Rediscovering Clozapine: Adverse Effects Develop—What Should You Do Now?
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SECOND OF 3 PARTS Rediscovering clozapine: Adverse effects develop—what should you do now? Benefit comes at the expense of monitoring for, and treating, an array of potential problems lozapine is a highly effective antipsychotic with supe- rior efficacy in treatment-resistant schizophrenia, but Cits side effect profile is daunting (Figure 1).1 Adverse reactions lead to approximately 17% of patients who take clozapine eventually discontinuing the medication.1 As we noted in Part 1 of this 3-part series,2 clozapine remains the most efficacious, but most tedious, antipsychotic available to psychiatrists because of its monitoring requirements and potential side effects. A powerful rationale for prescribing clozapine, despite its drawbacks, is its association with a reduced risk of all-cause mortality.3,4 People with serious mental illness, including schizophrenia, have a median 10-year shorter life expectancy CAP PANNELL than the general population.5 Brianne M. Newman, MD A recent cohort study6 examined electronic health records William J. Newman, MD to test whether intensive monitoring or lower suicide risk might account for the reduced mortality with clozapine. • • • • The authors found that the reduced mortality rate was not Associate Professors of Psychiatry directly related to clozapine’s clinical monitoring or other Department of Psychiatry Saint Louis University School of Medicine confounding factors. They did find an association between St. Louis, Missouri clozapine use and reduced risk of death from both natural Dr. W. J. Newman is a member of the Editorial Board and unnatural causes. of CURRENT PSYCHIATRY. This second article in our series examines clozapine’s adverse effects from a systems perspective. Severe neutrope- nia, myocarditis, sedation, weight gain, orthostatic hypoten- sion, and sialorrhea appear to be the most studied adverse effects, but myriad others can occur.7 We offer guidance to help the astute clinician continue this effective antipsychotic Disclosures Current Psychiatry The authors report no financial relationships with any company whose products are mentioned in 40 August 2016 this article or with manufacturers of competing products. Figure 1 Common side effects of clozapine Sedation (21%) Tachycardia (17%) Constipation (16%) Dizziness (14%) Hypotension (13%) Fever (13%) Sialorrhea (13%) Hypertension (12%) Headache (10%) Clinical Point Concomitant treatment with Source: Adapted from reference 1 clozapine and lithium can affect white blood cell and absolute neutrophil by monitoring carefully, treating side effects significant—change in ANC values.11 The early, and managing potential drug interac- authors noted that viral infection might count values tions (Table 1, page 42).8 lead to blood dyscrasia early in illness, and that oseltamivir has been associated with a small incidence of blood dyscrasia.11-13 This Hematologic events information might be useful when treat- Severe neutropenia, defined as abso- ing influenza in patients taking clozapine, lute neutrophil count (ANC) <500/µL, is although no specific change in manage- a well-known adverse effect of clozapine ment is recommended. that requires specific clinical monitoring, a Similarly, concomitant treatment with requirement that was updated by the FDA clozapine and lithium can affect both in 2015.2 The incidence of severe neutrope- white blood cell and ANC values.14,15 nia peaks in the first 2 months of clozap- Lithium-treated patients often demon- ine therapy and tapers after 6 months, but strate increased circulating neutrophils some risk always remains. via enhancement of granulocyte-colony Older efficacy studies in the United States stimulating factor.16 Case studies describe gauged the 1-year cumulative incidence of how initiating lithium treatment enabled severe clozapine-induced neutropenia to some patients to continue clozapine after be 2%.9 A 1998 study of the effects of using developing neutropenia.14,17 Leukocytosis a clozapine registry reported a lower inci- can affect blood monitoring, possibly mask- dence—0.38%—than the 2% noted above.10 ing other blood dyscrasias, when lithium is Early recognition and recommended inter- used concurrently with clozapine. Discuss this article at ventions can improve clinical outcomes.2 Eosinophilia (blood eosinophil count www.facebook.com/ CurrentPsychiatry >700/µL) occurs in approximately 1% of clo- Drug interactions and neutropenia. A ret- zapine users, usually in the first 4 weeks of rospective study of mental health inpatients treatment.18 It can be benign and transient or taking clozapine concurrently with oselta- a harbinger of a more rare adverse reaction mivir during an influenza outbreak found such as