Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT2C) plays a key role in control of appetite and satiety. A 5-HT2C Cys23Ser substitution, coded for by a single nucleotide polymorphism (Cys23Ser) within the 5-HT2C gene, has been shown to influence 5-HT2C function. We hypothesized that Cys23Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys23Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p = 0.044) and Cys23Ser was associated with weight (p = 0.039), body mass index (BMI; p = 0.038), and seasonal appetite change (p = 0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys23Ser was associated with minimum lifetime BMI (p = 0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys23Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys23Ser in the behavioral regulation of body weight.
Seasonal affective disorder/winter type (SAD) is characterized by recurrent depressive episodes of DSM IV major depressive or bipolar disorder in fall and winter (Rosenthal et al., 1984). Most patients with SAD, particularly females, meet DSM-IV criteria for atypical depression subtype as they exhibit atypical vegetative symptoms such as carbohydrate craving, increased appetite, weight gain, fatigue, and hypersomnia when depressed (Rosenthal et al., 1984 and Partonen and Lonnqvist, 1998). These seasonal changes in mood, eating behavior, energy, and sleep, termed seasonality, have a heritable component (Jang et al., 1997 and Madden et al., 1996), and have been associated with alterations in brain serotonin (5-HT) receptor function (Levitan et al., 1998 and Schwartz et al., 1997). Multiple lines of evidence suggest a genetic link between SAD and eating disorders, possibly involving a number of serotonin-related genes with small interactive and additive effects (Collier et al., 1997, Enoch et al., 1999, Levitan et al., 2004, Sher, 2001 and Sorbi et al., 1998). Receptor genes within the 5-HT system that play a role in eating behavior and weight regulation are thus excellent candidates to study SAD and seasonality.
The 5-HT2C receptor gene is of special interest in SAD and other disorders associated with disturbed body weight regulation, as this receptor subtype is expressed predominantly in the medial hypothalamus, a brain region known to be a regulator of food intake and energy metabolism (Lentes et al., 1997). Animal studies give evidence for an important role of 5-HT2C in the control of appetite: 5-HT2C knockout mice develop hyperphagia and midlife obesity (Chou-Green et al., 2003 and Tecott et al., 1995), while 5-HT2C receptor mutant mice show higher food intake (Nonogaki et al., 1998), and a decreased satiety response to d-fenfluramine, a releaser of 5-HT (Vickers et al., 1999). In humans, the 5-HT2C agonist mCPP leads to both hypophagia and weight loss (Sargent et al., 1997), while the 5-HT2c antagonist clozapine is associated with increased eating and weight gain (Leadbetter et al., 1992). The functional state of 5-HT2c receptors in SAD has been examined in vivo, revealing abnormal hormonal and behavioral responses to the nonselective 5-HT2C agonist mCPP in patients compared to normal controls (Garcia-Borreguero et al., 1995, Joseph-Vanderpool et al., 1993, Levitan et al., 1998 and Schwartz et al., 1997).
A functional Cys23Ser substitution has been identified in the first hydrophobic region of the 5-HT2C receptor (Lappalainen et al., 1995). It is coded by a single nucleotide polymorphism within the 5-HT2C receptor gene on the X-chromosome (Xq24). Male subjects are therefore either hemizygous for Cys23, or hemizygous for Ser23. Frequencies of the Cys23 and Ser23 alleles in unrelated Caucasians are 0.87 and 0.13, respectively. A recent study has shown that the Cys23Ser substitution influences 5-HT2C receptor function, with the Ser23 variant being constitutively more active than Cys23 in the absence of the endogenous ligand, 5-HT (Okada et al., 2004). An association study investigating several 5-HT-related polymorphisms in patients with SAD found no association of Cys/Ser genotype with the diagnosis of SAD, but higher seasonal variation in mood and eating behavior in Cys/Ser heterozygous women as expressed by the Global Seasonality Score (GSS) (Johansson et al., 2001). In addition, there is significant evidence that the Cys23Ser polymorphism plays a role in body weight regulation per se. The Ser23 allele was found to be associated with weight loss in teenage girls (Westberg et al., 2002). Ser23 was also associated with the diagnosis of anorexia nervosa, and the severity of illness, as expressed by low body max index (BMI) values (Hu et al., 2003 and Westberg et al., 2002). Another study in late onset Alzheimer’s disease found an association between Cys23Ser and the presence of hyperphagia (Holmes et al., 1998). These various studies suggest that at least in certain populations, the Cys23Ser polymorphism plays an important role in body weight regulation.
The current study examined the influence of the Cys23Ser polymorphism on both the overall diagnosis of SAD as well as body weight regulation parameters in two independent female samples from Austria, and Canada, respectively. Our first hypothesis was that 5-HT2c Cys23Ser genotype distribution would differ between female patients with SAD and female healthy controls. Our second hypothesis was that in patients with SAD, atypical subtype – a patient collective with a high degree of seasonal changes in energy, appetite and weight – there would be an association between Cys23Ser genotype and disturbances in appetite and weight regulation (body weight, BMI, BMI fluctuations, seasonal changes in appetite, seasonal overeating and weight gain).
