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<p class="title-left"><span class="bold">Clozapine-Induced Enuresis:</span></p>
<p class="subtitle">An Underrecognized and Undertreated Problem</p>
<p class="byline-regular">Nicole Luche, BA,<span class="superscript">a</span> and Dimitry Francois, MD<span class="superscript">a,b,</span><span class="asterisk">*</span></p>
<p class="drop-cap-with-body-text"><span class="bold-14pt-for-cap"><span class="bold">C</span></span>lozapine is a particularly efficacious second-generation antipsychotic, although its use has been restricted to treatment-refractory cases due to a plethora of side effects. The most life-threatening side effects are agranulocytosis, seizures, and myocarditis; however, sedation, sialorrhea, tachycardia, dizziness, constipation, and gastrointestinal upset are most common.<span class="htm-cite"><a href="#ref1">1</a></span> We identified new-onset enuresis in one of our patients, which we propose to be an underreported side effect of clozapine.</p>
<p class="subheads-subhead-2">Case Report</p>
<p class="body-text">A 69-year-old woman with schizoaffective disorder, bipolar type (<span class="italic">DSM-5 </span>criteria) and over 20 past psychiatric hospitalizations was admitted to our inpatient service for uptitration of clozapine in the setting of recent medication noncompliance and paranoid thinking. Over the course of her 15-day hospitalization, clozapine was uptitrated from 25 mg to 300 mg daily with favorable response. Vital signs and weekly absolute neutrophil counts were consistently within normal limits.</p>
<p class="body-text">On the second evening of clozapine use (25 mg daily dose), the patient began to experience nighttime enuresis with incontinence during 4 of the next 5 nights of therapy. This incontinence caused the patient substantial subjective distress per the nursing staff, despite no change in her interaction with the psychiatrists. The patient was placed on desmopressin 0.2 mg on the seventh day of therapy (clozapine 150 mg/day), with supplementary nighttime awakenings to urinate. The patient had only 1 episode of enuresis after initiation of this regimen and was able to be discharged on clozapine 300 mg/day and desmopressin 0.2 mg/day. Because our patient only responded to explicit questioning regarding urinary patterns during admission, we hypothesized that outpatient providers might likewise experience difficulty in eliciting reports of nighttime enuresis on clozapine and that this side effect might be underreported as a result. We searched PubMed using the MeSH database terms [<span class="italic">clozapine</span>] AND [<span class="italic">enuresis</span>] OR [<span class="italic">urinary incontinence</span>] AND [<span class="italic">clozapine/adverse effects</span>] AND [<span class="italic">prevalence</span>] in our initial research.</p>
<p class="subheads-subhead-2">Discussion</p>
<p class="body-text">In a study<span class="htm-cite"><a href="#ref2">2</a></span> of 103 patients taking clozapine, only 1 patient volunteered new-onset enuresis, but an additional 39 patients with enuresis were identified through direct questioning. Another study of 61 patients on clozapine found enuresis in 27 individuals (44% of patients).<span class="htm-cite"><a href="#ref3">3</a></span> In the setting of these 2 studies,<span class="htm-cite"><a href="#ref2">2</a>,<a href="#ref3">3</a></span> as well as a selection of case reports and series,<span class="htm-cite"><a href="#ref4">4–7</a></span> it is our view that clozapine-induced enuresis represents a problem that has not yet been sufficiently addressed in the psychiatric community.</p>
<p class="body-text">It should be noted that clozapine-induced enuresis as a clinical phenomenon remains poorly understood. We chose desmopressin for our patient based on its known ability to treat generic enuresis, but other therapies have been successfully employed, as described in various case reports and series.<span class="htm-cite"><a href="#ref4">4–7</a></span> These therapies include aripiprazole (10–15 mg daily), amitriptyline (25 mg daily), trihexyphenidyl (5 mg daily), ephedrine (≤<span class="thinspace"> </span>150 mg daily), and pseudoephedrine (30 mg 4 times daily).<span class="htm-cite"><a href="#ref4">4–7</a></span> Relevant etiologic explanations fail to account for why other drugs with distinct mechanisms of action have also been efficacious by report.<span class="htm-cite"><a href="#ref4">4–6</a></span> The etiology of clozapine-induced enuresis is therefore likely to be multifactorial and requires further investigation to more completely describe.</p>
<p class="subheads-subhead-2">Conclusion</p>
<p class="body-text">This case report and literature review demonstrate that clozapine-induced enuresis is most likely underreported and that direct questioning regarding enuresis may have greater success than vague inquiries into side effects.<span class="htm-cite"><a href="#ref2">2</a></span> The reported incidence of urinary abnormalities is substantially lower in published pharmacotherapeutic reference material<span class="htm-cite"><a href="#ref8">8</a></span> than in the few studies<span class="htm-cite"><a href="#ref2">2</a>,<a href="#ref3">3</a></span> that have been conducted on this matter, and, as with our patient, any resulting potential failure to inquire about side effects after new-onset enuresis may have profound consequences for the patient’s quality of life. It is likewise important to highlight the number of successful therapeutic strategies that have been reported, which may mitigate such distressing side effects and may be useful for outpatient psychiatrists and primary care providers alike.</p>
<p class="end-matter"><span class="bold-italic">Published online:</span> May 14, 2020.</p>
<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> None.</p>
<p class="end-matter"><span class="bold-italic">Funding/support:</span> None.</p>
<p class="end-matter"><span class="bold-italic">Patient consent:</span> Consent was received from the patient to publish the case report, and information has been de-identified to protect anonymity.</p>
<p class="references_references-heading"><span class="bold">REFERENCES</span></p>
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<p class="front-matter-rule"><span class="superscript">a</span>Weill Cornell Medicine, New York, New York</p>
<p class="front-matter"><span class="superscript">b</span>New York-Presbyterian Westchester Division, White Plains, New York</p>
<p class="front-matter"><span class="asterisk">*</span><span class="italic">Corresponding author:</span> Dimitry Francois, MD, 21 Bloomingdale Rd, White Plains, NY 10605 <span class="hyperlink">(<a href="mailto:dif9013@med.cornell.edu">dif9013@med.cornell.edu</a>)</span>.</p>
<p class="front-matter"><span class="italic">Prim Care Companion CNS Disord 2020;22(3):19l02530</span></p>
<p class="front-matter-rule"><span class="bold-italic">To cite:</span> Luche N, Francois D. Clozapine-induced enuresis: an underrecognized and undertreated problem. <span class="italic">Prim Care Companion CNS Disord</span>. 2020;22(3):19l02530.</p>
<p class="doi-line"><span class="bold-italic">To share:</span> https://doi.org/<span class="doi">10.4088/PCC.19l02530</span></p>
<p class="front-matter"><span class="italic">© Copyright 2020 Physicians Postgraduate Press, Inc.</span></p></div>
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