In search of sex-related mediators of affective illness

Sex differences in the rates of affective disorders have been recognized for decades. Studies of physiologic sex-related differences in animals and humans, however, have generally yielded little in terms of explaining these differences. Furthermore, the significance of these findings is difficult to interpret given the dynamic, integrative, and highly context-dependent nature of human physiology. In this article, we provide an overview of the current literature on sex differences as they relate to mood disorders, organizing existing findings into five levels at which sex differences conceivably influence physiology relevant to affective states. These levels include the following: brain structure, network connectivity, signal transduction, transcription/translation, and epigenesis. We then evaluate the importance and limitations of this body of work, as well as offer perspectives on the future of research into sex differences. In creating this overview, we attempt to bring perspective to a body of research that is complex, poorly synthesized, and far from complete, as well as provide a theoretical framework for thinking about the role that sex differences ultimately play in affective regulation. Despite the overall gaps regarding both the underlying pathogenesis of affective illness and the role of sex-related factors in the development of affective disorders, it is evident that sex should be considered as an important contributor to alterations in neural function giving rise to susceptibility to and expression of depression.