The impact of sex as a biological variable in the search for novel antidepressants

Abstract

A roadblock to successful treatment for anxiety and depression is the high proportion of individuals that do not respond to existing treatments. Different underlying neurobiological mechanisms may drive similar symptoms, so a more personalized approach to treatment could be more successful. There is increasing evidence that sex is an important biological variable modulating efficacy of antidepressants and anxiolytics. We review evidence for sex-specific effects of traditional monoamine based antidepressants and newer pharmaceuticals targeting kappa opioid receptors (KOR), oxytocin receptors (OTR), and N-methyl-D-aspartate receptors (ketamine). In some cases, similar behavioral effects are observed in both sexes while in other cases strong sex-specific effects are observed. Most intriguing are cases such as ketamine which has similar behavioral effects in males and females, perhaps through sex-specific neurobiological mechanisms. These results show how essential it is to include both males and females in both clinical and preclinical evaluations of novel antidepressants and anxiolytics.

Keywords: Antidepressants; Depression; Kappa opioid receptor; Ketamine; Oxytocin social behavior; Sex differences.

Figure 1. Effects of KOR antagonists in the forced swim test and on anhedonia

Effects of AZ-MTAB on percent preference levels for sucrose water two weeks following social defeat stress in California mice (A, 7–14 per group). Effects of norBNI on time spent immobile in the forced swim test in C57Bl6/J mice (B, n=5–10 per group). *p<0.05 versus vehicle; ***p<0.0001 versus same-sex stress/vehicle; † p < 0.01 vs. same-sex control/vehicle.

Figure 2. Proposed oxytocin circuit in female California mice

Neural circuits mediating anxiolytic and anxiogenic effects of OT. Oxytocin neurons within the PVN send projections to the mPFC and CEA where activation of OTR exerts anxiolytic effects. Oxytocin neurons in the BSTav are activated by stress and OTR in the adjacent BSTam induces social anxiety responses. The LS also received OT projections from the PVN, but activation of OT in LS can promote social fear. PVN: paraventricular nucleus, mPFC: medial prefrontal cortex, CEA: central nucleus of the amygdala, LS: lateral septum, BSTav: bed nucleus of the stria terminalis anteroventral, BSTam: bed nucleus of the stria terminalis anteromedial.