Evaluating the evidence for sex differences: a scoping review of human neuroimaging in psychopharmacology research

Although sex differences in psychiatric disorders abound, few neuropsychopharmacology (NPP) studies consider sex as a biological variable (SABV). We conducted a scoping review of this literature in humans by systematically searching PubMed to identify peer-reviewed journal articles published before March 2020 that (1) studied FDA-approved medications used to treat psychiatric disorders (or related symptoms) and (2) adequately evaluated sex differences using in vivo neuroimaging methodologies. Of the 251 NPP studies that included both sexes and considered SABV in analyses, 80% used methodologies that eliminated the effect of sex (e.g., by including sex as a covariate to control for its effect). Only 20% (50 studies) adequately evaluated sex differences either by testing for an interaction involving sex or by stratifying analyses by sex. Of these 50 studies, 72% found statistically significant sex differences in at least one outcome. Sex differences in neural and behavioral outcomes were studied more often in drugs indicated for conditions with known sex differences. Likewise, the majority of studies conducted in those drug classes noted sex differences: antidepressants (13 of 16), antipsychotics (10 of 12), sedative-hypnotics (6 of 10), and stimulants (6 of 10). In contrast, only two studies of mood stabilizers evaluated SABV, with one noting a sex difference. By mapping this literature, we bring into sharp relief how few studies adequately evaluate sex differences in NPP studies. Currently, all NIH-funded studies are required to consider SABV. We urge scientific journals, peer reviewers, and regulatory agencies to require researchers to consider SABV in their research. Continuing to ignore SABV in NPP research has ramifications both in terms of rigor and reproducibility of research, potentially leading to costly consequences and unrealized benefits.