Women are 1.7 times more likely to experience a major depressive episode in their lifetime. Additionally, women are more likely to be prescribed antidepressants and have a greater likelihood of having TRD. Menopause is a vulnerable time, and 20 percent of women may experience depression during the transition. In the perimenopausal period, the gonadal hormones are in flux. There are reports that post-menopausal women have a poorer response to monoamine-antidepressants. Hence the need to look at ketamine.
The weakness of the study is using age cut-offs for menopausal status rather than biochemical assays. The study ratings did not have a blinding, and ketamine was used as an adjunct to antidepressants. No control group either.
The study simulated real-world practice and had a good sample size. This study used validated rating scales.
Estrogen receptors are protective against glutamate-induced neurotoxicity. Preclinical data suggest that estrogen enhances NMDA receptor function. This is thought to happen via the upregulation of the receptor subtypes. Allopregnanolone, a neuroactive steroid, influences glutamatergic signaling through effects on GABA receptors.
The lack of menopausal status affecting the response to ketamine is important to note as it did not attenuate the improvement in anxiety, anhedonia, and workplace, and family function, unlike monoamine antidepressants. This is a replication of a prior study by (Freeman et. al 2019) and replicated findings are important.
The suicidal ideation (SI) finding is interesting too, a more rapid reduction in postmenopausal women (first infusion) while premenopausal women had reduction SI after the third infusion. This may be the issue related to a larger sample size of this study compared to the Freeman et. al 2019 study. The premenopausal women experienced a rapid improvement in social functioning. The transition in social roles that occurs during the menopausal transition may contribute to depression.
The important point is the finding of the lack of difference between the response to ketamine infusion in premenopausal and postmenopausal women. Previous studies have reported monoaminergic antidepressants as not being effective in postmenopausal women.
In summary: In my opinion, these findings are interesting but not strong enough for us to make any clinical distinctions about ketamine response based on menopausal status. More prospective research is needed to validate these findings.