (Table 2).

Diffuse slowing of background activity is the most common EEG change found in myxedema.¹³ ECG might show slow, regular sinus rhythm or bradycardia, low voltage, prolonged QTc interval, and flattened T waves.¹⁴ Prolonged QRS complexes on ECG indicate delayed ventricular repolarization.^11,15 Torsades de pointes, the potentially fatal ventricular tachycardia, can result from a prolonged QTc interval in rare myxedema cases.¹⁶

Table 2

Is it myxedema? Check the lab findings

Component	Values that suggest myxedema
Serum cholesterol	>200 mg/dL
Free T4
Total T4 (serum thyroxine)
Total T3 (serum triiodothyronine)
TSH (thyrotropin)	>4.5 mIU/L
EEG	Diffuse slowing
EKG	Prolonged QTc interval

Treating 2 sets of symptoms

Prescribe concomitant dessicated thyroid and low-dose antipsychotics over 4 to 6 months to treat both the thyroid dysfunction and psychosis. Because weight gain is common in myxedema, choose an antipsychotic that carries a relatively low risk of weight gain, such as risperidone, 2 mg bid, or aripiprazole, 5 to 10 mg/d.

Many patients reach euthyroidism and their psychosis improves gradually but notably over weeks or months after starting thyroid hormone replacement. Psychosis could recur if desiccated thyroid is stopped; restarting it will improve the patient’s mental state.¹⁷ Recovery takes about 3 months on average.⁴

Continue the SGA until delusion perception is gone and reality testing improves, then taper the medication until all psychotic symptoms have abated. Monitor thyroid function monthly.

For patients with myxedema-induced depression, supplement thyroid hormone replacement with a selective serotonin reuptake inhibitor such as sertraline at regular starting dosages.

Dr. Lachover’s observations

Consider contributing medical illness in any patient with psychosis, particularly with psychotic symptom onset after age 40 and lack of response to weeks of adequate antipsychotic therapy.

A meticulous search to rule out medical disorders in all patients with psychosis and/or depression is essential to planning treatment. Testing is especially urgent for elderly patients, as multiple medical comorbidities or medication side effects can mask hypothyroidism’s signs and symptoms and delay diagnosis.¹⁸

 

Check complete blood count, electrolytes, thyroid panel, urinalysis, urine drug screen, blood urea nitrogen, and creatinine to rule out an underlying metabolic or endocrinologic cause for psychosis. Watch for signs of anticholinergic syndrome during physical examination.

If any of the above results suggest a medical problem, test for the following as clinical suspicion warrants:

• serum copper/ceruloplasmin and liver function to rule out Wilson’s disease, a genetic disorder that causes copper to accumulate in the liver and brain
  
• systemic lupus erythematosus
  
• lead, magnesium, mercury, or manganese to rule out metal poisoning.
  

Order additional blood testing to check for vitamin B₁₂ deficiency, brain MRI to rule out Alzheimer’s or subcortical dementia, EEG to check for an infectious or malignant disorder or for cerebral dysfunction, or ECG to rule out a metabolic or degenerative disorder or electrolyte imbalance.

Related resources

• Cronin AJ. The Citadel. Boston: Little, Brown & Co.;1937:399.
  
• Asher R. Myxoedamatous madness. BMJ 1949;2:555-62.
  

Drug brand names

• Aripiprazole • Abilify
  
• Captopril • Capoten
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Levothyroxine • Synthroid
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

History: ‘They want to kill me’

Police and security agents arrest Ms. A, age 64, at a metropolitan airport. She is extremely agitated and behaving bizarrely, yelling that “the Mafia” is trying to kill her. She has spent 3 days hiding in area hotels, fleeing her “assailants.”

Police arrange Ms. A’s return home; under court order, she is hospitalized in a psychiatric facility. She is diagnosed with paranoid schizophrenia and receives IM haloperidol, 2 mg bid, but shows minimal improvement after 2½ weeks. Her psychotic symptoms improve slightly after the psychiatrist switches her to risperidone, 2 mg bid, but she still cannot function normally. Three weeks after admission, she is transferred to a nursing home for long-term care. She continues risperidone but remains paranoid and delusional.

Three months later, Ms. A is rehospitalized. She is anxious, delusional, confused, and hallucinating at admission. The patient is verbally and physically combative, fearful that medical staff will harm her. She is too violent to be examined, but staff notice that her skin appears thickened, her eyes puffy, and her hair coarse. Her voice sounds low and raspy.

I speak with Ms. A’s son, who reports that before his mother’s arrest he found her in the kitchen wielding a knife, exclaiming she wanted to kill herself. He says she heard a “whoosh” or “ringing” in her right ear while a male voice in her left ear told her, “End it, end it.”

