Major Depressive Disorder Research Roundup: July 25, 2025

The Role of GABA, Glutamate, and Glx Levels in Treatment of Major Depressive Disorder: A Systematic Review and Meta-Analysis

In a recent meta analysis, investigators tracked neurotransmitter levels (GABA, glutamate, G1x) in patients with major depressive disorder (MDD) before and after 4 main treatment types: selective serotonin reuptake inhibitors, ketamine, repetitive transcranial magnetic stimulation, electroconvulsive therapy. Through the 41 studies and total 918 patients analyzed, they found a significant increase in Glx levels, especially when analysis was restricted to prefrontal regions. The most significant Glx increases were from patients classified as responding to treatment for MDD. For glutamate and GABA, there was no significant difference in levels after treatment for any treatment type.

From the meta analysis, the authors proposed that modulation of G1x may be a neurobiological mechanism underlying patients’ response to therapies for MDD. Investigators noted that their “findings challenge the notion that acute restoration of GABA and glutamate is essential for treatment efficacy but provide tentative evidence supporting a role for the composite measure Glx.”

Reference

Godfrey K, Douglass H, Erritzoe D, et al. The role of GABA, glutamate, and Glx levels in treatment of major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2025:111455.

Transcranial Magnetic Stimulation for Major Depressive Disorder in Pregnancy: A Literature Review

SSRIs can pose a risk to pregnant mothers and fetal development. In a meta analysis, Shah et al explored 3 studies to evaluate the efficacy and safety of transcranial magnetic stimulation (TMS) to treat MDD. Investigators found that for pregnant women in their 2nd or 3rd trimester, low frequency TMS at the right dorsolateral prefrontal cortex was related to a significant reduction in depression symptom reduction. The US Food and Drug Administration has currently “approved TMS for adults with depression who have failed a single antidepressant trial in the current depressive episode” and it “can be considered as a safe option for pregnant women who are not willing to be on antidepressants.” While there has not been a wealth of studies on this topic, researchers stated that TMS for MDD in pregnancy was a “promising alternative” to taking psychiatric medication while pregnant.

Reference

Shah MR, Jampa A, Kaur M, et al. Transcranial magnetic stimulation for major depressive disorder in pregnancy: a literature review. Cureus. 2019;11(8):e5431.

Verbal Memory in Major Depressive Disorder in a Long-Term Perspective: a Five-Year Longitudinal Study of First Episode Patients

Researchers investigated verbal memory, depressive symptoms, and relapse in first episode MDD over a period of 5 years. Using the trait, state, and scar perspectives, researchers investigated whether deficits in memory preexist, manifest in MDD, or are exacerbated with each MDD episode. The control-case study matched 30 controls with 30 patients with MDD and evaluated results of the California Verbal Learning Test and depression severity at acute (less than 1 year), 1 year, and 5 year follow ups. Findings were that those with first episode MDD showed normal verbal memory performance at 1 year and 5 year checks. Patients with MDD had impaired performance on the immediate free recall task during the acute phase compared with the control group; however, correction for multiple comparisons did not reach statistical significance.

Authors stated their results “do not support the hypothesis of verbal memory deficit in the acute phase of illness, but rather show that the patients perform worse on the first trial, indicating deficits in acquisition and auditory attention.” They also found a limited association between depression symptom severity and cognitive functioning. For the trait, state, and scar perspectives, there was no support found for the trait perspective, the state perspective was partially supported, and results indicated no scarring effects.

Reference

Schmid M, Ronold EH, Løchen M, et al. Verbal memory in major depressive disorder in a long-term perspective: a five-year longitudinal study of first episode patients. Front Psychiatry. 2025;16:1623126.