Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be?

Abstract

Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in the frequency, severity, or response to treatment. The goal of this circumspective is to provide two views on the current state of the art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific end points, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: (1) persistent vs transient across the lifespan; (2) context independent vs dependent; (3) dimorphic vs continuous; and (4) a direct vs an indirect consequence of sex. To accurately classify a sex difference along these dimensions, one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and on sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization, and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders.

Sex as a Biological Variable: Who, What, When, Why, and How

“…In addition, there is great potential to gain mechanistic insight from studies where sex differences are identified. The antiquated myth that females are 'messy' and make research more difficult is not supported by the evidence, and articles such as this one, and those from other investigators who have been considering sex and gender in their research for decades, will help promote the inclusion and importance of SABV in biomedical research (Bale and Epperson, 2015;Miller et al, 2015;Becker and Koob, 2016;Joel and McCarthy, 2016).…”

“…First, as discussed in the Circumspective by McCarthy and Joel in this issue, to include SABV does not suggest that the researchers are asking nor are they powered to ask, if sex differences are present (Joel and McCarthy, 2016). Including both sexes and examining outcomes for potential differences between sexes in the results should provide insight as to whether major differences would be present and if further studies are warranted.…”

“…For instance, if you are running a Barnes maze behavioral test and knowing that males and females use different strategies to locate the hidden escape box, then you know that the latency for both groups may be different, but the interpretation of the difference is not that females have decreased spatial ability, but rather that their less risk-aversive serial search strategy requires additional travel time (Mueller and Bale, 2007). This is an example of a sexually dimorphic outcome where the measure exists in two forms, one more prevalent in one sex vs the other (ie, females using a serial search strategy, males using a spatial navigation strategy in this test; Joel and McCarthy, 2016). Knowing this, you might design your study to ask about differences within sex for a given manipulation rather than between sexes.…”

“…As another example, in post-puberty rodents, the HPA stress axis has a significant sex difference in the amount of ACTH and corticosterone produced in response to a given acute stressor Romeo et al, 2004;Romeo and McEwen, 2006;Goel and Bale, 2007;Goel and Bale, 2008;Goel and Bale, 2009;Handa et al, 2009;Weiser and Handa, 2009). This would be an example of a sex difference that is along a continuum, with females producing the same hormones and in the same direction as males (increased following stress), but just at higher levels (Joel and McCarthy, 2016). In this example, one should be aware that when designing studies comparing sexes, most biological responses have floor and ceiling effects.…”

“…Importantly, the sexually dimorphic brain, similar to most sex differences, does not fall into a hard binary readout-but rather is on a continuum or spectrum with each cell and each brain region comprised of varying degrees of 'male' and 'female' (Hines, 2005;Joel and McCarthy, 2016). This is because the influences from very early neurodevelopmental time points, and perhaps even earlier than fertilization, are complex and multifaceted and frequently depend on the sex chromosome compliment of the individual or the sex of the parent contributing a given gene.…”