Clozapine for Treatment-Resistant Schizophrenia.

The antipsychotic properties of clozapine, a newly synthesized dibenzodiazepine, were described in 1971, and the first clinical trials were reported in 1973 and 1974, as researchers from Czechoslovakia and Sweden demonstrated its efficacy in comparisons with perphenazine and chlorpromazine. The initial documented report of its use in the United States was published in 1974 by the George Simpson’s group at the Rockland Research Institute in Orangeburg, NY. Approved for use in some European countries, the drug’s safety came under a harsh spotlight in 1975, when clinicians from Finland reported 8 deaths among 13 cases of clozapine-associated agranulocytosis. An attempt to attribute the life-threatening complication to some undefined characteristic of the Finns was debunked when no local factor, either environmental or genetic, was found. At about the same time, in 1978, George Simpson and Thomas Cooper established the fact that clozapine may induce seizures during treatment with usual doses, as long as the plasma level was greater than 600 ng/mL. A drug known to produce agranulocytosis and seizures had no chance of approval by the Food and Drug Administration for use in the United States unless its superiority over the existing antipsychotics had been clearly demonstrated. “Compassionate” use seems to have been permitted, and a registry was in place, allowing the determination that the incidence of agranulocytosis was at most 2% in more than 800 cases. Clinical experience in the United States was also sufficiently ample to suggest that clozapine could improve the symptoms of schizophrenia in patients who seemed to be beyond the reach of conventional treatment. By the mid-1980s, the accumulated knowledge justified a clinical trial of the drug in patient with treatment-resistant schizophrenia, a task led by John Kane at Hillside Hospital in Glen Oaks, NY. The 319 patients (256 males and 63 females) were enrolled at 16 participating clinical sites. According to the authors, the typical patient was a 35-year-old male with the diagnosis of undifferentiated schizophrenia, in hospital for the past 2 years at the time of the study. All patients were considered treatment resistant based on stringent historical, contemporary, and prospective criteria. The historical data had to indicate that the subject had no period of good function in the past 5 years, despite at least 3 periods of treatment with antipsychotic drugs from at least 2 different chemical classes. The neuroleptics used had to have been equivalent to or greater than 1000 mg/d chlorpromazine and had to be administered for at least 6 weeks each without clear improvement in symptoms. The contemporary cross-sectional requirements were a score of at least 45 on the Brief Psychiatric Rating Scale (BPRS) and a minimum Clinical Global Impression rating of 4, both of which being consistent with a moderate or greater severity of the clinical syndrome. In addition, the subjects had to have BPRS rating indicating moderate severity for 4 specified items, conceptual disorganization, hallucinating behavior, suspiciousness, and abnormal thought content. The prospective component was assessed after a 6-week trial of treatment with haloperidol (up to 60 mg/d or greater) administered concurrently with benztropine mesylate (6 mg/d) for prevention of extrapyramidal side effects. Only 2% of the patients responded to treatment with haloperidol. After the lead-in phase, 268 nonresponders to haloperidol (mean dosage, 61 6 14 mg/d) were randomized to double-blind treatment with either clozapine or chlorpromazine, for 6 weeks. Patients treated with chlorpromazine were also given benztropine mesylate (6 mg/d). The uptitration of neuroleptics was accomplished in 2 weeks. Clozapine (up to 900 mg/d) outperformed chlorpromazine (up to 1800 mg/d) starting at week 1, as measured by the improvement on the BPRS. At the conclusion of the study, 30% of patients on clozapine met response criteria, which were at least 20% improvement over baseline in the BPRS score, a total BPRS score of 35 or less, and a Clinical Global Impression of no more than 3. Only 4% of the patients treated with chlorpromazine met these criteria. Notably, superior improvement on clozapine was not limited to positive symptoms, but negative symptoms improved as well. Fever, neutropenia, and hypersalivation were observed more frequently in the group treated with clozapine, although more patients receiving clozapine developed hypotension and xerostomia. None of the subjects developed agranulocytosis. American Journal of Therapeutics 23, e1133–e1134 (2016)