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17. Clozapine
Keywords
ClozapineHistoryClozapine registryIndicationsMetabolismBenign ethnic neutropenia (BEN)Therapeutic drug monitoringSide effectsAugmentationEssential Points
Clozapine is a broad-spectrum antipsychotics with course-stabilizing properties. It is our most effective antipsychotic that works in many patients (around 50% of chronic patients, almost 75% in first-episode patients) who are treatment resistant to first-line antipsychotics.
Clozapine should be used early (as soon as treatment resistance has been established which may be during the first psychotic episode) in the course of schizophrenia and not be relegated to third-line status.
Clinical indications for clozapine are not limited to the two FDA indications (treatment-resistant schizophrenia and suicidality in patients with psychosis). Patients who are sensitive to extrapyramidal symptoms are an important third group of patients who may benefit from clozapine (clozapine is “atypical” in not causing EPS). Other, less established, indications include aggression and substance use.
The agranulocytosis risk (0.8%) is managed by registry-based prescribing. All patients need to be registered with the Clozapine REMS Program that stipulates the frequency of neutrophil monitoring. In the United States, monitoring is mandated as long as a patient is on clozapine.
Clozapine is metabolized partly by cytochrome P450 1A2 which is an enzyme inducible by smoking. Smokers may require a higher clozapine dose as outpatients when they resume smoking after leaving the hospital.
Therapeutic drug monitoring (TDM) is well-established for clozapine. TDM should be routinely used to avoid toxic drug levels (increase in seizure risk) and subtherapeutic blood levels. A blood level of at least 450 ng/mL is necessary in patients who show no response.
Clozapine carries five black box warnings: agranulocytosis, myocarditis, seizures (which are dose related), orthostatic hypotension with syncope and cardiorespiratory arrest, and increased mortality in elderly patients with dementia-related psychosis (class warning for all antipsychotics).
Myocarditis is a side effect unusual for antipsychotics. Its risk is highest in the first month of treatment and requires a high index of suspicion (malaise, palpitations, chest pain).
Constipation is very common and more than a nuisance side effect since it can lead to bowel obstruction. Constipation needs to be monitored and actively managed.
The long-term medical management of clozapine is mainly focused on its metabolic problems (weight gain and diabetes) that require monitoring and proactive management.
Clozapine augmentation strategies with medications to improve psychopathology are unimpressive. Consider, however, adding aripiprazole to blunt weight gain and reverses metabolic abnormalities associated with clozapine use.
“Per aspera ad astra.”
(Through hardship to the stars.)
Clozapine is psychiatry’s specialty drug, and it is our most effective but also our most difficult to use antipsychotic. Because of its importance, I dedicate a whole chapter to it, to have information about clozapine all in one place. Every psychiatrist who treats patients with psychosis needs to be able to prescribe clozapine. While more difficult to use than other antipsychotics, clozapine’s benefits are quite rewarding, as the Latin epigraph succinctly says. Clozapine may save a patient’s life – literally (reducing mortality from untreated or poorly treated illness [1]) and figuratively (allowing patients to pursue their life goals in the community as a result of clozapine’s illness course-stabilizing properties [2]). In our own hospital, we have a mandatory rotation in a clozapine clinic to prepare younger colleagues in the competent use of clozapine [3]. My teaching points from this clozapine rotation are the basis for this chapter. Establishing treatment-resistant schizophrenia which in most cases (including in first-episode patients) is the reason for a clozapine trial is discussed in detail in Chap. 12.
