David Marcovitz, MD

Clozapine is a life-saving medication for many patients with schizophre­nia, including those who have a schizophrenia spectrum disorder with sui­cidality or treatment-resistant disease, but clinicians’ discomfort with managing its risk profile has led to it being underutilized. Clinicians who are prepared to discuss the risks and benefits of clozapine—and alternatives, including no treatment—with patients may encounter less reluctance when they recommend a time-limited trial of the drug.

Risks
Clinicians need to be aware of both 1) seri­ous adverse effects that can occur when clozapine needs to be interrupted or dis­continued (Table)¹ and 2) common side effects associated with continued use that can be managed without stopping the drug.² Common side effects that patients may experience as treatment is initiated include sedation, orthostatic hypotension, constipation, drooling, tachycardia, and metabolic side effects such as weight gain, diabetes, and hyperlipidemia, which are problematic in the long term.

Reassure patients that frequent monitor­ing of metabolic metrics (including baseline HbA_1C, lipid panel, waist circumference, and body mass index, as well as weight monitor­ing at each visit and metabolic laboratory monitoring every 3 to 6 months thereafter) should be expected, along with early inter­vention (eg, adding metformin) as appropri­ate. Constipation is common and can lead to serious, large bowel ileus. Ask about drool­ing, which can be treated by reducing the dosage or adding glycopyrrolate.

Extrapyramidal symptoms (EPS) includ­ing parkinsonism, dystonia, akathisia are uncommon (clozapine was the first “atypi­cal” antipsychotic for this reason), but neuro­leptic malignant syndrome (NMS) can occur. Although tardive dyskinesia (TD) is a small risk, clozapine will improve established TD in many patients once they are switched to clozapine. Blood dyscrasias include granu­locytopenia and the rare risk of agranulo­cytosis which are monitored by means of a prescribing registry. Myocarditis and pancre­atitis are likely idiosyncratic immune-related side effects that are unique to clozapine among antipsychotics. Other dangerous side effects include a dosage-related risk of seizure, severe hyperglycemia, and dia­betic ketoacidosis.

Benefits
Clozapine is FDA-approved for treatment-resistant schizophrenia and for schizo­phrenia spectrum disorders with recurrent suicidality. Clozapine can be the best anti­psychotic for patients who are sensitive to EPS and for those with TD. Antipsychotic efficacy often can be determined in a 2 to 3 month time-limited trial, although, in prac­tice, you might need to wait 6 to 12 months to observe how well clozapine’s benefits have accrued.

Alternatives
Not using the most effective antipsychotic, or using no antipsychotic when one is indi­cated, often results in unstable psychiatric illness, which increases the risk of adverse outcomes (eg, suicide, accidents). Unstable psychiatric disease also complicates treat­ment of medical problems. An 11-year follow-up study in Finland of patients with schizophrenia showed a lower all-cause mortality with clozapine than with other antipsychotics, all of which collectively were associated with lower mortality com­pared with no antipsychotic use.³ Clozapine also is associated with the lowest discontin­uation rate of any antipsychotic, which sug­gests that patients perceive its risk-benefit ratio favorably. Last, patients who might benefit from clozapine, but do not receive it, often will receive polypharmacy, which poses its own risks.

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

Clozapine is a life-saving medication for many patients with schizophre­nia, including those who have a schizophrenia spectrum disorder with sui­cidality or treatment-resistant disease, but clinicians’ discomfort with managing its risk profile has led to it being underutilized. Clinicians who are prepared to discuss the risks and benefits of clozapine—and alternatives, including no treatment—with patients may encounter less reluctance when they recommend a time-limited trial of the drug.

Risks
Clinicians need to be aware of both 1) seri­ous adverse effects that can occur when clozapine needs to be interrupted or dis­continued (Table)¹ and 2) common side effects associated with continued use that can be managed without stopping the drug.² Common side effects that patients may experience as treatment is initiated include sedation, orthostatic hypotension, constipation, drooling, tachycardia, and metabolic side effects such as weight gain, diabetes, and hyperlipidemia, which are problematic in the long term.

Reassure patients that frequent monitor­ing of metabolic metrics (including baseline HbA_1C, lipid panel, waist circumference, and body mass index, as well as weight monitor­ing at each visit and metabolic laboratory monitoring every 3 to 6 months thereafter) should be expected, along with early inter­vention (eg, adding metformin) as appropri­ate. Constipation is common and can lead to serious, large bowel ileus. Ask about drool­ing, which can be treated by reducing the dosage or adding glycopyrrolate.

