A study of clozapine discontinuation

In what they call the largest study to date of clozapine discontinuation, researchers examined a Veterans Administration cohort in the United States of 320 patients with schizophrenia or schizoaffective disorder, 91% male, who received clozapine. The Brief Psychiatric Rating Scale (BPRS) was used to assess symptoms. During 15 years of follow-up, 57% of patients had at least one discontinuation, which occurred most often between 3 and 6 months after treatment initiation.

Factors associated with an elevated likelihood of discontinuation were:
• African-American race
• Older age
• Lower disability award from the VA
• Smaller reduction in BPRS score

The top three causes of discontinuation were nonadherence (35%), adverse effects (28%), and administrative reasons (19%). The adverse effects related to discontinuation in order of frequency were:
• Hematologic, most often neutropenia
• Nervous system including sedation and seizures
• Cardiovascular including hypotension and tachycardia
• Autonomic including sialorrhea
• Weight gain

Agranulocytosis occurred in 3 patients, whereas lesser cases of granulocytopenia which still eliminated the possibility of rechallenge occurred in 4 patients; 3.3% of discontinuations therefore precluded restarting clozapine. One patient died of agranulocytosis; the only other clozapine-related death was in a patient with adynamic bowel and consequent aspiration.

The investigators looked at outcomes following discontinuation. Among 183 patients who stopped clozapine, only 16% restarted it and about half of those continued it. Among the approximately 170 patients who remained off clozapine and who received at least 3 months treatment with another antipsychotic, the mean BPRS score rose significantly from 39 to 52.

The limitations of the study include its naturalistic design and retrospective method.

The data confirm clinical impression that clozapine trials often do not succeed, and the chief challenges are managing adherence and adverse effects. Patients who can’t tolerate clozapine do poorly. We need more options for treatment-resistant psychosis.

Reference

Davis MC, Fuller MA, Strauss ME, Konicki PE, Jaskiw GE. Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients. Acta Psychiatr Scand. Published online 2 Dec 2013. Abstract