Clozapine is effective, approved and underused

Clozapine in adult treatment-resistant schizophrenia (TRS) is not only the sole approved agent in many countries [1], but is universally recommended in 17 expert guidelines [2]. Canada and the UK allow clozapine in paediatric schizophrenia, including TRS [1]. TRS is diagnosed when adherent patients do not adequately respond to correct dosages of two different antipsychotics, prescribed sequentially, each for at least 6 weeks. TRS affects 20–50% of patients with schizophrenia, and has a poor prognosis [1].

TRS may be a schizophrenia subtype, different to disease that responds to dopamine D2-receptor blockers, and possibly associated with glutamate dysfunction [1]. While its detailed pathophysiology is outside the scope of this article, clozapine’s benefits may relate to its interaction with serotonin, muscarinic, adrenergic and histaminergic receptors, its relatively low affinity for D2 receptors [3] and its modulation of glutamate levels [1].

Clozapine improves TRS symptoms, including negative and cognitive symptoms, and reduces hospitalisations, suicides and mortality [1, 3]. The all-cause mortality rate ratio for clozapine versus other antipsychotics was 0.56 in a meta-analysis [4]. However, many practitioners are hesitant to prescribe clozapine [1]. Delays contribute to lower likelihoods of TRS remission [1] and reflect factors such as limited familiarity with clozapine, adverse drug event (ADE) concerns and monitoring requirements [1, 5, 6]. These disadvantages of clozapine need to be balanced against its benefits [1]. This article outlines the initiation and management of clozapine in adults with TRS, as reviewed by Correll et al. [1] and de Leon et al. [7].

Metabolism is affected by many factors...

Prescribers need to understand a patient’s comorbidities, coadministered medications and demographic and lifestyle factors (Table 1), all of which may affect clozapine’s metabolism (Fig. 1).

Table 1 Suggested clozapine dosage regimens based on potential clozapine metabolism, as reviewed by de Leon et al. [7]
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Fig. 1
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Suggested initiation of clozapine in patients with treatment-resistant schizophrenia [1, 7, 8]

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Fig. 2
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Suggested management of severe adverse events in patients with treatment-resistant schizophrenia receiving clozapine [1, 7, 8]

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Clozapine is a substrate for cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2D6 enzymes, among others, and numerous coadministered medications that induce or inhibit these enzymes have the potential to affect plasma concentrations (Fig. 1). CYP1A2 inhibitors are particularly important [1]. While lower clozapine dosages are suggested in patients receiving strong inhibitors (Fig. 1), patient response should be assessed and the dosage increased if needed [8]. Dosage adjustments may not be required for moderate or weak CYP1A2 inhibitors [8]. Inflammation and caffeine, a CYP1A2 substrate, may both increase clozapine concentrations, while smoking, which induces CYPA12, tends to reduce concentrations [1]. Concomitant use of strong CYP3A4 inducers is not recommended, but if unavoidable, dosages may need to be increased, depending on the patient’s clinical response to clozapine [8].

... including demographics

Patient ethnicity, age and sex can also affect clozapine’s metabolism, although data are limited in special patient groups [1]. Dosage regimens may differ based on likely rates of clozapine metabolism in different patients (Table 1) [7]. Some ethnic groups (Table 1) have relatively low CYP1A2 expression, tending to increase their clozapine plasma levels [7]. Patient age and sex can also affect clozapine metabolism; females and older patients have increased blood concentrations of clozapine through reduced clearance [9]. The European Medicines Agency specifies a lower starting dose and slower titration in older patients [10]. Clozapine’s pharmacological profile in paediatric patients appears to be similar to that in adults [11]. It may be the best of limited options in pregnant women, but is contraindicated in breastfeeding [1].

Non-responders may benefit from augmentation

Up to 60% of TRS patients do not respond to an adequate clozapine trial and, provided patients have clozapine levels of ≥ 350 ng/mL, augmentation is suggested for those with persistent symptoms [12]. Consensus guidelines define an effective trial of clozapine in most cases as treatment, subject to tolerability, for at least 12 weeks from the achievement of therapeutic levels. Due to delayed responses, a 16-week trial period is suggested for those with negative or cognitive symptoms. Conversely, a shorter 8-week trial for patients with aggression or suicidality is optimal [12].

Consensus guidelines for augmentation are based on limited evidence and vary with the patient’s symptom profile [12]. For positive symptoms, a median 12 episodes of electroconvulsive therapy at a rate of 3 per week, and the addition of amisulpride or aripiprazole are suggested. Adding antidepressants is recommended for negative symptoms, with mood stabilisers such as lithium or lamotrigine as augmentation for patients with suicidal ideation. Adding mood stabilisers is also suggested for aggression. Finally, cognitive behavioural therapy may help negative and mixed symptoms [12].

