Sex: a key consideration in understanding the etiology of psychiatric disorders and improving treatment

For decades, the existence of a male or female brain was widely debated in popular culture; however, consensus has finally been reached. Data confirm, without a shadow of a doubt, that biological sex plays a critical role in brain health and disease. We have at last begun to crack the neurobiological code underlying mental health conditions, and the resulting verdict is clear: sex-related factors hold an important key to unravelling mechanisms of cerebral dysfunction. When breakthroughs such as these occur, the curious among us like to ask, “Why now? ” Does serendipity alone mark paradigm shifts in medicine? Or is luck inevitable when preparation meets opportunity? In the case of sex-related investigations, robust attention was already being paid to male–female differences in the lifetime risk for psychiatric disorders. It was broadly recognized that there are sex differences in the prevalence, course and/or symptom profiles of many psychiatric disorders (e.g., autism, attention-deficit/hyperactivity disorder, eating disorders, schizophrenia, major depressive disorder, anxiety disorders and substance use disorders). However, the reasons for these differences are undoubtedly complex, and our understanding of the mechanisms behind them was only rudimentary. Policies put in place during the last few years by funders such as the Canadian Institutes of Health Research and the US National Institutes of Health unquestionably accelerated the pace of mechanistic discovery by mandating that applicants outline how the analysis of both sexes will be included in experimental models where appropriate. For far too long, single-sex — usually male — cells, tissues and organisms were used as the default in basic science, owing in part to the myth that females were more variable because of their estrous cycle.1 Even when both sexes were included, few attempts were made to disaggregate the data. Push-back on funders’ policies to compare both sexes was vocal at first, but resistance has waned. More researchers are aware of important discoveries concerning sex differences in normal brain development and in the pathophysiology of some psychiatric disorders, and adjust their methodological approaches to include both sexes. To build capacity, new guidelines describe how to analyze sex differences in animal and clinical research through the use of more efficient study designs that examine main effects as well as sex interactions.2,3 The majority (~75%) of psychiatric disorders first emerge during adolescence and young adulthood, emphasizing the potential importance of brain developmental factors in their etiology. Substantial neuroimaging evidence from studies on children and youth now documents differences in male versus female brain structural measures, such as total brain volume, regional brain volumes, cortical thickness, white matter organization and developmental trajectories, during development.4 Interestingly, recent research indicates that microglia, the most abundant innate immune cells in the brain, appear to be sexually dimorphic during development and play an active role in both normal brain developmental processes and in brain responses to insults that are risk factors for psychiatric illness, such as perinatal infection and early life adversity.5 Neuroimaging studies also support the presence of sexdependent structural and functional alterations in the case of some psychiatric disorders. For example, many larger scale studies of autism have documented differential changes in brain neuroanatomy and in functional organization of the brain in males versus females.6 Several meta-analyses have also reported differential reductions in regional grey matter volumes in females versus males with schizophrenia.4 Sex differences in brain anatomy and function have also been observed in youth at clinical high risk for psychosis, as reported in a recent large study of 1095 youth with and without psychosis spectrum symptoms, noting sex by psychosis symptom interactions in regional brain volumes and functional striatocortical connectivity.7 While sex-dependent changes in brain volumes do not appear to be widespread in bipolar disorder (BD), a recent ENIGMA Consortium study of 1710 patients with BD and 2594 controls found a significant increase in volume of the thalamus in male but not female participants.8 In the case of major depressive disorder (MDD), a recent study of 610 community-dwelling participants found that lifetime diagnosis of MDD was associated with regional grey matter volume changes, some of which