Clozapine: More Side Effects but Still the Best Antipsychotic

C lozapine, the gold-standard antipsychotic, has had a fascinating history.Hippius 1 documented this history well, but, in essence, at a time when everyone believed that antipsychotic activity and extrapyramidal symptoms (EPS) were inseparable.Wander AG laboratories, Basel, Switzerland, developed clozapine, which does not produce EPS.In our initial 1974 study, 2 the most memorable effect appeared to be on the nurses, who marveled at patients' improvement in the absence of EPS while being treated with clozapine.Routine treatment at that time was to increase the dose until improvement took place or EPS were noted.For someone like Haase, 3 this meant subclinical EPS, ie, changes in handwriting, which he claimed correlated with the therapeutic dose.We were able to confirm Haase's findings and also showed that clozapine did not produce cramping of handwriting.1,2 In our small-sample study, 2 clozapine was shown to be active and to produce sedation and salivation, but no EPS.Tardive dyskinesia that was present in 2 patients improved.We also saw changes in heart rate and blood pressure as well as significant weight gain.Withdrawal symptoms, including confusion, were noted when clozapine was abruptly withdrawn.2 Soon after this study came the report of deaths in Finland from agranulocytosis, which meant that in our next study 4 of clozapine to treat tardive dyskinesia, we carried out twice-weekly white blood cell counts.Side effects noted included neutropenia, seizures, hypotensive collapse, tachycardia, and QT flattening, but no EPS.There was improvement in tardive dyskinesia, and 3 of the 12 treated patients elected to continue on clozapine treatment after the study was over.Nonetheless, the side effect burden was large considering the small sample size of the study.4 The experience in Finland brought about curtailment of the use of clozapine in some countries.However, because of the almost universal view of the superior efficacy of clozapine, its availability in other countries kept it afloat and ultimately resulted in Study 30, for which much credit goes to Gilbert Honigfeld, Sandoz Labs, John Kane, and Herbert Meltzer (see reference 5).This large study convincingly showed the superiority of clozapine in treatment-resistant schizophrenia