Harrison-Woolrych et al ^{Reference Harrison-Woolrych, Skegg, Ashton, Herbison and Skegg1} present an interesting exploration of the association between nocturnal enuresis and clozapine (and other atypical antipsychotic) use. They report a significantly higher rate of nocturnal enuresis with clozapine use than with the other antipsychotics assessed in the study. This suggests a possible mechanism specific to clozapine in causation of this event.

Clozapine has been shown to adversely influence bladder control. ^{Reference Jeong, Kim, Ahn, Lee, Kim and Jung2–Reference Clark4} Various putative mechanisms to explain this observation include retention overflow consequent to inhibition of detrusor contraction due to anticholinergic action, reduced sphincter tone due to anti-adrenergic activity, ^{Reference Warner, Harvey and Barnes5} sedation and lowering of the seizure threshold, ^{Reference Kho and Nielsen6} drug-induced diabetes mellitus resulting in polyuria ^{Reference Kho and Nielsen6} and drug-induced diabetes insipidus. ^{Reference Bendz and Aurell7} Preclinical studies have demonstrated clozapine’s effects on urodynamics, with a centrally regulated reduction in activity of the external urethral sphincter. ^{Reference Vera and Nadelhaft8}

Bladder deregulation among patients with schizophrenia was described by Kraepelin, who postulated it to be an accompaniment of the ongoing ‘dementia’ process, as evident by the neuropsychological correlates of this process. ^{Reference Kraepelin and Barclay9} More recent works ^{Reference Bonney, Gupta, Hunter and Arndt10,Reference Gupta, Bonney, Sethi and Hunter11} have also established bladder dysfunction among patients with schizophrenia. The cause was reported to be detrusor hyper-reflexia in both studies based on the findings of urodynamic studies.

Similarly, high rates of bladder dysfunction have been reported among patients with schizophrenia being treated with clozapine. ^{Reference Jeong, Kim, Ahn, Lee, Kim and Jung2–Reference Clark4} However, the reports implicating clozapine in causation of bladder dysregulation have been criticised for concomitant use of other antipsychotics in these individuals. ^{Reference Clark4} Likewise, the dose of clozapine reported in these cases has been on the higher side.

In this context, it would be interesting to make a mention of a paper reporting a possible curative role of clozapine in neurogenic bladder. ^{Reference Kumar, Chadda, Kumar, Balan and Srinivasan12} This effect of clozapine was observed in a patient with schizophrenia. However, resolution of urinary incontinence in this case was found to be unrelated to the clinical response for schizophrenia. A high Naranjo algorithm score (<9), single-photon emission computed tomography and urodynamic findings lend support to the arguments put forward by the authors. Another interesting observation in the case was a therapeutic window phenomenon. Urinary incontinence responded to a dose range of 250–300 mg/day. No response was observed at a lower dose and incontinence reappeared at doses exceeding 300 mg/day. The authors postulated a possible central mechanism for this observation. Reversal of the facilitatory role of the 5-HT₇ heteroreceptor on acetylcholine release by clozapine could underlie its possible role in urge incontinence. ^{Reference Saifullah and Tomioka13}

There are no further reports or studies on the possible role of clozapine in correction of neurogenic bladder, nor has the dose–response effect been studied. It would be interesting to analyse the data by Harrison-Woolrych et al ^{Reference Harrison-Woolrych, Skegg, Ashton, Herbison and Skegg1} for the effect of dose of clozapine and to see whether there is any pattern with regard to change in nocturnal enuresis.