Sialorrhea develops in 13% of patients taking clozapine.1 As in Ms. B’s case, this side effect can be embarrassing, can limit social or occupational functioning, and might lead patients to discontinue clozapine treatment despite efficacy. Nonpharmacotherapeutic options include covering the pillow with a towel, lowering the clozapine dosage or titrating slowly (or both), and using sugarless gum or candy to increase swallowing.
If the benefits of additional medications targeting side effects outweigh the risks, pharmacotherapeutic intervention may be appropriate. Options include the tricyclic antidepressant amitriptyline31; alpha-adrenergic agonists or antagonists (clonidine, terazosin); and anti-muscarinic medications (benztropine, atropine, trihexyphenidyl, glycopyrrolate) (Table 231). Scopolamine transdermal patch is another possible treatment strategy; however, the scopolamine patch was used for clozapine-induced sialorrhea in only a few case reports, and it is not considered a first-line treatment choice.30
When prescribing, consider the possibility of combined side effects with clozapine and adjunct medications having antimuscarinic or alpha-adrenergic activity, or both. Even atropine ophthalmic drops, administered sublingually, are readily absorbed and cross the blood–brain barrier.31 Another antimuscarinic agent, glycopyrrolate, is less likely to cross the blood–brain barrier and therefore is less likely to cause cognitive side effects. Glycopyrrolate is 5 times more potent at blocking the muscarinic receptor than atropine.31,32 Ipratropium bromide, another nonselective muscarinic receptor antagonist, has less systemic absorption than atropine drops, with less anticholinergic side effects when administered sublingually.
Limited evidence supports the efficacy of alpha-adrenergic medications for managing clozapine-induced sialorrhea. Monitor blood pressure when prescribing terazosin or clonidine, which could potentiate clozapine’s hypotensive effects.
Endocrine side effectsAmong antipsychotics, clozapine is associated with the greatest weight gain—averaging nearly 10% of body weight.33,34 Similarly, the risk of new-onset diabetes mellitus is highest with clozapine in relation to other antipsychotics: 43% reported in a 10-year naturalistic study.35 The risk of hyperlipidemia also increases with clozapine treatment.36 These metabolic changes increase the risk of cardiovascular-related death, with a 10-year mortality rate from cardiovascular disease reported at 9% in clozapine-treated patients.35
Despite clozapine’s metabolic side effects, patients with schizophrenia who are treated with clozapine show a significant reduction in overall mortality compared with patients not treated with clozapine.6 Effective identification and management of metabolic side effects can prevent the need to discontinue clozapine.
Behavioral weight management and exercise are recommended as initial therapy.20 If, based on clinical judgment, these alone are insufficient, data support the use of pharmacotherapeutic interventions. Metformin demonstrates a positive effect on body weight, insulin resistance, and lipids, making it the first choice for adjunctive treatment of clozapine-induced metabolic side effects.37-39
Gastrointestinal side effectsClozapine’s anticholinergic activity can lead to serious gastrointestinal (GI) side effects, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus.8 Ileus has produced more fatal adverse reactions with clozapine than has severe neutropenia.20,40 Co-administered anticholinergic medications could increase the risk of ileus. Obtaining a GI review of systems and monitoring bowel movements (in inpatient or residential facilities) can aid in early identification and limit morbidity and mortality from GI adverse events. A high-fiber diet, adequate hydration, bulk laxatives in patients who can reliably maintain hydration, and GI consultation (if needed) may help manage GI side effects.20
Constitutional side effectsFever can occur with clozapine, most often in the first month of treatment, but the incidence is quite variable (0.5% to 55%).20,41 Although benign fever is common, agranulocytosis with infection, NMS, and other systemic illness must be ruled out. The recommended workup when a patient develops fever while taking clozapine includes physical examination and relevant testing (urinalysis, measurement of ANC and serum creatine kinase, chest radiograph, ECG, and, possibly, blood cultures).41
If evidence supports a serious adverse reaction, stop clozapine immediately.20 If benign clozapine-related fever is suspected, acetaminophen or another antipyretic might provide symptomatic relief; discontinuing clozapine is then unnecessary.41
Pregnancy. When a patient with schizophrenia requires clozapine treatment during pregnancy, reliable clinical guidance is limited. The American College of Obstetricians and Gynecologists Practice Bulletin on the use of psychiatric medications during pregnancy and lactation can be a useful resource.42
Be aware that the FDA very recently made major changes to the format and content of pregnancy and lactation labeling, removing the letter categories that have been used for medications approved on or after June 30, 2001. The manufacturers of medications (such as clozapine) that were approved before June 30, 2001, have 3 years to comply with new requirements.43
The FDA had rated clozapine a pregnancy risk category B medication, meaning no evidence of risk in humans. In 2011, the FDA issued a general warning that antipsychotic use in pregnancy can cause extrapyramidal symptoms and discontinuation symptoms in newborns.44,45