Ms. A is severely obese (weight 325 lbs, body mass index 49 kg/m²). Blood pressure is 140/90 mm Hg, and she is taking captopril, 50 mg bid, for hypertension. Pulse rate and temperature are normal.

Dr. Lachover’s observations

Ms. A’s hallucinatory experiences are atypical, and her psychotic symptoms show little response after 2 months of aggressive inpatient treatment. Three months after discharge, she is rehospitalized in a florid paranoid psychotic state.

The patient’s weight poses an additional obstacle. I avoided second-generation antipsychotics (SGAs) that can cause weight gain, such as clozapine or olanzapine. I tried the SGA risperidone after IM haloperidol, a first-generation antipsychotic, produced minimal response.

Ms. A’s physical symptoms (thickened skin, coarse hair, puffiness under her eyes, and vocal raspiness) suggest an underlying organic process that might be causing her psychosis.

TESTING: Telling results

I order laboratory and other tests to check for an underlying organic disorder:

• Brain MRI is normal, as are CBC, renal and liver function, and serum copper, ceruloplasmin, vitamin B12, and heavy metal levels.
  
• Slit lamp eye exam reveals no Kayser-Fleischer ring, which would have indicated Wilson’s disease.
  
• EEG shows a diffuse, nonspecific, abnormal pattern of slowing and decreased amplitude, suggesting diffuse cerebral dysfunction.
  
• ECG shows sinus bradycardia and a significantly prolonged corrected QT (QTc) interval, indicating delayed ventricular repolarization.
  
• Thyroid panel is abnormal with markedly elevated thyrotropin (31.07 mIU/L).
  

I consult an internist, who diagnoses hypothyroidism based on Ms. A’s thyroid panel (Table 1). An endocrinologist also is consulted. Ms. A is started on levothyroxine, 0.025 mg/d, and continues risperidone, 2 mg bid, to address her paranoia and delusions.

Across 3 weeks, Ms. A’s delusional perceptions and hallucination intensity decrease, and her reality testing and socialization skills improve. She is discharged, after which the internist and I see her weekly to monitor thyroid function and psychiatric symptoms, respectively. Thyroid function gradually returns to normal over 4 to 6 months, and she is maintained on levothyroxine, 0.025 mg/d. Her weight gradually decreases over 12 months to 229 lbs.

Six months after discharge, Ms. A is notably more adept at activities of daily living. Mental status exam shows progressively improved reality testing and decreased paranoia. She is more active, and her mood and affect have brightened. Risperidone is stopped 10 months after discharge, and she has not been rehospitalized for psychiatric problems.

Table 1

Ms. A’s thyroid panel values

Component	Ms. A’s readings	Normal values
Serum cholesterol	310 mg/dL	100 to 199 mg/dL
TSH (thyrotropin)	31.07 mIU/L	0.25 to 4.30 mIU/L
Free T4	0.34 ng/dL	0.80 to 1.80 ng/dL
Total T4 (serum thyroxine)	1.5 µg/dL	4.6 to 12 µg/dL
Total T3 (serum triiodothyronine)	67 ng/dL	70 to 180 ng/dL

Dr. Lachover’s observations

Erroneously diagnosed with paranoid schizophrenia, Ms. A endured 2 extended hospitalizations. Her psychosis and mental state—both of which improved with thyroid replacement therapy—appear to have been a psychiatric manifestation of severe hypothyroidism, or “myxedema madness” (Box).^1-3

Myxedema prevalence in the general public has been reported at 0.5% to 18%. It is roughly 10 times more common in women than in men,⁴ and 5% to 15% of patients with myxedema might develop signs of psychosis.⁴ Myxedema-induced psychosis usually occurs during middle age but has been reported between ages 18 and 73. Prevalence increases with age.⁴

 

Recognizing ‘myxedema madness’

Detecting and treating myxedema in patients with treatment-resistant psychosis can resolve psychiatric and medical symptoms and restore quality of life. Left untreated, it can impair cognitive function and cause lethargy, dysarthria, myopathy, neuropathy, status epilepticus, and coma.^5-7

Psychiatric manifestationsof severe hypothyroidism vary greatly, and a pre-existing psychotic disorder can worsen the presentation. Confusion, disorientation, persecutory delusions, hallucinations, and violent episodes are common symptoms.⁸ The patient may resist medical examination, fearing her life is in danger or the physician is conspiring to harm her.

