Sex matters! Identification of novel therapeutic targets to mitigate the increased prevalence of depression in women versus men.

Stress, particularly early life, is a major risk factor for several psychiatric disorders including depression. The prevalence of depression is twice as high in women compared with men. Thus in addition to stress, biological sex is an important contributor of depression susceptibility. The neurobiology underlying increased vulnerability of women to depression is unknown. However, the divergence in prevalence emerges during puberty, thus suggesting that puberty is a key period of life during which sex-dependent vulnerability to this stress-related disorder is established. Yet, how stress during puberty affects the brain in both males and females and across their life span remains under-investigated. Alarmingly, 80% of preclinical animal studies neglect to include females and analyse biological sex as a variable. This startling inattention to biological sex is impeding drug discovery and may partly explain the poor translation of discoveries made in animal models to successful new treatments in the clinic. This is particularly worrying in the context of depression because current antidepressants have a slow onset of action, unwanted side-effects and are ineffective in at least one third of individuals. Moreover, most individuals receiving antidepressants are female, and yet the majority of preclinical studies for identifying new targets for antidepressant drug development are conducted in males only. The aim of this project is identify novel sex-dependent and sex-independent druggable targets for the treatment of depression. This will be achieved by identifying the neurobiological mechanisms that underlie sex-dependent and sex-independent vulnerability of the pubertal brain to stress-induced depression. In this way, we will identify new targets for antidepressant drug development which may be effective in both sexes or that might be more effective in one sex but not the other. These findings will drive novel antidepressant target selection in this era of personalised medicine.

Award Date: 29 June 2017
Award Value: €357498
Principal Investigator: Dr Olivia O'Leary
Host Institution: University College Cork
Scheme: Investigator Led Projects