Mr. CH had no history of childhood or adult-onset enuresis prior to his treatment with risperidone. His enuresis presented rather acutely but rapidly resolved upon switching to quetiapine. There was no evidence of diuretic consumption during this time and no past history of polyuria secondary to diabetes mellitus.
Secondary enuresis is a relatively rare side-effect that is seen among different classes of psychiatric medications. SSRIs alone, as well as SSRIs when used in conjunct with risperidone, have been shown to cause enuresis in both adolescent and young adult patients with a variety of psychiatric conditions. Enuresis resolved upon discontinuation of the drug or switch to a different agent within the same pharmacological class [8, 9]. Possible mechanisms of action include serotonin reuptake inhibition causing potentiation of cholinergic neurotransmission in human detrusor muscle , central action, or possible peripheral action on modulation of voltage-dependent calcium channels in smooth muscle . Despite these cases, in 2000, enuresis was reported to be the 6th most common reason for prescribing SSRIs to children . A 61-year-old man and a 42-year-old man both developed diurnal enuresis after addition of bupropion HCL SR and XL, respectively, to their medication regimen for depression. In both patients, urinary symptoms resolved after discontinuation of bupropion [12, 13].
After review of the literature, it appears that pharmacological treatment of psychiatric medication-induced enuresis has rarely been attempted except in the context of patients with psychiatric conditions well-controlled with atypical antipsychotics. Trihexyphenidyl, an M1 antagonist, has been effective in treatment of both clozapine-induced enuresis and sialorrhea . Aripiprazole has been used to treat clozapine-induced enuresis, possibly due to D2 agonist activity in the clozapine-induced hypodopaminergic state within the basal ganglia . TCAs have established antienuretic properties and have been effective in resolving SSRI and clozapine-induced enuresis . Methylphenidate was shown to cause enuresis in two adolescent boys, one with ADHD, the other with ADHD with comorbid methylphenidate-induced anxiety. In the patient with only ADHD, discontinuation of MPH and initiation of atomoxetine resolved his enuresis. In the patient with ADHD and comorbid anxiety and enuresis, addition of milnacipran improved both methylphenidate response in the patient, while improving his anxiety and completely resolving his enuresis .
Different mechanisms have been proposed for how certain atypical antipsychotics can cause enuresis. It is possible that the anticholinergic properties of atypical antipsychotics cause decreased detrusor function, leading to increased post-void residuals and overflow incontinence . Risperidone specifically has had Ki values reported as high as 10,000 nM, indicating that there is no significant interaction between risperidone and muscarinic receptors. It is possible that serotonergic blockade could cause nocturnal enuresis, as clozapine, risperidone, and olanzapine all have relatively high affinity for the 5-HT2a receptor . Functional studies have shown that serotonergic antagonists stimulate parasympathetic activity and suppress sympathetic and somatic activity, which could lead to increased detrusor function and decreased internal urethral sphincter tone [10, 20, 21].
For risperidone specifically, alpha-1-adrenergic blockade has been implicated as a possible mechanism of pathologic enuresis . However, many of the therapeutic benefits of risperidone are due to its conversion to its active moiety 9-hydroxyrisperidone. 9-hydroxyrisperidone can be administered directly through the newer atypical antipsychotic paliperidone. Paliperidone has been shown to exhibit weak affinity for alpha-1 and alpha-2 adrenergic receptors when compared to risperidone in vivo [19, 23]. It is possible that the reason only a certain subset of patients experiences enuresis when given risperidone is because of differences in metabolism of risperidone to its active moiety. Risperidone is converted to its active moiety by CYP2D6 and to a lesser extent by CYP3A4. Poor metabolizers of risperidone are known to have two inactive copies of the CYP2D6 gene, causing accumulation of risperidone instead of its active moiety. While these patients have been shown to have larger decreases in symptoms of schizophrenia, they are also more likely to experience extrapyramidal symptoms and likely enuresis . Thus, it is possible that patients who saw large improvement in their psychotic symptoms on risperidone that were forced to switch medications due to enuresis lacked functional CYP2D6 enzymes, leading to a larger than normal blockade of alpha-1-adrenergic receptors. It seems likely that 9-hydroxyrisperidone may lead to less enuresis.
However, risperidone has also been shown to treat urinary incontinence , giving strength to the idea that atypical antipsychotic-induced pathologic enuresis has a multifactorial cause.