Possible Interaction of Clozapine and Lisinopril

Mr. A, a 39-year-old Asian man with treatment-resistant schizophrenia, was receiving 300 mg/day of clozapine; his blood level of the drug was 490 ng/ml. In addition, he had diabetes that was controlled with glipizide, 10 mg/day. One year later, he developed hypertension, so lisinopril treatment, 5 mg/day, was initiated. Shortly afterward, his blood levels of clozapine and one its metabolites, norclozapine, were 966 ng/ml and 512 ng/ml, respectively. Six months later, his dose of lisinopril was increased to 10 mg/day. His blood levels of clozapine and norclozapine, as measured on two consecutive occasions 1 month apart, were 1092 and 380 ng/ml and 1245 and 392 ng/ml, respectively.

Mr. A became more disorganized and had frequent episodes of irritability and angry outbursts. He experienced severe sleep disturbances and frequent nightmares and awakenings. He also salivated excessively. Other known side effects of clozapine, such as anticholinergic toxicity or seizures, were not observed. Laboratory values, including measures of renal functions, were found to be within normal limits.

Mr. A’s clozapine dose was decreased to 200 mg/day. His blood levels, measured after 6 weeks, remained high: clozapine, 1335 ng/ml, and norclozapine, 428 ng/ml. When we suspected a drug interaction, his antihypertensive was changed from lisinopril to diltiazem, 240 mg/day. Repetition of laboratory tests after 6 weeks resulted in clozapine and norclozapine levels that had decreased to 693 and 254 ng/ml, respectively. Although Mr. A continued to experience psychotic symptoms and sialorrhea, his sleep disturbances and irritability had improved.