Major Depressive Disorder, or MDD, is a chronic, disabling condition that is unfortunately not very well understood. This lack of understanding is highlighted by the limited impact of selective serotonin reuptake inhibitors (SSRIs). This limited understanding of how the disorder develops is also combined with statistically significant sex differences that further limit our knowledge of the disorder. Limited knowledge combined with mediocre methods of treatment has therefore driven researchers to find more rapid, effective methods of treatment for those suffering from MDD.
Recent studies, specifically Powers et al., have focused not on serotonin, but on glutamate, the most common excitatory neurotransmitter in the body. One notable difference between females and males with MDD is glutamate transporter gene expression, specifically in the dorsolateral prefrontal cortex (DLPFC). Females with MDD have a significantly higher expression of glutamate transporters in this region of the brain, but gene expression of glutamate transporters in males remains the same. This abnormality could be a result of differences in autobiographical memory recall between males and females. Previous studies have suggested that deficits in autobiographical memory are present in females but not males, and that this is most likely do to cognitive differences in processing. Women particularly utilize circuitry in the DLPFC more than men for autobiographical memory processing, and for this reason autobiographical memory processing is significantly more impaired. Abnormal gene expression of glutamate transporters is generally present, but it differs between the sexes. Powers et al. proposed a mechanism in females that might explain these differences. Females experience the activation of estrogen in response to stress. Estrogen binds to Estrogen receptors, which then attach to estrogen response elements. These estrogen response elements are practically right next to the EAAT2 genes, therefore EREs may activate EAAT genes' expression in response to stress. This mechanism removes glutamate from the synapse lessening the excitotoxic apoptosis. It was generally suggested that EAAT1 and EAAT2, the EAAT genes, could have neuroprotective effects. Unsurprisingly, decreased expression of EAAT1 and EAAT2 were observed in males. Researchers concluded that EAAT1 and EAAT2 can have neuroprotective effects for both male and female patients, removing excess glutamate from the synapse and reducing excitotoxicity in the synapse, and addressing the decreased activity in the DLPFC that is associated with MDD.
Benitah et al. 2022 reviewed studies that investigated ketamine as a potential treatment for MDD. Ketamine has a wide range of effects on the body, with one of the most well-documented mechanisms being the blockade of NMDARs (an ionotropic glutamate receptor), but overall the mechanisms of ketamine are not very well understood. In addition there were heterogenous usage of methods to study the clinical effects of ketamine, small sample sizes, and lack of research on sex differences specifically. The review also found that while most studies did not demonstrate any sex differences between males and females, some studies did find differences. In one of the studies reviewed, the general antidepressant effects did not differ between males and females, the magnitude of antidepressant effects was significantly different. Males with MDD that were treated with ketamine experienced a greater magnitude of antidepressant effects that females with MDD. The authors of this review, similar to Powers et al., state that this is most likely due to difference in hormone concentrations between males and females.
These sex differences and novel treatments have ushered in a new era of MDD research. There are a seemingly infinite number of directions to take with treatment and research. Hopefully this direction is beneficial and fruitful.
References:
Benitah, K., Siegel, A., Lipsitz, O., Rodrigues, N. B., Meshkat, S., Lee, Y., Mansur, R. B., Nasri, F., Lui, L. M., McIntyre, R. S., & Rosenblat, J. D. (2022). Sex differences in ketamine’s therapeutic effects for mood disorders: A systematic review. Psychiatry Research, 312, 114579. https://doi.org/10.1016/j.psychres.2022.114579
Powers, B. E., Joyce, C., Kleinman, J. E., Hyde, T. M., Ajilore, O., Leow, A. D., & Sodhi, M. S. (2020). Sex differences in the transcription of glutamate transporters in major depression and suicide. Journal of Affective Disorders, 277, 244–252. https://doi.org/10.1016/j.jad.2020.07.055
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