Along with metabolic problems, there are a number of other adverse effects not unique to clozapine, but which present unique treatment considerations given the absence of alternatives to clozapine for many patients. An important part of prescribing clozapine is developing patient rapport, and conveying the message that embarrassing adverse effects such as nocturnal enuresis and incontinence can occur in up to 40% of patients, and will be addressed, especially if persistent. Normalizing the experience through education and elucidation of a prior history of such problems is a helpful means of initiating the discussion, and imparting to patients that this is not an unusual issue, and that there are standard approaches to these problems. Nonetheless, direct inquiry is the best method for elucidating complaints about enuresis or incontinence. Large studies of clozapine treatment discontinuation often cite “patient preference” when no specific reason is provided. Given the high prevalence of enuresis early in treatment, and the fact that it may persist in 20% of patients, the absence of this complaint from the literature on clozapine discontinuation suggests a lack of communication with providers.

Clozapine provides the best option for treatment-resistant schizophrenia patients, but at least 40% will have suboptimal response. Although numerous adjunctive pharmacological strategies have been explored in clozapine nonresponders, none present a compelling picture of superior outcomes. Echoing this sentiment, a 2015 review on biological approaches notes that improvement is modest with medication strategies, although electroconvulsive therapy (ECT) is more promising despite the paucity of controlled studies. These conclusions may engender a certain amount of therapeutic nihilism; however, before deciding that clozapine is ineffective and embarking on a litany of adjunctive options, there is a short list of strategies that may convert nonresponders into responders. Given the tepid response to adjunctive options, the best hope for most patients is optimizing clozapine exposure through assessment of plasma levels and addressing tolerability issues that impose barriers to titration.

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. 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. 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. 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. 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.

The primary use of clozapine is for schizophrenia spectrum patients with a history of suicidality or treatment-resistant psychosis. Although clozapine itself imposes significant metabolic burden, this is overlaid on the twofold higher rates of metabolic disorders (type 2 diabetes mellitus, metabolic syndrome) and twofold greater standardized mortality rates for cardiovascular disease in this patient population. Multiple factors contribute to this risk profile including lifestyle (e.g. smoking, dietary habits, sedentary behavior), metabolic effects of medications, and biological aspects of schizophrenia itself detectable in treatment-naive patients. Given clozapine’s metabolic impact, combined with the reality that patients may remain on clozapine throughout their lives, ongoing management of cardiometabolic risk is integral to the care of clozapine-treated individuals. Despite this confluence of medication and disease-related risk, the use of clozapine is associated with lower mortality rates from unnatural and natural causes. Investigators compared mortality trends in 14,754 individuals with schizophrenia, schizoaffective disorder or bipolar disorder followed in London from 2007 to 2011. There was a significant association between clozapine use (n = 748) and lower mortality even after controlling for confounders including clinical monitoring and disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = 0.001). This adds to prior data from an 11-year Finnish study which showed that clozapine markedly reduces suicide-related mortality, while no pronounced differences for ischemic heart disease mortality were found between antipsychotics.

The year 2018 marked the 60th anniversary of clozapine’s synthesis, and the 30th anniversary of the September 1988 Archives of General Psychiatry paper by Kane and colleagues documenting clozapine’s superior efficacy in treatment-resistant schizophrenia. The peer view literature since 1988 demonstrates ongoing interest in clozapine, with 350–450 papers per year listed in PubMed (see Figure 1). The ensuing decades have also seen other evidence-based uses for clozapine (e.g. schizophrenia patients with suicidality or aggression, Parkinson’s disease psychosis, treatment-resistant mania), but treatment-resistant schizophrenia spectrum disorders remain the most common indication. Lamentably, clozapine remains significantly underutilized for treatment-resistant schizophrenia despite compelling evidence of efficacy in this population, and the enormous individual and societal benefits that can accrue from effective management of treatment-resistant patients.