Questions and Answers About Clozapine, Part 2: A Dialogue About Indications for Clozapine, Managing Adverse Effects, and More

CATEGORY 1 CME

Premiere Date: July 20, 2024

Expiration Date: January 20, 2026

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

The purpose of this activity is to review management of several clozapine-related adverse effects and outline considerations when addressing inadequate positive symptom response to clozapine.

LEARNING OBJECTIVES

1. To outline best practices for managing sedation, tachycardia, constipation, and fever during treatment with clozapine.

2. To educate clinicians about when to consider adjunctive strategies and which options are best supported by the literature when confronted with inadequate positive symptom response to clozapine.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC and Psychiatric Times. Physicians’ Education Resource, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received.

OFF-LABEL DISCLOSURE/DISCLAIMER

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION

Meyer reports that he receives grant/research support from Alkermes plc; Axsome Therapeutics, Inc; BioXcel Therapeutics, Inc; Bristol Myers Squibb/Karuna Therapeutics, Inc; Cerevel Therapeutics; Intra-Cellular Therapies, Inc; Neurocrine Biosciences, Inc; Otsuka America, Inc; Relmada Therapeutics, Inc; Sumitomo Pharma Co, Ltd; and Teva Pharmaceuticals (as a consultant); AbbVie; Alkermes plc; Axsome Therapeutics, Inc; Bristol Myers Squibb/Karuna Therapeutics, Inc; Intra-Cellular Therapies, Inc; Neurocrine Biosciences, Inc; Sumitomo Pharma, Co, Ltd; and Teva Pharmaceuticals (Speaker’s Bureau); and 4M Therapeutics Inc (as a stock/shareholder). None of the staff of Physicians’ Education Resource, LLC or Psychiatric Times of this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

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An important concept in managing clozapine’s clinical issues and adverse effects is that not all approaches possess the highest levels of evidence from randomized clinical trials (RCTs), leaving clinicians to choose the best option as inferred from case series or open-label studies. When RCT-level data do exist, meta-analyses are limited by the quality of the studies, with trial design, dose, subject selection, and duration all playing important roles in parsing out the value of conclusions.

The management of clozapine-related sialorrhea represents 1 of many examples. This is a potentially serious adverse effects due to its impact on medication adherence and the increased risk for pneumonia,^1,2 and it is mechanistically related to norclozapine’s agonist properties at salivary gland muscarinic M1 receptors.³ Although use of a muscarinic antagonist seems like an elegant strategy to manage this problem, a population-based study of 26,720 patients with schizophrenia found that chronic exposure to systemically acting anticholinergics increases the risk for ileus, that clozapine and other anticholinergics have additive effects on ileus risk, and that the onset of ileus occurred on average more than 3 years after the first prescription of the offending drug.⁴

Despite the fact that multiple systemically acting anticholinergics (eg, glycopyrrolate, diphenhydramine, doxepin) were included in a 2023 meta-analysis of interventions for clozapine-related sialorrhea, the investigators noted that active interventions did not differ significantly from placebo regarding constipation.⁵ The absence of this finding may relate to the relatively short duration of these studies (ie, weeks) for a problem that may develop insidiously over months or years; moreover, the investigators communicated their low confidence in the findings of this meta-analysis and the need to exercise caution in the interpretation of the results.

The combination of systemically acting anticholinergics with clozapine is concerning enough that the US Food and Drug Administration (FDA) issued a safety communication on this subject on January 28, 2020,⁶ and it is for that reason clinicians initially use orally administered anticholinergics with limited systemic absorption (eg, atropine 1% drops, ipratropium 0.06% spray)^7,8 or salivary gland botulinum toxin injections before proceeding to agents such as glycopyrrolate.^9,10 With the limitations of the literature in mind, below are answers to more questions posed by clinicians about clozapine.

Neuroleptic Malignant Syndrome

For patients with a history of neuroleptic malignant syndrome (NMS), would clozapine be the preferred antipsychotic? Would your decision be any different if the patient developed NMS while on a combination of clozapine and a first-generation antipsychotic (FGA)?

In general, NMS risk is related to the potency of dopamine D2 receptor antagonism, with higher risk and more severe outcomes seen among patients treated with an FGA.¹¹ However, there are case reports describing NMS with nearly every antipsychotic that possesses D2 antagonism, including second-generation antipsychotic (SGA) partial agonists such as aripiprazole and weak D2 antagonists such as quetiapine and clozapine.¹² The paucity of reports for lurasidone,¹³ brexpiprazole,¹⁴ and cariprazine,¹⁵ as well as the absence of lumateperone-related cases (to date), is likely a product of limited worldwide usage.

