Introduction

The 60th anniversary of clozapine’s synthesis by Schmutz and Eichenberger at Wander Pharmaceuticals was celebrated in 2018, although the chemists involved hoped that their tricyclic compound HF-1854 would possess antidepressant effects [ 1 ]. In January 1961, the first pharmacological report on HF-1854 described an agent with sedative and antiadrenergic properties that resembled chlorpromazine, but which did not induce catalepsy [ 1 ]. Further animal testing reported in December 1961 established a range of activities comparable to chlorpromazine but without the catalepsy induction seen with haloperidol. In 1962 the first open clinical trial of HF-1854 found limited efficacy at the dose of 160 mg TID (n  = 19), but later that year Gross and Langer in Vienna found good results in 21 of 28 patients at similar dosing, again without neurological adverse effects [ 2 ]. Further trial reports to Wander Pharmaceuticals in 1966 by Hippius in Berlin and Engelmeier in Vienna indicated that this was an effective but sedating antipsychotic that appeared free of neurological side effects. Wander completed further toxicological assays in 1967 and embarked on multiple clinical trials resulting in product registration in 1971, and marketing the following year under the trade name Leponex [ 1 ]. A spate of severe neutropenia cases from Finland in 1975 led to clozapine’s withdrawal from the market in most countries, although it was available under humanitarian programs with hematological monitoring [ 3 ].

Principles

• Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia. When treatment resistance is rigorously defined using all three Kane criteria, the response rate to most antipsychotics is < 5%, and for olanzapine 7%.

• Delaying clozapine initiation beyond 3 years after illness onset significantly reduces the likelihood of response.

• Compared to other antipsychotics, real-world data indicate that clozapine-treated patients have lower rehospitalization rates, and decreased mortality from all causes (natural and unnatural).

• Clozapine is uniquely effective in schizophrenia patients with psychogenic polydipsia.

• Clozapine is effective for schizophrenia patients with suicidality on the basis of a large clinical trial vs. olanzapine. Clozapine has an approved indication for this purpose in the US.

• Clozapine’s impact on suicidality and aggression is independent of the antipsychotic effect.

• Clozapine has proven efficacy in treatment-resistant mania when used adjunctively with mood-stabilizing medications, and is effective in nonpsychotic bipolar patients.

• Prior to the development of pimavanserin, clozapine was the antipsychotic with the strongest evidence for efficacy and tolerability in Parkinson’s disease psychosis.

Three double-blind studies comparing clozapine to other antipsychotics were published in the 1970s and 1980s based on perceived benefit in those who did not respond to other agents, or improved tolerability in patients with a history of severe intolerance to D ₂ antagonism (i.e. akathisia, parkinsonism, tardive dyskinesia (TD) or neuroleptic malignant syndrome (NMS)). While clozapine was clearly better tolerated and more effective than chlorpromazine among those with a history of D ₂ sensitivity [ 4 ], the two large efficacy trials used modest dosages of the comparator antipsychotics (chlorpromazine 360 mg/day, haloperidol 7.6 mg/day), raising doubts about clozapine’s greater effectiveness [ 5 ]. The latter question was definitively settled with publication of the pivotal clozapine trial for treatment-resistant schizophrenia in 1988, using criteria elaborated by Dr. John Kane for this purpose [ 6 ]. A crucial element of the trial design was the third criterion for treatment resistance: demonstrating in a prospective manner failure to respond to high levels of D ₂ antagonism. Fewer than 2% of patients met response criteria in the prospective haloperidol arm of the Kane study (mean dose 61 mg/day), while 80% were nonresponders and 18% intolerant of high-dose haloperidol. Using only those schizophrenia patients who met all three of the treatment-resistance criteria (n  = 268), response rates in the short (6-week) double-blind, randomized trial were 4% for the chlorpromazine arm vs. 30% for the clozapine group [ 6 ]. Additional experience over the next decade combined with insights regarding therapeutic plasma levels has increased the expected clozapine response rate to at least 40% in longer-term studies, with values up to 60% reported [ 7 ]. Clozapine has also demonstrated efficacy in schizophrenia patients with psychogenic polydipsia, an effect seen with doses as low as 300 mg/day [ 8 ].

Box 1.1 Essential Components of the Kane Definition of Treatment-Resistant Schizophrenia for Patients Enrolled in the Pivotal Clozapine Trial

• 1. At least three periods of treatment in the preceding 5 years with antipsychotics (from at least two different chemical classes) at dosages equivalent to or greater than 1000 mg/day of chlorpromazine for a period of 6 weeks, each without significant symptomatic relief.

• 2. No period of good functioning within the preceding 5 years.

• 3. Failure to respond to a prospective high-dose trial of a typical antipsychotic (haloperidol at doses up to 60 mg/day or higher administered with benztropine 6 mg/day). Response was defined as a 20% decrease in the Brief Psychiatric Rating Scale (BPRS) total score plus either a post-treatment Clinical Global Impression (CGI) severity rating of mildly ill (≤ 3) or a post-treatment BPRS score≤ 35.

The unique benefits of clozapine extend beyond treatment-resistant schizophrenia and include a number of other uses, many of which are supported by rigorous double-blind, placebo or active comparator trials. In some instances, the value of clozapine lies in its low affinity for D ₂ receptors, thus permitting treatment of schizophrenia patients intolerant of D ₂ antagonism, or Parkinson’s disease psychosis (PDP) patients. For other applications, the underlying mechanism for clozapine’s effectiveness is unknown, but it appears independent of the antipsychotic effect when employed for treatment-resistant mania, in schizophrenia patients with persistent aggression, and in schizophrenia patients with a history of suicidality. By mastering the details of hematologic monitoring and management of adverse effects, clinicians have a range of evidence-based uses for clozapine in difficult-to-treat patient groups.