History
Clozapine’s unique “atypical” properties (i.e., antipsychotic efficacy without neurolepsis in animal models) were recognized already in the 1950s, but it was taken off the market in the 1970s after a series of deaths from agranulocytosis in Finland [4]. A handful of committed psychiatrists and pharmacologists from Sandoz AG (now Novartis, after a merger with Ciba-Geigy in 1996) conducted a seminal clinical trial (see below) that convinced the FDA to reintroduce clozapine for refractory schizophrenia in 1990, albeit with the safeguard of mandatory registry-based prescribing to mitigate the risk of dying from agranulocytosis. Clozapine’s side effects and administrative burden due to the registry lead too many patients and psychiatrists to forgo a clozapine trial. This is tragic: I cannot emphasize enough that clozapine can be life-saving and life-altering for patients who need it and that all psychiatrists ought to be able to offer it when indicated [3]. It should not be relegated to third-line status, but patients should receive it as early as needed for one of its clinical indications (which usually but not exclusively is treatment resistance [5]). Organizing care around a clozapine clinic may offer one solution to the ongoing low-prescribing rates of clozapine [6].
Efficacy for Refractory Psychosis
Clozapine is the most effective intervention for psychosis (other than ECT) that we have in our armamentarium. In the seminal study by Kane and colleagues [7], clozapine led to some improvement in 30% of patients who were prospectively treated with at least two antipsychotics (at the time, first-generation antipsychotics) and judged refractory. The superiority of clozapine has since been confirmed in several other trials, including in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) cohort which included patients who had failed second-generation antipsychotics [8]. In younger, first-episode patients, up to 75% may benefit from a switch to clozapine [9]. In more chronic populations, fewer patients will benefit, probably about 50% [10]. At least two meta-analyses [11, 12] confirm the clinical impression that clozapine is a different drug that can be helpful for those patients who respond poorly to other antipsychotics. One analysis estimated that 40% of patients have a clinically meaningful response to clozapine, with an average symptom reduction of 25% [13]. I suspect that part of its effectiveness is not based on pharmacology alone but stems from the need to provide good psychiatric care, with close and regular clinical follow-up of patients.
Indications
Clinical indications for clozapine
Treatment-resistant schizophreniaa |
Suicidality in the context of schizophrenia spectrum disordersa |
Aggression in the context of schizophrenia spectrum disorders |
Refractory mood disorders |
EPS sensitivity to antipsychotics |
Tardive dyskinesia |
Psychogenic polydipsia |
Schizophrenia with comorbid substance use |
Psychosis in Parkinson’s disease or other neurological conditionsb |
Agranulocytosis and the Clozapine Registry
Clozapine has a risk of around 0.8% to cause agranulocytosis which is higher than seen with other antipsychotics [21]. Its mechanism may be due to an activation of the immune system that leads to altered neutrophil kinetics in susceptible patients [22]. In the United States, clozapine can only be dispensed by a pharmacist if a patient is registered with the nationwide Clozapine REMS Program (a unified clozapine case registry) and submits to regular blood draws (“no blood, no drug”) [23]. In 2015, a single registry replaced previous independent registries and databases and created one single access point for all clozapine products.
Absolute neutrophil count (ANC) monitoring. Neutrophils refer to the neutrophilic granulocytes. The absolute neutrophil count is calculated by multiplying the WBC with the percentage of neutrophils (segs plus bands). (According to [23])
Consistent with the nonlinear agranulocytosis risk (highest at the beginning of treatment, with a decline over 6–12 months but never reaching a zero risk), ANC is monitored weekly for 6 months, then every other week for 6 months, and then every 4 weeks indefinitely as long the patient continues on clozapine.
Tip
Emphasize to patients who are often worried about weekly blood work that they are only agreeing to a time-limited trial of a few months; they may not take clozapine in the long run unless there is benefit. Those patients who benefit usually put up gladly with the eventual monthly blood work. (Point-of-care testing using finger sticks is under development for routine clinical use which would be helpful to have as an option.)
