The decision to start clozapine therapy derives from the accepted, evidence-based uses for this medication including treatment-resistant schizophrenia spectrum disorders, schizophrenia patients with a history of suicidality, schizophrenia spectrum patients with persistent aggression, treatment-resistant mania, and psychosis associated with Parkinson’s disease (see Chapter 1). As was discussed in Chapter 1, the greatest conundrum in determining whether a schizophrenia patient is truly resistant to other treatment is high rates of nonadherence, with subtherapeutic plasma antipsychotic levels seen in 35–44% of outpatients deemed to have treatment-resistant illness. Once a patient is a candidate based on clinical criteria, patients and caregivers must be educated about the unique benefits of clozapine, its common adverse effects, and the demands of monitoring. With many outpatients this is a conversation that is often performed over an extended period as patients try and fail other options and come to trust the clinician’s suggestion that the benefits of clozapine outweigh the burdens of treatment. An important principle to guide these discussions is that significant delays in starting clozapine may reduce the likelihood of response in treatment-resistant schizophrenia. A review of response rates among 90 patients who remained on clozapine for at least 3 months found that the response rate was 82% for those who started clozapine within 2.8 years of meeting clinical criteria for treatment resistance, but fell to 31% when clozapine was started > 2.8 years after reaching this benchmark.

One need not specialize in hematology to prescribe clozapine, but the concern about neutropenia compels all clinicians to develop expertise with concepts such as benign ethnic neutropenia (BEN), and the dose-dependent impact of divalproex/valproate on neutrophil counts and neutropenia risk. The mandatory monitoring has also revealed a propensity for clozapine to induce other hematological abnormalities including eosinophilia, neutrophilia, abnormal platelet counts, and anemia. This spectrum of hematologic abnormalities is not unique to clozapine, but an analysis of 285 antipsychotic-treated patients found that persistent anemia, neutrophilia and eosinophilia occurred at significantly higher rates compared to other antipsychotics during the first 18 weeks of therapy. A retrospective Canadian study of 1-year hematologic outcomes among 101 new clozapine starts found a cumulative incidence of 48.9% for neutrophilia (> 7500/mm3), 5.9% for eosinophilia (> 1500/mm3), and 3% each for thrombocytosis (> 500,000/mm3) and thrombocytopenia (< 100,000/mm3). An Italian study of 2404 patients reported a leukocytosis rate of 7.7% using the total WBC threshold of 15,000/mm3. Most of the aberrations were self-limited and did not necessitate treatment interruption. Anemia may have multiple causes, and one study of 96 new clozapine starts found that 24.5% developed anemia during the first 2 years of treatment, but it was not a cause of treatment discontinuation.

Constipation is a common problem in western societies, but gastrointestinal hypomotility (GIH) assumes greater significance during clozapine therapy for several reasons: GIH is highly prevalent; GIH accounts for 36% of all medically related causes of treatment discontinuation; and in its most severe form, paralytic ileus, there is a fatality rate of 15.0–27.5%. Gastrointestinal illness accounted for 20% of all medically related hospital admissions for clozapine-treated patients at one major US medical center, of which 61% were for hypomotility-related problems. The magnitude of clozapine’s effect on motility is dramatic: the median colonic transit time (CTT) in one study was 23 hours among inpatients on nonclozapine antipsychotics, compared to 104 hours for those on clozapine. Moreover, 80% of the clozapine-treated patients had evidence of GIH, and transit times in all colonic segments were abnormal. Importantly, clozapine-associated GIH occurred irrespective of gender, age, ethnicity, or length of clozapine treatment. Only plasma clozapine level correlated with GIH severity as measured by transit time.

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.