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Psych Congress NetworkGABAergic Deficit Hypothesis Offers New Framework to Reinvigorate MDD Treatment, Experts Say in Review Article

Shifting Focus from Monoamine to GABAergic Deficit Hypothesis Could Change How You Treat Depression

As traditional treatments for major depressive disorder (MDD) show limitations in effectiveness, a new review article advocates for pivoting towards the GABAergic (gamma-aminobutyric acid) deficit hypothesis as a new framework for MDD treatment strategies. Authored by noted experts in the field, the paper delves into both preclinical and clinical data to validate the GABAergic system’s role in depression and discusses the potential of neuroactive steroids (NASs) to fulfill unmet treatment needs.

HCN Medical Memo
Physicians should be aware that, although traditional monoamine-based treatments for MDD have limitations, the GABAergic deficit hypothesis offers new avenues for effective treatment. Considering the promising data on NAS GABAA receptor PAMs, it may be worthwhile to stay updated on the latest research and approved therapies that target the GABAergic system for treating depression.

Key Points:
  • Authors Andrew J. Cutler, MD; Gregory W. Mattingly, MD; and Vladimir Maletic, MD highlight the shortcomings of standard-of-care antidepressants like slow onset of effects and low response rates.
  • The review examines the association between depression and “diverse defects” in the GABAergic system, revealing decreased levels of GABA and NASs in adults with depression.
  • Brexanolone, an FDA-approved treatment for postpartum depression, is cited as an example of a NAS GABAA receptor positive allosteric modulator (PAM) that could offer rapid and sustained antidepressant effects.

“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.”
– Authors of the Review

Additional Points:
  • The FDA recently approved zuranolone for postpartum depression but rejected its application for MDD treatment due to insufficient evidence.
  • Further research is necessary to better understand the role of NAS GABAA receptor PAMs in MDD treatment.

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