If granulocytopenia develops during treatment, treatment either has to be monitored more frequently (for mild neutropenia, ≥1000/μL and <1500/μL) or temporarily interrupted (for moderate neutropenia, ≥500/μL and <1000/μL) until the granulocyte count recovers. For severe neutropenia, (<500/μL) discontinue clozapine. Consult the REMS Programs’ monitoring table for the exact rules if there are problems (see Additional Resources). With this blood-monitoring schedule, the risk of dying from agranulocytosis is low (obviously monitoring alone does not prevent bone marrow toxicity; it just detects it early enough so clozapine can be discontinued, and a patient can be monitored and treated for infections). Other countries with different risk tolerance have less stringent ANC monitoring requirements, particularly after the period of highest risk (the first 6–12 months) is over. Currently, no genetic marker combination is available to flag patients at high-risk for agranulocytosis [24]. Patients who developed clear-cut severe neutropenia or agranulocytosis due to clozapine (sometimes the etiology of a lower granulocyte count in a complex, medically ill patient is not so clear) should probably not be rechallenged as the risk of recurrence is high [25]. However, the registry allows for a rechallenge with clozapine in those selected cases where the clinical outcome without clozapine is dire. Granulocyte colony-stimulating factor (G-CSF) is often used to reduce the duration of neutropenia in cases of clozapine-induced agranulocytosis [26]. Its role during a clozapine rechallenge is unclear [27].
Benign Ethnic Neutropenia
You will find patients with habitually (genetically) low ANC counts (benign ethnic neutropenia or BEN) [28]. BEN is not a pathological condition; you may see it in patients of African descent, for example. A diagnosis of BEN is made if, in a patient of appropriate ethnic background, mild and persistent (i.e., on repeated, spaced out blood draws) neutropenia is observed. Consider asking hematology for help if your patient with a low neutrophil count does not fit the ethnic background for BEN and if there are frequent infections which are not characteristic for BEN. Most BEN patients fluctuate around a neutrophil count above 1000/μL (in the mild neutropenia range) and can be safely managed with clozapine [29]. Patients in the BEN population follow a different monitoring schedule in order to be eligible to receive clozapine (e.g., a lower cut-off of at least 1000/μL is acceptable for routine clozapine prescribing). Prior to the unified registry which introduced special considerations for BEN patients, patients with BEN could either not received clozapine or clinicians had to resort to bone marrow-stimulating approaches like adding lithium to boost a patient’s granulocyte count – an example of structural unfairness in medicine [30].
Metabolism and Dosing
Clozapine has a complex receptor profile. It still features D2-5-HT2 antagonism which is typical for all second-generation antipsychotics. Of note, it has only loose dopamine-2 receptor binding which, together with being strongly anticholinergic, can explain its lack of extrapyramidal side effects. It is a very strong alpha antagonist which explains its cardiac effects (orthostatic hypotension). Its unique efficacy is likely related to other properties (e.g., NMDA).
Metabolism
Clozapine is metabolized by the cytochrome P450 enzymes 1A2 and 3A4, with smaller contributions from 2D6 and 2C19 [31]. The most important drug interactions are mediated via 1A2, either by drugs that block 1A2 (e.g., fluvoxamine) or that induce it (e.g., cigarette smoking). Cigarette smoking has enough of an effect on clozapine blood levels that smoking status needs to be taken into account (see Chap. 20). Male smokers have the highest dose requirements. Severe infections via their inhibitory effect on drug metabolism may be an underappreciated risk of clozapine toxicity in hospitalized patients [32]. Norclozapine (desmethylclozapine) is clozapine’s main metabolite. It has 10% of clozapine’s activity, contributing thus very little to the active moiety. For most practical purposes, you can safely ignore it.
Dosing
Clozapine has a short half-life of less than 12 hours. While early clinical trials used three times daily dosing, most patients can be managed with nightly dosing to minimize the effects of sedation. Some patients prefer twice daily dosing to reduce a hang-over effect in the morning. More frequent dosing can be used for those patients who want to experience the ataractic effects of clozapine more directly.
Clozapine needs to be titrated slowly because of (1) the risk for seizures, (2) sedation, and (3) syncope. Predictable early side effects that most patients experience when they start clozapine are sedation and orthostatic hypotension.
