The Dopamine-4 Receptor Gene Associated with Binge Eating and Weight Gain in Women with Seasonal Affective Disorder: An Evolutionary Perspective Robert D. Levitan, Mario Masellis, Vincenzo S. Basile, Raymond W. Lam, Allan S. Kaplan, Caroline Davis, Pierandrea Muglia, Bronwyn Mackenzie, Subi Tharmalingam, Sidney H. Kennedy, Fabio Macciardi, James L. Kennedy Background: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. Methods: The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. Results: Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [ 2 (1)= 8.32, p = .004; odds ratio = 3.25, 95% confidence interval 1.43, 7.41]. Conclusions: Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other. Key Words: Seasonal affective disorder, genetics, weight gain, binge eating, dopamine-4 receptor gene, positive selection S easonal affective disorder (SAD) is a mood disorder characterized by the predictable onset of depression in the fall/winter months with spontaneous remissions in the spring/summer period (Rosenthal et al 1984). The typical patient with SAD is a premenopausal woman with marked craving for high-carbohydrate/high-fat foods and significant weight gain during winter depressive episodes. As a result, SAD has been described as a naturally reversible form of obesity (Rosenthal et al 1987). Appetitive symptoms are particularly sensitive to bright light therapy in SAD patients (Kräuchi et al 1993), making this a potentially treatable form of weight gain as well. It has been suggested that fall/winter increases in eating behavior and weight might reflect the human expression of a basic evolutionary process, present across multiple species, ensuring maximum conservation of energy when food sup- plies are becoming scarce (Rosenthal et al 1987; Thomson 1950). In humans, although adaptive over the course of evolution, this same process might be maladaptive when highly palatable, high-caloric foods are readily available, as is the case in modern developed countries. Seasonal weight gain in the context of SAD might thus reflect a classic gene– environment interaction, whereby a previously adaptive gene becomes a vulnerability gene when circumstances change. If so, this could have relatively broad public health implications in that 1) seasonal weight gain occurs in a large proportion of the North American population (Kasper et al 1989); and 2) gene– environment interactions acting at a behavioral as op- posed to a metabolic level might best explain the very rapid increase in obesity in recent history (Blundell and Cooling 2000; Hewitt 1997). We recently reported an association between the seven- repeat (7R) allele of the dopamine-4 receptor gene (DRD4) and obesity in a sample of women with SAD (Levitan et al 2004). In that initial report, we did not examine whether the increase in body mass associated with the 7R allele was attributable to a change in eating behavior per se. Other dopamine-based mechanisms, such as a decrease in physical activity, could also account for such a finding. The goal of the current analysis was to extend these findings and to more directly test the hypothesis that in overeating women with SAD, the putative association between DRD4 and increased body mass is mediated by increased eating behavior. The specific hypothesis was that the 7R allele would be associated with binge eating behavior and weight gain in overeating women with SAD. Methods and Materials Sample The current study group consisted of consecutive women 18–65 years of age who met DSM-IV criteria for major depression with a winter seasonal pattern. Some study sub- jects were presenting for a mood disorder consultation at the Centre for Addiction and Mental Health in Toronto, Canada, whereas others were recruited through advertisements in a local newspaper. The current sample included the same Toronto probands described in our prior report (n = 83; Levitan et al 2004), in addition to several new Toronto From the Mood and Anxiety Division (RDL, BM) and the Neurogenetics Section (MM, VSB, PM, ST, FM, JLK), Centre for Addiction and Mental Health; and the Eating Disorders Program (ASK, CD), Toronto General Hospital (SHK), University Health Network; University of Toronto, De- partment of Psychiatry, Toronto, Ontario; and Department of Psychiatry (RWL), University of British Columbia, Vancouver, British Columbia, Can- ada. Address reprint requests to Robert Levitan, M.D., Centre for Addiction and Mental Health, University of Toronto, Department of Psychiatry, 250 College Street, Room 1126, Toronto, Ontario M5T 1R8, Canada; E-mail: robert_levitan@camh.net. Received March 24, 2004; revised July 16, 2004; accepted August 25, 2004. BIOL PSYCHIATRY 2004;56:665– 669 0006-3223/04/$30.00 doi:10.1016/j.biopsych.2004.08.013 © 2004 Society of Biological Psychiatry