Psychiatry Research 118 (2003) 241–247 0165-1781/03/$ - see front matter  2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0165-1781Ž03.00096-9 Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression Francesco Benedetti*, Alessandro Serretti, Cristina Colombo, Roberta Lilli, Cristina Lorenzi, Enrico Smeraldi Department of Neuropsychiatric Sciences, Universita Vita-Salute San Raffaele, School of Medicine, Milan, Italy ` Received 14 February 2002; received in revised form 27 November 2002; accepted 29 December 2002 Abstract Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of dopamine receptor D3 (DRD3) and dopamine receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder. One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon GlyySer variants and DRD2 codon 311 SeryCys variants using polymerase chain reaction techniques. DRD3 and DRD2 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. The tested gene variants are not a main factor influencing TSD outcome in bipolar disorder.  2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depression; Treatment outcome; Bipolar disorder; Dopamine receptors 1. Introduction Total sleep deprivation (TSD) has rapid and marked antidepressant effects in patients affected by bipolar depression, but it shows a large individ- ual variability both in terms of intensity and persistence of improvement (e.g. Leibenluft and *Corresponding author. Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, Via Sta- mira d’Ancona 20, 20127 Milan, Italy. Tel.: q39-02-2643- 3229; fax: q39-02-2643-3265. E-mail address: benedetti.francesco@hsr.it (F. Benedetti). Wehr, 1992). This individual variability could be at least, in part, explained by genetic factors affecting the activity of brain neural pathways. Though several hypotheses have been proposed, the neurobiological mechanism of action of TSD in the treatment of depression must still be consid- ered unclear (e.g. Duncan et al., 1980; Vogel et al., 1980; Wu and Bunney, 1990; Kuhs and Tolle, ¨ 1991; Wirz-Justice and Van den Hoofdakker, 1999; Wu et al., 2001). Clinical studies showed a strong synergistic interaction between TSD and seroto- nergic and mixed serotonergic–noradrenergic anti-