myocarditis, pancreatitis, hepatitis, Current Psychiatry a statistically significant—but not clinically colitis, or nephritis.19 If a patient taking clo- Vol. 15, No. 8 41 Table 1 Clinically relevant drug interactions with clozapine Mechanism of interaction Medications and other substances involved Effect on clozapine CYP1A2 strong Fluvoxamine, ciprofloxacin ↑ Clozapine levels inhibitors CYP1A2 weak or Oral contraceptives, caffeine May ↑ clozapine levels Clozapine moderate inhibitors CYP2D6 and CYP3A4 Antidepressants (escitalopram, paroxetine, May ↑ clozapine levels inhibitors bupropion, fluoxetine, duloxetine, sertraline) Antibiotic (erythromycin) Miscellaneous (cimetidine, quinidine, terbinafine) CYP1A2 moderate Smoking ↓ Clozapine levels inducer CYP3A4 strong Carbamazepine, phenytoin, St. John’s wort, ↓ Clozapine levels inducersa rifampin Clinical Point CYP2D6 substrates Certain antidepressants (fluoxetine), Clozapine may ↑ levels phenothiazines, carbamazepine, Type 1C of these medications Reducing the dosage antiarrhythmics (propafenone, flecainide) aClozapine dosing instructions recommend against concurrent use of clozapine with strong CYP3A4 inducers of clozapine or CYP: cytochrome P450 enzymes slowing titration Source: Adapted from reference 8 could reverse common cardiac side effects zapine develops eosinophilia, clozapine’s sion (Figure 1, page 41).1 Orthostatic hypo- package insert recommends that you: tension, bradycardia, and syncope also can • evaluate promptly for other systemic occur, especially with rapid clozapine titra- involvement (rash, other evidence of tion. Baseline electrocardiogram (ECG) allergic reaction, myocarditis, other organ- can help differentiate whether abnormali- specific disease) ties are clozapine-induced or related to a • stop clozapine immediately if any of preexisting condition. these are found. Reducing the dosage of clozapine or If other causes of eosinophilia are iden- slowing titration could reverse cardiac tified (asthma, allergies, collagen vascular side effects.8 If dosage reduction is not an disease, parasitic infection, neoplasm), treat option or is ineffective, first consider treat- these and continue clozapine. ing the side effect rather than discontinu- The manufacturer also mentions the ing clozapine.20 occurrence of clozapine-related eosino- Sinus tachycardia is one of the most philia without organ involvement that can common side effects of clozapine. First, rule resolve without intervention, with care- out serious conditions—myocarditis, car- ful monitoring over several weeks.8 In diomyopathy, neuroleptic malignant syn- this scenario, there is flexibility to judge drome (NMS)—then consider waiting and whether clozapine should be stopped or monitoring for the first few months of clo- re-challenged, or if close monitoring is zapine treatment. If tachycardia continues, adequate. Consulting with an internal consider dosage reduction. Slower titra- medicine or hematology specialist might tion, or treatment with a cardio-selective be helpful. beta blocker such as atenolol.21,22 Note that a recent Cochrane Review concluded that there is not enough randomized evidence Cardiovascular side effects to support any particular treatment for Most common events. Three of the 10 most clozapine-induced tachycardia; the pre- common clozapine side effects are cardiac: scriber must therefore make a case-by-case Current Psychiatry 42 August 2016 tachycardia, hypotension, and hyperten- clinical judgment.22 Similarly, orthostatic hypotension can risk. Tonic-clonic seizures are the most com- be managed with a reduced dosage of clo- mon type associated with clozapine. zapine or slower titration. Increased fluid The manufacturer recommends caution intake, compression stockings, and, if neces- when using clozapine in patients with a sary, fludrocortisone also can be initiated.20 known seizure disorder, alcohol use disor- der, or other CNS pathology.8 Patients with Rare, potentially fatal events. Myocarditis, a seizure disorder may be at increased risk pericarditis, and cardiomyopathy are of experiencing clozapine-induced seizures, among the rare but potentially fatal adverse but this is not an absolute contraindica- effects of clozapine. A recent study reported tion.26 Smoking cessation increases clozap- the incidence of myocarditis with clozapine ine blood levels by an average of 57.4%, at a range of 0.015% to 1.3%; cardiomyopa- further increasing seizure risk.26,27 thy was even more rare.23 Pulmonary embo- Discontinuing clozapine is unneces- lism and deep venous thrombosis also are sary when a patient experiences a seizure. very rare possibilities; keep them in mind, Instead, you can: however, when patients taking clozapine • halve the dosage prescribed at the time report new cardiovascular symptoms. of the seizure (or at least reduce to the last Clinical