While weight gain and other adverse effects can be challenging to treat, seizure management is extremely successful to the extent that recent reviews comment that it should never be a reason to discontinue clozapine treatment. Evidence suggests that psychiatric providers may have adopted this position, as case data on 316 new clozapine starts from 2007 to 2011 at the South London and Maudsley National Health Service Foundation Trust did not list seizures among reasons for clozapine cessation, although 20 other types of adverse drug reactions were cited. Seizures are not unique to clozapine, and antipsychotic package insert warnings in the United States consider this a class effect, although the mechanisms for this common property remain unknown. Recent reviews note rates ranging from 0.2% to 0.5% with other antipsychotics, and a 9% incidence with high-dose chlorpromazine (≥ 1000 mg/day)

Clozapine’s effectiveness for treatment-resistant schizophrenia and mania, and its anti-aggressive properties, has led to trials for younger and older patients with severe mental disorders, and for those with intellectual disability (ID) who have treatment-resistant psychosis or nonpsychotic behavioral disorders. There is a paucity of double-blind data supporting some of these uses, but a compelling picture of efficacy based on case series and a small number of clinical trials. The common theme for these patient groups is managing tolerability concerns through adjustment of initial titration, use of plasma clozapine levels, and careful tracking of adverse effects. Pregnant women represent a patient population with a different set of issues; however, recent developments in the literature on major congenital malformations and first-trimester antipsychotic exposure support the conclusion that atypical antipsychotics as a class are not associated with increased risk. This finding is consistent with the available clozapine case data, and thereby allows clinicians to focus their energies on monitoring for maternal gestational diabetes, and minimization of postnatal exposure to avoid excessive sedation in the newborn. Clinicians should be familiar with the risk nomenclature and data on psychotropics during breastfeeding as a matter of routine clinical competence; however, due to risk of neutropenia, clozapine is the only antipsychotic that is absolutely contraindicated in breastfeeding women.

Managing clozapine-treated patients requires clinicians to become familiar with specific medical concerns not typically seen with other antipsychotics. Among the many unique adverse events associated with clozapine treatment is a constellation of fever and immune-mediated pathologies including myocarditis, interstitial nephritis, serositis and drug reaction with eosinophilia and systemic symptoms (DRESS). While the onset of fever during the first weeks of clozapine treatment is a common and often benign occurrence, swift action is necessary with the goal of recognizing and addressing more serious issues or minimizing a treatment interruption when evidence for systemic problems is lacking. The latter concept is important, as fever during the first weeks of therapy may appear in approximately 20% of patients, and therefore is not a reason to permanently discontinue clozapine treatment when there is no evidence for myocarditis, interstitial nephritis, or other systemic drug reactions. Cardiomyopathy is another unusual clozapine-related syndrome that is typically a later development, but presents a distinct group of clinical and ethical challenges when clozapine withdrawal fails to induce meaningful improvements in left ventricular ejection fraction (LVEF). Through a greater understanding of the time course and phenomenology of fever, myocarditis, interstitial nephritis, serositis, DRESS and cardiomyopathy clinicians can make evidence-based decisions about withholding clozapine treatment, and when resumption or rechallenge appears feasible.

The need to discontinue clozapine is a lamentable but medically necessary event in certain circumstances, and at times must be accomplished abruptly. In instances when the patient can be tapered off gradually (e.g. dilated cardiomyopathy), the risk of cholinergic rebound symptoms is lessened and the clinician can focus on making an informed choice about antipsychotic treatment. Although no agent equals clozapine’s efficacy for treatment-resistant schizophrenia, 35% of a group of schizophrenia outpatients with poor antipsychotic response (n = 99) who were considered candidates for clozapine had subtherapeutic plasma levels of their current antipsychotic. Thus, a certain fraction of patients who end up on clozapine were failures due to inadequate dosing of prior antipsychotics, poor adherence or kinetic issues. As will be discussed below, this is an important consideration for patients deemed treatment-resistant but who did not experience adverse effects of prior antipsychotic treatment, particularly those related to D2 antagonism. This understanding may open the door to revisiting prior antipsychotics, but with careful monitoring of adherence and drug exposure via use of plasma levels.

Clinicians must be knowledgeable about the mechanisms, metabolic pathways, and kinetics of all prescribed medications, but this is especially true for agents with narrower therapeutic indices such as clozapine. Armed with this information, one can maximize the potential for a successful clozapine trial in a patient who may lack other viable therapeutic options. While the properties underlying clozapine’s unique efficacy profile are not fully elucidated, there are extensive data on peripheral and central nervous system (CNS) kinetics, drug–drug and environmental interactions, and plasma levels to inform routine clinical care. (Throughout this volume clozapine plasma levels will be presented in ng/ml and nmol/l units. Some laboratories may report levels in μg/l, which is exactly equivalent to ng/ml.)

Sialorrhea may be the most common adverse effect of clozapine treatment, with prevalence estimates ranging from 30% to 90%, yet it is often underreported, underrecognized, and undertreated, leading to treatment dissatisfaction and discontinuation, social consequences, and possible medical morbidity in the form of aspiration events. Recent data indicate that the prevalence is likely closer to the 90% figure based on a detailed 2016 study of 98 clozapine-treated patients who were assessed for hypersalivation using two rating scales: the Nocturnal Hypersalivation Rating Scale and the Drooling Severity and Frequency Scale. Sialorrhea was experienced by 92% of subjects overall, more commonly at night (85% of subjects) than in the daytime (48%). Daytime symptoms were severe in 18%, and sialorrhea was considered frequent or occurring on a constant basis in 20%. Importantly, sialorrhea had at least a moderate impact on the quality of life in 15% of study subjects. While many studies of clozapine discontinuation focus on physician determined medical concerns, sialorrhea emerges as the third most common adverse drug reaction cited by patients as a reason for discontinuing treatment, behind sedation and nausea. Importantly, sialorrhea during clozapine therapy has been associated with reports of aspiration pneumonia. The extent of pneumonia risk from clozapine treatment has been quantified in three studies, with rates 1.99–3.18 times higher in clozapine-treated patients compared with other antipsychotics. Supporting this concept is the finding that pulmonary illness was the most common cause (32%) of medically related hospital admissions for clozapine-treated patients at one major US medical center, of which 58% were for pneumonia. Lastly, parotitis has also been reported and associated with hypersalivation.

Many nonchemotherapy medications are associated with neutropenia risk, but it was the cluster of 16 severe clozapine-related neutropenia cases reported from Finland in mid-summer 1975 with a 50% fatality rate that prompted clozapine’s withdrawal. Clozapine was subsequently reintroduced to the world market in the late 1980s based on demonstrable efficacy in treatment-resistant schizophrenia, albeit with mandatory hematologic monitoring and patient tracking.

In 2016 the United States Food and Drug Administration (FDA) added the category of falls as subsection 5.9 of the Warnings and Precautions listings for all antipsychotic package inserts. This mandated language reflected the concept that changes in blood pressure or alertness may not meet criteria for orthostatic hypotension or sedation as an adverse event during clinical trials, yet together they increase the risk of falling. Increased fall risk, especially among older patients, is one concern related to sedation and orthostasis when starting clozapine, but the other concern is that a patient will find tiredness or dizziness unacceptable when commencing treatment and refuse to continue with clozapine. Using case register data from the South London and Maudsley National Health Service Foundation Trust, it was found that 45% of 316 new clozapine starts from 2007 to 2011 discontinued clozapine within 2 years of initiation. Moreover, 52% of the discontinuations were due to patient decision, and adverse drug reactions were 2.6 times more likely to be the cause than dislike of laboratory visits.