Introduction

Sialorrhea may be the most common adverse effect of clozapine treatment, with prevalence estimates ranging from 30% to 90%, yet it is often underreported, underrecognized, and undertreated, leading to treatment dissatisfaction and discontinuation, social consequences, and possible medical morbidity in the form of aspiration events. Recent data indicate that the prevalence is likely closer to the 90% figure based on a detailed 2016 study of 98 clozapine-treated patients who were assessed for hypersalivation using two rating scales: the Nocturnal Hypersalivation Rating Scale and the Drooling Severity and Frequency Scale [ 1 ]. Sialorrhea was experienced by 92% of subjects overall, more commonly at night (85% of subjects) than in the daytime (48%). Daytime symptoms were severe in 18%, and sialorrhea was considered frequent or occurring on a constant basis in 20%. Importantly, sialorrhea had at least a moderate impact on the quality of life in 15% of study subjects. While many studies of clozapine discontinuation focus on physician determined medical concerns, sialorrhea emerges as the third most common adverse drug reaction cited by patients as a reason for discontinuing treatment, behind sedation and nausea [ 2 ]. Importantly, sialorrhea during clozapine therapy has been associated with reports of aspiration pneumonia [ 3 ]. The extent of pneumonia risk from clozapine treatment has been quantified in three studies, with rates 1.99–3.18 times higher in clozapine-treated patients compared with other antipsychotics [ 3 ]. Supporting this concept is the finding that pulmonary illness was the most common cause (32%) of medically related hospital admissions for clozapine-treated patients at one major US medical center, of which 58% were for pneumonia [ 4 ]. Lastly, parotitis has also been reported and associated with hypersalivation [ 5 ].

Principles

• A highly prevalent problem that causes social embarrassment, increases risk for treatment discontinuation, and may result in medical complications (e.g. aspiration pneumonia).

• Locally applied therapies must be tried first, as use of systemic anticholinergic medications will double the risk for ileus. Atropine 1% drops sublingually or ipratropium 0.06% spray intraorally are first-line agents.

• When patients fail first-line therapy, botulinum toxin-B injections into salivary glands is the preferred second-line therapy due to extensive double-blind, placebo-controlled trial data for sialorrhea due to medications or neurological causes.

• If botulinum toxin-B injections are not effective, other nonanticholinergic options to consider include alpha-adrenergic modulators (e.g. clonidine) and possibly amisulpride.

• A systemic anticholinergic medication should be considered the treatment of last resort due to the increased risk for ileus, and for fatal ileus. If a systemic anticholinergic must be used, glycopyrrolate is the preferred medication due to limited CNS penetration. The addition of glycopyrrolate must be accompanied by vigilant tracking of constipation, and aggressive management of gastrointestinal hypomotility should it occur.

Unfortunately, clinicians are forced to confront this problem with a virtual absence of well-designed clinical trials that focus specifically on clozapine and sialorrhea. The 2008 Cochrane review on clozapine-induced hypersalivation lamented: “The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable.” They concluded: “There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high” [ 6 ]. Nonetheless, there are some insights and treatment principles that can be gleaned from these studies. Importantly, sialorrhea is not unique to clozapine treatment, and is seen in an array of neurological disorders (i.e. cerebral palsy, Parkinson’s disease), or secondary to medications such as acetylcholinesterase inhibitors [ 7 , 8 ]. Fortunately, there are a large number of randomized, double-blind, placebo-controlled trials in this literature, including six studies alone utilizing botulinum toxin-B [ 9 ]. As the pathophysiology of hypersalivation during clozapine treatment is not distinct from other common etiologies, one can use this larger body of data from sialorrhea treatment studies to devise rational strategies for managing this vexing issue during clozapine therapy.