Extrapyramidal symptoms (EPS) includ­ing parkinsonism, dystonia, akathisia are uncommon (clozapine was the first “atypi­cal” antipsychotic for this reason), but neuro­leptic malignant syndrome (NMS) can occur. Although tardive dyskinesia (TD) is a small risk, clozapine will improve established TD in many patients once they are switched to clozapine. Blood dyscrasias include granu­locytopenia and the rare risk of agranulo­cytosis which are monitored by means of a prescribing registry. Myocarditis and pancre­atitis are likely idiosyncratic immune-related side effects that are unique to clozapine among antipsychotics. Other dangerous side effects include a dosage-related risk of seizure, severe hyperglycemia, and dia­betic ketoacidosis.

Benefits
Clozapine is FDA-approved for treatment-resistant schizophrenia and for schizo­phrenia spectrum disorders with recurrent suicidality. Clozapine can be the best anti­psychotic for patients who are sensitive to EPS and for those with TD. Antipsychotic efficacy often can be determined in a 2 to 3 month time-limited trial, although, in prac­tice, you might need to wait 6 to 12 months to observe how well clozapine’s benefits have accrued.

Alternatives
Not using the most effective antipsychotic, or using no antipsychotic when one is indi­cated, often results in unstable psychiatric illness, which increases the risk of adverse outcomes (eg, suicide, accidents). Unstable psychiatric disease also complicates treat­ment of medical problems. An 11-year follow-up study in Finland of patients with schizophrenia showed a lower all-cause mortality with clozapine than with other antipsychotics, all of which collectively were associated with lower mortality com­pared with no antipsychotic use.³ Clozapine also is associated with the lowest discontin­uation rate of any antipsychotic, which sug­gests that patients perceive its risk-benefit ratio favorably. Last, patients who might benefit from clozapine, but do not receive it, often will receive polypharmacy, which poses its own risks.

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

Clozapine is a life-saving medication for many patients with schizophre­nia, including those who have a schizophrenia spectrum disorder with sui­cidality or treatment-resistant disease, but clinicians’ discomfort with managing its risk profile has led to it being underutilized. Clinicians who are prepared to discuss the risks and benefits of clozapine—and alternatives, including no treatment—with patients may encounter less reluctance when they recommend a time-limited trial of the drug.

Risks
Clinicians need to be aware of both 1) seri­ous adverse effects that can occur when clozapine needs to be interrupted or dis­continued (Table)¹ and 2) common side effects associated with continued use that can be managed without stopping the drug.² Common side effects that patients may experience as treatment is initiated include sedation, orthostatic hypotension, constipation, drooling, tachycardia, and metabolic side effects such as weight gain, diabetes, and hyperlipidemia, which are problematic in the long term.

Reassure patients that frequent monitor­ing of metabolic metrics (including baseline HbA_1C, lipid panel, waist circumference, and body mass index, as well as weight monitor­ing at each visit and metabolic laboratory monitoring every 3 to 6 months thereafter) should be expected, along with early inter­vention (eg, adding metformin) as appropri­ate. Constipation is common and can lead to serious, large bowel ileus. Ask about drool­ing, which can be treated by reducing the dosage or adding glycopyrrolate.

Extrapyramidal symptoms (EPS) includ­ing parkinsonism, dystonia, akathisia are uncommon (clozapine was the first “atypi­cal” antipsychotic for this reason), but neuro­leptic malignant syndrome (NMS) can occur. Although tardive dyskinesia (TD) is a small risk, clozapine will improve established TD in many patients once they are switched to clozapine. Blood dyscrasias include granu­locytopenia and the rare risk of agranulo­cytosis which are monitored by means of a prescribing registry. Myocarditis and pancre­atitis are likely idiosyncratic immune-related side effects that are unique to clozapine among antipsychotics. Other dangerous side effects include a dosage-related risk of seizure, severe hyperglycemia, and dia­betic ketoacidosis.

Benefits
Clozapine is FDA-approved for treatment-resistant schizophrenia and for schizo­phrenia spectrum disorders with recurrent suicidality. Clozapine can be the best anti­psychotic for patients who are sensitive to EPS and for those with TD. Antipsychotic efficacy often can be determined in a 2 to 3 month time-limited trial, although, in prac­tice, you might need to wait 6 to 12 months to observe how well clozapine’s benefits have accrued.

Alternatives
Not using the most effective antipsychotic, or using no antipsychotic when one is indi­cated, often results in unstable psychiatric illness, which increases the risk of adverse outcomes (eg, suicide, accidents). Unstable psychiatric disease also complicates treat­ment of medical problems. An 11-year follow-up study in Finland of patients with schizophrenia showed a lower all-cause mortality with clozapine than with other antipsychotics, all of which collectively were associated with lower mortality com­pared with no antipsychotic use.³ Clozapine also is associated with the lowest discontin­uation rate of any antipsychotic, which sug­gests that patients perceive its risk-benefit ratio favorably. Last, patients who might benefit from clozapine, but do not receive it, often will receive polypharmacy, which poses its own risks.

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