Enuresis as a premorbid developmental marker of schizophrenia

There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia (SCZ). We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with SCZ and with measures of brain abnormalities also associated with SCZ. A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) based history of enuresis, volumetric brain MRI scans and neuropsychological testing were obtained in patients with SCZ, their non-psychotic siblings (SIB) and non-psychiatric controls (NC). The subjects were 211 patients (79.6% male), 234 of their SIB (43.2% male) and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using voxel-based morphometry on matched subsets of probands (n = 82) with or without enuresis (n = 16, n = 66, respectively) and controls (n = 102) with or without enuresis (n = 11, n = 91, respectively). Patients with SCZ had higher rates of childhood enuresis (21%) compared with SIB (11%; chi(2) = 6.42, P = 0.01) or controls (7%; chi(2) = 23.65, P < 0.0001) and relative risk for enuresis was increased in SIB (lambda(S) = 2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t = 1.97, P = 0.05, df = 200) and Category Fluency (t = 2.15, P = 0.03, df = 200)] as compared with non-enuretic patients. Voxel-based morphometry analysis revealed grey matter volume reductions in several frontal regions (right BA 9, right BA 10 and bilateral BA 45) and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t > 3.57, all P < 0.001). The high frequency of childhood enuresis associated with SCZ and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to SCZ. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors.