Making clozapine safer: current perspectives on ...

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Management Perspective

Making clozapine safer: current perspectives on improving its tolerability

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Bosky Nair1 & James Hunter MacCabe*,2

Clozapine is by far the best-supported treatment for patients with treatment-resistant schizophrenia A recent multiple-treatments meta-analysis comparing 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia has shown that clozapine is way ahead of its competition in terms of efficacy (Figure 1) [3] . It has consistently shown a reduction in aggression, mortality rates and suicide [4–6] ; however, it remains underprescribed. Current prescribing guidelines suggest offering clozapine to patients with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs, where at least one of the drugs was a nonclozapine second-generation antipsychotic [7] . Approximately 30% of patients with schizophrenia have treatment-refractory illness according to these definitions, yet only a third of those eligible receive clozapine [8,9] . The delays in prescribing and premature withdrawal over concerns of adverse effects mean that clozapine is prescribed on an average 4 years too late [10] . It is common for patients taking clozapine to discontinue in their first year of treatment with 42% discontinuing over 24 months [11] . A large proportion of patients, (48%) discontinue clozapine based on patient preference [12] . In more than a third of those discontinuing, adverse effects are recorded in the case record as the reason for discontinuation [12] . In this article, we will discuss strategies aimed at reducing adverse effects of clozapine and increasing its acceptability, thus improving outcomes for this patient group. [1,2] .

Keywords 

• adverse drug reactions • clozapine • safety • schizophrenia • tolerability • treatment resistant

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Abstract: Clozapine is the gold standard treatment for refractory schizophrenia and its benefits are supported by an evidence base. Yet, it remains largely underused in clinical practice. This is because of low acceptability from patients and reluctance in initiating, and delays in prescribing by clinicians. A major deterrent is often the common adverse reactions, which clinicians are apt to disregard, focusing instead on the severe but rare complications of clozapine, such as agranulocytosis. We will review recent evidence on increasing the prescription of clozapine, focusing particularly on improving the safety and tolerability of the drug, by effective management of its adverse effects. The adverse effects considered in our review include sedation, seizures, myoclonus, hypersalivation, nausea, constipation, hypotension, hypertension, tachycardia, myocarditis, cardiomyopathy, weight gain, diabetes, dyslipidemia, neutropenia, agranulocytosis, fever, nocturnal enuresis and obsessive–compulsive symptoms. We will also discuss strategies to enable successful clozapine rechallenge after severe cardiac and hematological adverse reactions, thus aiming to offer patients their best chance at recovery.

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National Psychosis Unit, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent, BR3 3BX, UK Institute of Psychiatry, King’s College London, National Psychosis Unit, Bethlem Royal Hospital, South London & Maudsley NHS Foundation Trust, Monks Orchard Road, Beckenham, Kent, BR3 3BX, UK *Author for correspondence: Tel.: +44 20 7848 0757; Fax: +44 20 7848 0287; [email protected]

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10.2217/FNL.14.23 © 2014 Future Medicine Ltd

Future Neurology (2014) 9(3), 313–322

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ISSN 1479-6708

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Management Perspective  Nair & MacCabe

Overall change in symptoms

SMD (95% Crl)

Clozapine -0.88 (-1.03 to -0.73) Amisulpride -0.66 (-0.78 to -0.53) Olanzapine -0.59 (-0.65 to -0.53) Risperidone -0.56 (-0.63 to -0.50) Paliperidone -0.50 (-0.60 to -0.39) Zotepine -0.49 (-0.66 to -0.31) Haloperidol -0.45 (-0.51 to -0.39)

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Quetiapine -0.44 (-0.52 to -0.35) Aripiprazole -0.43 (-0.52 to -0.34) Sertindole -0.39 (-0.52 to -0.26)

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Ziprasidone -0.39 (-0.49 to -0.30) Chlorpromazine -0.38 (-0.54 to -0.23)

Lurasidone -0.33 (-0.45 to -0.21) Iloperidone -0.33 (-0.43 to -0.22) -1

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Asenapine -0.38 (-0.51 to -0.25)

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Figure 1. Forest plot for efficacy of antipsychotics drugs compared with placebo. Treatments are ranked according to their surface under the cumulative ranking values. CrI: Credible interval; SMD: Standardized mean difference. Reproduced with permission from [3].