On the outpatient side, I keep it simple and start with 25 mg/day (after a test dose of 12.5 mg to make sure there is not unusual sensitivity) and then increase the dose by 25 mg every week. Inpatient titration schedules can be more aggressive. No one titration schedule is set in stone: your main consideration is how a particular patient could compensate side effects, particularly orthostatic hypotension. Adjust your titration based on expected and observed tolerability. If clozapine treatment is interrupted, follow the REMS guidelines regarding restarting clozapine (see Additional Resources). Depending on the length of interruption, you may need to start from scratch; adherence to clozapine is therefore particularly critical. Patients, families, and group homes need to know that they cannot just restart clozapine at the full dose if several doses were missed.
With clozapine, dosing should be based on serum levels [33] as you cannot predict serum levels from the clozapine dose: the interindividual variability between achieved clozapine blood level for any given dose is large [34]. I check a clozapine level after reaching 100 mg/day. Assuming linear pharmacokinetics (“you double the dose, you double the level”), this first data point will give you some idea about the dose you will eventually need to achieve your target clozapine serum level range. One study found that a clozapine serum level range of 200–300 ng/mL was as effective as 350–450 ng/mL [34]. I therefore try to reach an initial target range of 200–300 ng/mL but increase the dose to above 450 ng/mL if there is no response, consistent with guidelines for refractory psychosis. Clozapine blood levels below 150 ng/mL are perhaps too low for most patients. I will add that an optimal highest dose for clozapine has not been established [35].
Key Point
Therapeutic drug monitoring (TDM) is well established for clozapine and a necessary component of prescribing clozapine safely and most effectively as there is very wide clozapine plasma level variability between patients for a given dose. TDM helps detect insufficient clozapine levels and avoid dangerously high levels, often assumed to be somewhere around 1000 ng/mL for the active moiety (clozapine plus norclozapine). Note, however, that the literature on clozapine TDM is based on clozapine alone, not on the active moiety.
Side Effects
Clozapine black box warnings
Agranulocytosis |
Myocarditis |
Seizures |
Orthostatic hypotension with syncope and cardiorespiratory arrest |
Increased mortality in elderly patients with dementia-related psychosisa |
Unfortunately, there is often no tachyphylaxis with regard to sedation which is common, and patients need to learn how to manage it (e.g., drinking coffee). This can be challenging in patients with negative symptoms who simply sleep a lot more than they already would. For the long-term management, weight gain and metabolic complications are most critical. Motor side effects (tremor, tardive dyskinesia) are less than with other antipsychotics (hence, “atypical”) but not impossible. NMS in particular occurs and can present atypically, with less prominent rigidity [36].
Agranulocytosis
As already noted earlier, clozapine causes agranulocytosis in approximately 0.8% [21]. The risk of agranulocytosis is highest during the first few months of treatment, then drops off but never returns to zero and increases with age. Other blood dyscrasias (leukocytosis, low platelet count, increased eosinophil count, low red blood cell count) have been described with clozapine use, but they usually do not prevent the use of clozapine.
Myocarditis
Myocarditis is a problem that is not usually associated with antipsychotics but that is clearly described with clozapine. Its frequency is a matter of some debate; it might be more common than agranulocytosis [37]. Following weekly markers of inflammation (CRP) and cardiac muscle damage (troponin) and obtaining an ECG in symptomatic patients during the high-risk period (4 weeks) are reasonable precautions [38] although there is no consensus about monitoring for myocarditis during treatment [39]. While a baseline ECG makes sense prior to starting clozapine (to have a comparison), obtaining a baseline echocardiograms like some have suggested would likely prevent the use of clozapine in many settings [40]. Clozapine has also been linked to cardiomyopathy during long-term treatment.
Key Point
Suspect myocarditis if malaise, chest pain, or palpitations develop during the initial clozapine titration phase (first month). A high clinical index of suspicion together with laboratory monitoring is needed as the non-specific symptoms of myocarditis overlap with typical side effects during the initiation of clozapine (fatigue, increased heart rate, light-headedness from orthostatic hypotension).
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