Prior to the development of other SGAs, patients who developed NMS on an FGA would not uncommonly be switched to clozapine, but the availability of multiple medications with low D2 receptor occupancy and low risk for D2-related adverse effects in schizophrenia trials (eg, lumateperone) provides reasonable alternatives to clozapine, with clozapine reserved for those rare patients who cannot tolerate other SGAs.^16,17

If a patient developed NMS while on an FGA in conjunction with clozapine, it is presumed that the FGA is the offending medication due to the rarity of NMS cases on clozapine monotherapy. In those instances, the FGA should be switched to an SGA to minimize the extent of D2 antagonism. For those rare patients who do experience NMS on clozapine monotherapy, a 2019 review noted successful rechallenge without NMS recurrence in 11 of 12 (92%) cases,¹² with recent reports affirming that a slower clozapine titration might be useful during the rechallenge.¹⁸

Clozapine Nonresponse

When should one consider adjunctive agents for suboptimal response to clozapine?

The primary consideration in moving to adjunctive strategies is determining whether one has extracted the maximum benefit from clozapine. A 2020 paper from 49 members of the Treatment Response and Resistance in Psychosis (TRRIP) Working Group noted the paucity of trials for clozapine-resistant schizophrenia but stated that plasma level–guided dose escalation is needed to achieve levels above the response threshold (350 ng/ml).¹⁹

Assuming a patient tolerates ongoing clozapine titration for positive symptom nonresponse, there is debate about when this titration should stop (assuming tolerability), with no consensus on the plasma level end point. Although many laboratories use values of 600 ng/ml or 700 ng/ml as the upper limit of their reference range,²⁰ there are multiple sources noting that certain patients may require levels in the range of 700 to 1000 ng/ml for response.^21-23 Managing adverse effects is the main issue at higher plasma levels, but one should not eschew levels above the reported laboratory reference range when tolerability is not limiting.

Which antipsychotics or medications have the greatest evidence base for clozapine-resistant positive symptoms?

Respondents in the 2020 TRRIP survey achieved consensus on the use of a second antipsychotic or augmentation with electroconvulsive therapy to manage inadequate positive symptom response.¹⁹ Among the antipsychotic options, there are supporting data for several FGA and SGA medications, including the dopamine partial agonist aripiprazole, so the clinician is left to choose which medication profile (eg, partial agonist vs antagonist, FGA vs SGA) seems appropriate.

The availability of a long-acting injectable formulation, or intolerance to specific D2-related adverse effects (parkinsonism, akathisia, hyperprolactinemia), are relevant considerations. Antipsychotics with anticholinergic properties (eg, quetiapine, olanzapine, chlorpromazine) should be avoided due to the increased ileus risk.

Managing Adverse Effects

What is the evidence for use of psychostimulants, modafinil, or armodafinil to manage problematic sedation despite low therapeutic clozapine doses or plasma levels?

The data for medication interventions are not strongly positive and consist primarily of case series and small studies, many of which are not positive. It is worth noting that the use of nonstimulant medications such as modafinil and its active isomer armodafinil do not induce exacerbation of positive symptoms.^24-26 There are encouraging data about the benefit of extended-release methylphenidate in case series, and without evidence for exacerbation of positive symptoms.^27,28

The literature is largely silent on the use of amphetamines for this purpose. There is a promising option that has yet to be studied for clozapine-related sedation but might be a future possibility: the histamine H3 antagonist pitolisant, an agent approved for the treatment of excessive daytime sleepiness in adults with narcolepsy.²⁹ There is preclinical evidence for putative benefit²⁹ and 2 case reports of pitolisant use in patients with schizophrenia (1 case for narcolepsy treatment and 1 case for mitigation of olanzapine-induced weight gain—in neither case were their adverse effects on core psychosis symptoms).^30,31 The absence of dopamine agonism and the fact that it is approved for excessive daytime sedation are appealing aspects of pitolisant’s mechanism of action for patients with schizophrenia who are struggling with clozapine-related sedation.

For patients who develop mild asymptomatic tachycardia on clozapine (90-120 beats per minute [BPM]), is it better to add a β-adrenergic blocker and normalize the heart rate, or follow?

Although patients may not necessarily complain of tachycardia, long-term untreated tachycardia increases all-cause mortality and is specifically associated with increased risk for multiple adverse cardiac outcomes, including sudden death and heart failure.³² The effect of heart rate is dose dependent, meaning the relative risk for these outcomes increases with every 10 BPM for resting heart rates exceeding 60 BPM, at times in a nonlinear manner.³² This fact alone argues that the goal of treatment is a resting heart rate as close as possible to the adult mean of 65 BPM.³³

Assuming that tachycardia is not the product of orthostatic hypotension, the medication of choice is atenolol, a selective β1 adrenergic receptor antagonist with limited central nervous system (CNS) effects and no significant drug-drug interactions due to its elimination via renal excretion, not hepatic metabolism.³⁴ The highly lipophilic β-adrenergic antagonist propranolol is often avoided due to its CNS penetration and associated risk of sedation.

What is the best treatment for constipation caused by clozapine?

