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.

Figure 1

A framework for interpreting sex differences. The effects of sex are typically studied by comparing a group of females with a group of males on specific end points. The diagram charts a series of questions needed for characterizing the sex difference observed in regards to the dimensions of persistent vs transient, context dependent vs context independent, and whether the end point is sexually dimorphic or continuous.

Figure 2

Direct and indirect effects of sex. The effects of sex on brain and behavior can be direct (ie, hormones and chromosome complement) or indirect, through sex differences in other physiological factors or in environmental factors. The direct effects of sex chromosomes and sex hormones may be synergetic or antagonistic. The indirect effects may exaggerate the direct effects of hormones or chromosome complement or act independently of other influences of sex to modulate brain and behavior. The physiological and the environmental factors through which sex may indirectly affect brain and behavior may themselves be a direct consequence of sex (eg, muscle mass, antlers, and parental behavior), or, in humans (dashed lines), may also be a consequence of gender (eg, sex roles and socioeconomic status). In addition to influencing physiological and environmental factors, components of gender may also affect components of sex itself (eg, level of testosterone).