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

Abstract

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.

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

“…Previous research and results from this study show that estrogen regulation of CYP2B6 gene expression can modulate differential response to ketamine in females (biological sex) ( Figure 5) (92). These results indicate that dose optimization is critically dependent on a patient's endogenous drug profile, biological sex, and age (12,91,92).…”

“…While exon variants in the CYP2B6 gene may differentially alter splicing but not protein structure or function (89), mutations that alter CYP2B6 mRNA splicing in the human brain contribute significantly to ketamine response variation in humans (90,91). Previous research and results from this study show that estrogen regulation of CYP2B6 gene expression can modulate differential response to ketamine in females (biological sex) ( Figure 5) (92). These results indicate that dose optimization is critically dependent on a patient's endogenous drug profile, biological sex, and age (12,91,92).…”

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration

“…Published work so far did not detect a role of gender in the behavioral response to (2R,6R)-HNK administration. Recently, we summarized the evidence of the role of sex in the effects of ketamine and (2R,6R)-HNK [15].The molecular mechanisms of action of ketamine and (2R,6R)-HNK are only partly understood: there are key neurobiological mechanisms that are well-known factors of MDD pathology and therapy, which were found to play a role in the rapid-acting effects of ketamine. For example, a single injection of ketamine activated the mammalian target of rapamycin (mTOR) and this enhanced synaptogenesis in the medial prefrontal cortex (mPFC) [16], reversing the stress-induced synaptic deficits in mice [17].…”

<p>Comorbid Premenstrual Dysphoric Disorder in Women with Bipolar Disorder: Management Challenges</p>

“…Several studies reported a gender difference in treatment response to antidepressants in mood disorders. 49 In particular, there is some evidence that women respond better to SSRI with respect to men 50,51 (probably due to the interactions between estrogen and serotonin in the brain). 52 When considering PMDD, The Korean Medication Algorithm project for Depressive Disorder, second revision, reported AD monotherapy as the treatment of choice.…”