Genetic dissection of drug effects in clinical practice: CLOCK gene and clozapine-induced diurnal sleepiness

Psychotic patients treated with clozapine often experience persistent daytime sleepiness. This is a frequent side effect of clozapine that may reduce patient compliance. We hypothesized that clozapine might interfere with the circadian rhythms regulated by the biological clock. In 171 patients with major psychosis, we investigated the association between hypersomnolence during clozapine therapy and a CLOCK gene polymorphism (3111 T/C substitution). Forty-six patients showed persistent daytime sleepiness and were classified as "sleepy". "Sleepy" patients were significantly more likely to have a mutated allele compared to both "non sleepy" patients and healthy subjects (χ ² = 20.36, d.f. = 1, P = 0.000007, and χ ² = 13.91, d.f. = 1, P = 0.0002, respectively). We conclude that an interaction between clozapine and the CLOCK gene polymorphism 3111 T/C substitution could explain persistent daytime sleepiness in a significant proportion of patients treated with clozapine.