Elicit adverse events at every follow-up

Once clozapine is started, systematic monitoring for ADEs, which cause around 17% of patients to discontinue treatment [3], is required (Tables 2 and 3; Fig. 1). Diarrhoea, rash, fatigue, extrapyramidal and urinary symptoms also occurred in 1–4% of clozapine recipients in the 2-year InterSePTTM study [8]. These may be self-limiting, and urinary incontinence may also respond to treatment with ephedrine [3].

Table 2 Common adverse drug events identified in clozapine recipients in clinical trials, as reviewed by Correll et al. [1]
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Table 3 Severe clozapine adverse drug events in treatment-resistant schizophrenia, as reviewed by Correll et al. [1] and de Leon et al. [7]
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Gradual clozapine titration appears to reduce the incidence of many ADEs (Tables 2 and 3) [7]. Alleviating common ADEs, such as constipation, hypersalivation, weight gain and tachycardia (Table 2) may reduce more severe sequelae, such as bowel obstruction, pneumonia and cardiovascular disease (Table 3) [1, 7]. Weight gain usually starts within 6–10 weeks of initiating clozapine, but the progression of associated metabolic abnormalities to ketoacidosis, severe hyperglycaemia, or significant increases in cholesterol or triglycerides was uncommon in one database review [3] (Fig. 2).

While severe neutropenia is a high-profile ADE and is the reason for clozapine’s US risk evaluation and mitigations strategies (REMs) status (Fig. 1), pneumonia is the event most likely to increase mortality in clozapine recipients (Table 3). New neutropenia (Table 3, Fig. 1), the precursor of agranulocytosis, needs to be distinguished from benign ethnic neutropenia (BEN) [1]. BEN is a chronic low ANC of 1000–1800/μL that may occur in people of African, Middle Eastern and West Indian descent (Fig. 1), which is not associated with increased risks of agranulocytosis or severe infections [1]. Neutropenia definitions differ in Europe and the US (Fig. 1) [8, 10].

Other ADEs may be very rare or medically benign [3, 8], but the latter can lead to clozapine discontinuation if they are distressing to the patient [1]. Nocturnal enuresis can be treated by limiting evening fluids, emptying the bladder before bedtime and bathroom alarms, with aripiprazole a potential pharmacological option [16]. Desmopressin is a second-line option requiring monitoring for hyponatraemia [16]. Conversely, priapism is an urological emergency and responds to goserelin acetate, which may be continued to allow patients to maintain their clozapine treatment [3]. Gradual clozapine titration may reduce the likelihood of benign hyperthermia as well as several more serious ADEs (Tables 2 and 3) [1, 7].

If clozapine is discontinued for > 2 days, then restarted, a 12.5 mg starting dose once or twice daily is recommended to reduce risk of bradycardia, hypotension and syncope [8]. Depending on tolerability, upward titration can sometimes be faster than the initial treatment titration [8]. In the absence of an emergency, when a decision is made to stop clozapine, a very slow discontinuation over 6 months, with another antipsychotic cross-titrated, is recommended [1].

Overcoming barriers to clozapine use

Two systematic reviews considered the barriers to clozapine prescription, which result in unmet needs for many patients, especially in certain countries [5, 6]. Both highlighted the complexity of blood monitoring, which in one review was the biggest barrier in most studies [6]. Insufficient provider training and education, ADEs, poor patient adherence and difficulty identifying suitable patients were other concerns, as were administrative and healthcare systems [5, 6].

Suggestions for increasing the level of prescribing of clozapine included better prescriber education (e.g. via clozapine certification during training; the US REMs status requires certification for prescribers and pharmacists [5]), integrated care (via clozapine clinics and interdisciplinary teams [5]) and simplified blood monitoring (e.g. via finger prick tests [6]). Overcoming practical, resource-based barriers, such as obtaining baseline blood tests and access to staff and facilities (especially at the time of clozapine initiation), would also be helpful [6].

Take home messages

  • Offer clozapine early to patients with treatment-resistant schizophrenia, i.e. those who have not responded to adequate trials of two other anti-psychotics.

  • Obtain a careful medical history before starting clozapine, including demographic and lifestyle factors (e.g. race, smoking and caffeine consumption). as these can affect clozapine metabolism.

  • Disadvantages of clozapine include the variable relationships between dosage, plasma concentration and clinical response, the need for blood monitoring, and serious ADEs (e.g. pneumonia, agranulocytosis and cardiac conditions).

  • Gradually titrate, with initial lower dosages, particularly in patients assessed as likely to metabolise clozapine more slowly, as well as TDM and active management of ADEs before they lead to severe sequelae.

  • Well-structured guidelines for starting clozapine in different patient groups and for monitoring and managing ADEs are readily available.