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In their survey of 130 patients assessing change 6 months or more after clozapine treatment, Waserman and Criollo, showed that patients reported hypersalivation as the most common subjective experience of adverse effect [13] . Other common side effects were weight gain, constipation and thirst (Figure 2) . This is a surprise to most clinicians, perhaps because clinicians are more focused on the medically serious adverse effects, including neutropenia, cardiac effects and diabetes, and give insufficient attention to the common and debilitating adverse effects that affect patients’ quality of life, and hence their adherence to treatment. Adverse reactions often occur when clozapine is initiated too hastily or titrated to a dose higher than necessary. Insufficient discussion of likely adverse effects can often make patients less prepared thus influence adherence to treatment.

Future Neurology (2014) 9(3)

The general principles in clozapine initiation and titration should include the following steps: ●● Starting low, and going slow; ●● Using the lowest effective dose; ●● Asking about adverse effects; ●● Offering reassurance about short-lived adverse

effects; ●● Treating adverse effects aggressively.

The guidelines for blood monitoring show national variation but the broad principles are similar in most developed countries. In the UK, current recommendations suggest monitoring the white cell count weekly for the first 18 weeks, then fortnightly until 6 months, and monthly thereafter. If the white blood count falls below 3.5 × 109/l and/or the absolute neutrophil count falls below 2.0 × 109/l, then the

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Making clozapine safer: current perspectives on improving its tolerability 

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clozapine can be very helpful. In the second scenario, the patient holds paranoid ideas about the purpose of the blood tests, and suspects that the blood may be used for malign purposes. In the third scenario, the patient may be ambivalent or even enthusiastic about taking clozapine, but has a fear of needles. In these cases it is helpful to discuss use of practical measures such as using lidocaine or prilocaine cream 60 min before venipuncture. Smaller butterfly needles can be less daunting for some patients. Premedication with low-dose benzodiazepines, prior to venepuncture or behavioral approaches to address needle phobia, can also be tried. When all other measures fail, the use of restraint may be warranted, if the legal framework permits this. It is also important to note that restraint may be unhelpful in ensuring compliance to clozapine treatment and thus used only after careful consideration of risks and benefits. It is important to keep the frequency of blood tests to a minimum and obviate unnecessary blood tests in order to maintain the therapeutic alliance with the patient. Below we have listed the common adverse effects of clozapine and recommendations on their management. CNS effects

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frequency of monitoring is increased. Clozapine must be withdrawn if the white cell count falls below 3.0 × 109/l and/or the ANC falls below 1.5 × 109/l (Table 1) . Often the stringent blood monitoring regime associated with clozapine can deter patients from an effective trial of clozapine. In a survey of patient perceptions on clozapine, need for blood tests topped the list of reasons the patients did not like clozapine as a treatment option [15] . Improving patients’ understanding of the need for blood tests may ensure that an effective trial is achieved. This can be addressed by discussion with the patient about the reasons why clozapine is being recommended, the evidence that this may be of benefit to the particular patient, the purpose of blood tests and any concerns that patients may have relating to blood tests. Some clinicians may be hesitant to initiate clozapine for patients who they consider may not be able to tolerate blood tests or adhere to treatment [16] . However, the increased insight gained on clozapine often results in improvements in adherence. Where a patient refuses clozapine due to frequent blood monitoring, there are three common scenarios. For some patients, blood tests are just one of a number of concerns about clozapine, and since blood tests are an essential prerequisite of clozapine treatment, the discussion becomes focused around blood tests, when the patients’ main concerns may be about other aspects of clozapine. In such cases a discussion and exploration of the patients’ concerns about

Management Perspective

●●Sedation

Sedation is almost a universal adverse effect in the first 3 months of treatment with clozapine, but usually improves. Reduction of sedative effects can be achieved by slowing down titration, asymmetric dose split with lower daytime

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Appetite Bloatedness Unusual movements Salivation during the day Dizziness Abdominal pain Urination Thirst Constipation Weight Salivation at night

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30 70 40 60 50 Ratings by 130 participants (%)

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Figure 2. Ratings in percentages by 130 patients on their subjective experience of clozapine treatment. Data taken from [13].

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Management Perspective  Nair & MacCabe Table 1. Clozapine monitoring routine and according to benign ethnic neutropenia criteria. Classification

Routine monitoring (×109/l)

BEN parameters (×109/l)

Neutrophils

WBC

Neutrophils

≥3.5

≥2.0

≥3.0

≥1.5

Amber

≥3.0 and