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 (chi2 = 20.36, d.f. = 1, P = 0.000007, and chi2 = 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.
Department of Neuropsychiatric Sciences, San Raffaele Scientific Institute, Vita-Salute University School of Medicine, via Stamira d'Ancona n 20, 20127 Milan, Italy. lattuada.enrico@hsr.it
Enrico
E
Lattuada
Roberto
R
Cavallaro
Francesco
F
Benedetti
Federica
F
Cocchi
Cristina
C
Lorenzi
Enrico
E
Smeraldi
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000097:blood; D056926:CLOCK Proteins; D016009:Chi-Square Distribution; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003024:Clozapine / Q000009:adverse effects* / Q000097:blood; D003545:Cysteine / Q000235:genetics; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D013912:Threonine / Q000235:genetics; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*
D014150:Antipsychotic Agents; D012333:RNA, Messenger; D015534:Trans-Activators; D013912:Threonine; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D003024:Clozapine; D003545:Cysteine