Constipation is a highly prevalent problem and can be associated with serious and potentially fatal outcomes due to ileus.^35,36 Compared with unmedicated individuals who do not have schizophrenia, one study demonstrated that 82% of the clozapine-treated cohort had abnormal gastrointestinal motility, with 41% experiencing delayed gastric emptying, 71% delayed small bowel transit, and 50% delayed colon transit (Table 1).³⁷

As many patients with slow transit times may not complain,³⁶ all clozapine-treated patients should receive prophylaxis at the onset of treatment beginning with docusate, then adding an osmotic agent (eg, polyethylene glycol 3350), and then a stimulant laxative (bisacodyl or senna).³⁵ Each subsequent agent should be added only after maximizing the dose of the prior strategy, and duplicate medications in the same class should not be used. In many instances, the 3-drug combination will not normalize transit times and a secretagogue must be used (eg, linaclotide).³⁸

The goal of treatment is an absence of straining and only rare need for PRN laxatives. Psyllium-based bulk laxatives should be avoided, as these tend to inspissate in patients with extremely slow colonic transit times, forming a gel that further exacerbates the problem.^39-41

What is the approach to fever during clozapine treatment, and when should one consider holding clozapine?

Benign fever is not uncommon, with surveillance studies noting that 20% of patients may experience fever during the early phase of clozapine titration, typically with onset in the second week of therapy (days 11-13). The greatest concern during the early weeks of treatment relates to the association of fever with myocarditis, interstitial nephritis, serositis, and drug reaction with eosinophilia and systemic symptom syndrome.^42-45 Rare sporadic cases of serositis can occur after prolonged clozapine use, but most myocarditis and nephritis cases appear during the first 6 weeks after initiation.

The vast majority of fevers after commencing clozapine are benign,46 but when the onset is in the initial 6 weeks of treatment, a workup must be quickly performed for typical causes of fever, for myocarditis (troponin I or T, C-reactive protein, ECG), and for nephritis (serum creatinine). Clozapine need only be held for the time required to perform the workup and should be resumed as soon as possible once the results are obtained.

If clozapine must be held for more than 24 hours, anticholinergics must be administered to mitigate cholinergic rebound in the ratio of 1 mg of benztropine or 25 mg of diphenhydramine for each 50 mg of clozapine (in nonsmokers) or 100 mg of clozapine (in smokers).

Absolute Neutrophil Count Monitoring

Has there been a recent change in the frequency of complete blood count monitoring?

The absolute neutrophil count (ANC) is the only hematological parameter that must be monitored, but for now there has been no change in the FDA-mandated monitoring requirements despite evidence that the risk for severe neutropenia is extremely low after the first 18 weeks of treatment.⁴⁷ Papers have commented on the impediment to clozapine treatment presented by onerous ANC monitoring after the period of greatest risk,⁴⁷ but as of now, no changes have been adopted within the United States.

How has the portable point-of-care device for ANC measurement been implemented?

Point-of-care devices from various manufacturers are available worldwide,⁴⁸ but within the United States, 1 device (Athelas) has been available for several years⁴⁹ and is now approved for home use.⁵⁰ Some positive features of the device are listed in Table 2.

There are no published data on the extent of the device use, but in my local area, it has been employed by group homes with significant numbers of patients treated with clozapine, outpatient clinics, long-term locked psychiatric facilities, and state hospital systems. Even within hospital settings, patient refusal of venipuncture can interfere with treatment, so the flexibility of obtaining results within minutes at any time throughout the day removes an important roadblock to starting and continuing clozapine.

Concluding Thoughts

This is an exciting time to be involved in the care of patients living with schizophrenia due to emerging antipsychotic mechanisms of action, such as muscarinic M1 and M4 receptor activation.^51-53 The benefit of muscarinic mechanisms is mediated through reduction of striatal presynaptic dopamine release selectively in those areas associated with the positive symptoms of psychosis, and with no biological effects on striatal motor or hypophyseal endocrine dopamine signaling.

The promise of novel antipsychotics without dopamine D2 receptor binding has enormous appeal, but research into the biological substrate of treatment-resistant schizophrenia (TRS) suggests that poor response to D2 receptor modulation is associated with relatively normal striatal dopamine synthesis capacity. Imaging studies suggest that individuals with TRS do not have presynaptic dopamine dysfunction, but instead show elevated glutamate levels in the anterior cingulate cortex and right caudate.^54,55

Muscarinic antipsychotics will avoid the motor and endocrine consequences of D2 receptor binding but may only address the type of schizophrenia where positive symptoms are associated with elevated presynaptic dopamine release. Importantly, imaging studies find that response to clozapine among patients with TRS is associated with reduction in caudate glutamate levels.⁵⁶

Until such time as new agents become available that provide clozapine’s unique benefits and pharmacology, clinicians must be adept at prescribing clozapine. With a little practice, the vast majority of all psychiatric providers are capable of learning to use clozapine, manage its adverse effects, and handle its other unique challenges, with the goal of providing the only evidence-based treatment available for TRS.

Dr Meyer is a voluntary clinical professor of psychiatry at the University of California, San Diego.

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