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GABAergic Deficit Hypothesis Offers New Framework to Reinvigorate MDD Treatment, Experts Say in Review Article
While depression treatment strategies have been guided by the monoamine hypothesis for the past several decades, embracing the GABAergic (gamma-aminobutyric acid) deficit hypothesis may help to reinvigorate treatment for major depressive disorder (MDD). The review article, authored by regular Psych Congress Network contributors Andrew J. Cutler, MD; Gregory W. Mattingly, MD; and Vladimir Maletic, MD, was published in Translational Psychiatry.
“Treatment responses to standard-of-care oral antidepressants have been suboptimal in many individuals with MDD, potentially due to slow onset of effects, low response rates, adverse effects, and the need for chronic treatment,” the authors indicated in the article. “There remains an unmet need for novel and effective treatments with rapid, robust, and sustained antidepressant effects; with better safety and tolerability than standard-of-care [antidepressant therapies (ADTs)], and ideally without the need for chronic treatment.”
Cutler et al. first reviewed the preclinical and clinical data that validate the association between depression and “diverse defects” in the GABAergic system of neurotransmission. In both preclinical and clinical data, decreased levels of GABA and neuroactive steroids (NASs) have been documented in adults with depression versus healthy controls. Further, these studies have shown that antidepressant treatment “normalized the altered levels of GABA and NASs.”
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Next, the authors reviewed approved or currently in clinical development treatment approaches for depression that target dysregulated GABAergic neurotransmission. Brexanolone, an intravenous NAS and a GABAA receptor positive allosteric modulator (PAM), is approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors.
The authors concluded their review with a discussion of how NAS GABAA receptor PAMs may fulfill the “unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.”
“Although the placebo effect in depression may be a factor associated with failure to establish efficacy of novel treatments in clinical trials, data reviewed here indicate that NAS GABAA receptor PAMs may potentially offer rapid and sustained antidepressant benefits for individuals with MDD,” Cutler et al. noted. “Further research is necessary to better understand the role of NAS GABAA receptor PAMs in MDD.”
This review article was published in an open access format and is available to read in full online.
Editor’s Note: The FDA approved zuranolone in August 2023 for postpartum depression, but rejected the medication for MDD treatment, arguing that the application for approval from Sage Therapeutics and Biogen did not provide “substantial evidence of effectiveness.”
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