Sex Differences in Psychiatric Disease: A Focus on the Glutamate System

Abstract

Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states. This review describes the clinical and preclinical evidence for these sex differences with a focus on two conditions that are more prevalent in women: Alzheimer's disease and major depressive disorder, and three conditions that are more prevalent in men: schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. These studies reveal sex differences at multiple levels in the glutamate system including metabolic markers, receptor levels, genetic interactions, and therapeutic responses to glutamatergic drugs. Our survey of the current literature revealed a considerable need for more evaluations of sex differences in future studies examining the role of the glutamate system in psychiatric disease. Gaining a more thorough understanding of how sex differences in the glutamate system contribute to psychiatric disease could provide novel avenues for the development of sex-specific pharmacotherapies.

Longitudinal Quantification of Metabolites and Macromolecules Reveals Age- and Sex-Related Changes in the Healthy Fischer 344 Rat Brain

“…To date, very little work has been done on the characterization of sex differences in the neurochemical profile with age, despite age-related neurodegenerative (and other) disorders such as Alzheimer's disease differring in prevalence and symptom presentation between sexes (Wickens, Bangasser, and Briand 2018;Komoroski et al 1999;Mazure and Swendsen 2016). In a longitudinal study of C57BL6 mice, sex differences were identified for many metabolites, including ones in which we also report effects of sex (i.e.…”

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

“…Only one study to date has analyzed sex differences in ketamine response and found no differences in efficacy or tolerability (38,39). These studies highlight the need for further studies of sex differences in the behavioral, neural, molecular, and genetic phenotypes of major depressive disorder to inform the development of more effective treatment options (40). Pvalb interneurons are noted for their fast-spiking properties at rest, and could also be involved in ketamine-mediated disinhibition (15).…”

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

“…As with GABA receptors, there are two broad families of glutamate receptors: ionotropic and metabotropic. The ionotropic receptor family can be further subdivided into AMPA, NMDA and kainate receptors . Notably, the subunit GluN2B appears to be preferentially located in extrasynaptic NMDA receptors on immature neurones (particularly GABAergic interneurones).…”

“…Dysfunction of the GABAergic and glutamatergic systems has been implicated in a number of psychiatric disorders including ADHD, anxiety and depression . Magnetic resonance spectroscopy in children aged between 8‐12 years with ADHD identified reduced concentrations of GABA in the brain compared to children without the disorder .…”

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