Myxedema can impair perception and intellectual functioning,⁹ and acute mania has been reported in some cases.¹⁰ Increasing delirium reduces integration of perceptual input, leading to misidentification and disorientation. Cognitive functioning may be impaired, and abnormal thyroid hormone levels might delay event-related brain potential.¹¹

Physical signs also can be telling. The patient might show general psychomotor retardation and slowed speech. The tongue might be swollen, the voice hoarse and croaking. Hair is often coarse and brittle, with hair loss along the sides of the eyebrows. Body temperature often dips below normal.⁴

Patients with hypothyroidism usually gain weight, leading to subcutaneous depositions of fat that frequently appear as a “buffalo-hump” or periorbital edema known as “myxedema facies.”¹² Because myxedema increases risk of heart disease, elevated cholesterol, and hypertension, immediate treatment is mandatory for severely obese patients such as Ms. A.

Dr. Lachover’s observations

Detecting Ms. A’s hypothyroidism early could have prevented needless hospitalizations and failed treatment. Order a baseline thyroid panel for every patient who presents with psychotic symptoms or depression, which is the primary affective disturbance seen in myxedema.

Box

Serum cholesterol >200 mg/dL, anemia and hypertension, basal metabolic rate≤20% of normal levels, triiodothyronine (T3) 4.5 mIU/L suggest myxedema (Table 2).

Diffuse slowing of background activity is the most common EEG change found in myxedema.¹³ ECG might show slow, regular sinus rhythm or bradycardia, low voltage, prolonged QTc interval, and flattened T waves.¹⁴ Prolonged QRS complexes on ECG indicate delayed ventricular repolarization.^11,15 Torsades de pointes, the potentially fatal ventricular tachycardia, can result from a prolonged QTc interval in rare myxedema cases.¹⁶

Table 2

Is it myxedema? Check the lab findings

Component	Values that suggest myxedema
Serum cholesterol	>200 mg/dL
Free T4
Total T4 (serum thyroxine)
Total T3 (serum triiodothyronine)
TSH (thyrotropin)	>4.5 mIU/L
EEG	Diffuse slowing
EKG	Prolonged QTc interval

Treating 2 sets of symptoms

Prescribe concomitant dessicated thyroid and low-dose antipsychotics over 4 to 6 months to treat both the thyroid dysfunction and psychosis. Because weight gain is common in myxedema, choose an antipsychotic that carries a relatively low risk of weight gain, such as risperidone, 2 mg bid, or aripiprazole, 5 to 10 mg/d.

Many patients reach euthyroidism and their psychosis improves gradually but notably over weeks or months after starting thyroid hormone replacement. Psychosis could recur if desiccated thyroid is stopped; restarting it will improve the patient’s mental state.¹⁷ Recovery takes about 3 months on average.⁴

Continue the SGA until delusion perception is gone and reality testing improves, then taper the medication until all psychotic symptoms have abated. Monitor thyroid function monthly.

For patients with myxedema-induced depression, supplement thyroid hormone replacement with a selective serotonin reuptake inhibitor such as sertraline at regular starting dosages.

Dr. Lachover’s observations

Consider contributing medical illness in any patient with psychosis, particularly with psychotic symptom onset after age 40 and lack of response to weeks of adequate antipsychotic therapy.

A meticulous search to rule out medical disorders in all patients with psychosis and/or depression is essential to planning treatment. Testing is especially urgent for elderly patients, as multiple medical comorbidities or medication side effects can mask hypothyroidism’s signs and symptoms and delay diagnosis.¹⁸

 

Check complete blood count, electrolytes, thyroid panel, urinalysis, urine drug screen, blood urea nitrogen, and creatinine to rule out an underlying metabolic or endocrinologic cause for psychosis. Watch for signs of anticholinergic syndrome during physical examination.

If any of the above results suggest a medical problem, test for the following as clinical suspicion warrants:

• serum copper/ceruloplasmin and liver function to rule out Wilson’s disease, a genetic disorder that causes copper to accumulate in the liver and brain
  
• systemic lupus erythematosus
  
• lead, magnesium, mercury, or manganese to rule out metal poisoning.
  

Order additional blood testing to check for vitamin B₁₂ deficiency, brain MRI to rule out Alzheimer’s or subcortical dementia, EEG to check for an infectious or malignant disorder or for cerebral dysfunction, or ECG to rule out a metabolic or degenerative disorder or electrolyte imbalance.

Related resources

• Cronin AJ. The Citadel. Boston: Little, Brown & Co.;1937:399.
  
• Asher R. Myxoedamatous madness. BMJ 1949;2:555-62.
  

Drug brand names

• Aripiprazole • Abilify
  
• Captopril • Capoten
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Levothyroxine • Synthroid
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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