The molecular background of sex difference in depressive disorders: still an enigma

Abstract

There is no doubt that adult females are significantly more often affected by depression and anxiety disorders than males. Virtual every study enrolls more women than men and it is assumed that the number of women suffering from depression doubles that of men. Interestingly, this difference is not present before adolescence. Not only the incidence and prevalence of depression is gender-specific, the same is true for the clinical phenomenology. The female excess is more pronounced in comorbid depression and anxiety and less in the pure forms. Other forms affecting women to a significantly higher degree than other subtypes are the so-called atypical depression [1] and somatic depression [2]. The main pathophysiological concept of depression relies on the biogenic amine 5-hydroxytryptophan (5HT) named serotonin. There is convincing evidence that the central serotonergic system plays a key role in the development, treatment and response rate of this affective disorder. Serotonin depletion induces depression in vulnerable subjects. Pharmacological restoration of high extracellular serotonin level relieves symptoms and is associated with termination of depressive episodes, which are frequently observed in the Western population and represent a relevant socioeconomic and medical problem. So far, the unequivocal facts for which strong evidence exist from epidemiologic studies and animal experiments. For in vivo studies on brain function in depression and other psychiatric disorders, nuclear medicine imaging provides a valuable and powerful imaging tool. By positron emission tomography, the serotonin transporter, the serotonin 2A and the serotonin 1A receptor binding potential (BP) can be selectively quantified. In this regard, particular interest is put on PET with [carbonyl-C]WAY-100635, a highly selective ligand for the 5-HT1A receptor that is the main inhibitory serotonergic receptor subtype. One should expect that, based on the overwhelming evidence for the predominance of female depressive patients, this armamentarium can easily visualise the molecular sex differences in the serotonergic system. However, the results remain inconsistent despite that the majority of investigators demonstrated a reduction of 5-HT1A receptor BP in distinct brain regions of depressive subjects [3–5], whereas no significant 5-HT1A receptor BP difference was found in patients with major depressive disorder (MDD) in comparison to controls in another comparable study by Parsey et al. [6]. Given that females show a significant predominance in depression, the consideration of a sex difference in 5-HT1A receptor BP is quite compelling. Indeed, a very recent study demonstrated a higher 5-HT1Areceptor BP and a lower serotonin transporter BP in females compared to males in healthy subjects [7]. Some years earlier, Parsey et al. also demonstrated a higher 5-HT1A receptor BP in females in several brain regions playing a role in mood disorders [8]. The study of Stein et al. in this EJNMMI issue focused on the 5-HT1A receptor BP in a sample of young healthy volunteers, determining the structure by two independent methods with the surprising result that there was a trend to though nonsignificant lower 5-HT1A receptor BP in females than in males [9]. These results were obtained by both an automated template-based method and by visual region of Eur J Nucl Med Mol Imaging (2008) 35:2156–2158 DOI 10.1007/s00259-008-0928-5