Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Int J Mol Sci. 2019 Feb 22;20(4):949. doi: 10.3390/ijms20040949.


Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.

Keywords: (2R,6R)-Hydroxynorketamine; Ketamine; antidepressant; depression; electroconvulsive therapy; endocrinology; gender; rapid-acting; sex difference.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / genetics
  • Electroconvulsive Therapy
  • Female
  • Humans
  • Ketamine / metabolism
  • Male
  • Treatment Outcome


  • Antidepressive Agents
  • Ketamine