Potential of GABAergic Medications in MDD

Jason Kellogg, MD, discussed emerging pharmacological mechanisms in major depressive disorder (MDD) and postpartum depression, the challenge of psychedelic clinical trials, and barriers in opioid use disorder, in an interview with Gus Alva, MD, previewing his sessions at the Southern California Psychiatry Regional Meeting.

Kellogg identified glutamatergic agents as having the deepest evidentiary base among emerging mechanisms in MDD, citing the landmark 2000 study by Berman and colleagues as the origin of the current research wave and noting that the 26 years of subsequent investigation has yielded FDA approvals for both dextromethorphan-bupropion and esketamine.¹ He highlighted an investigational AMPA receptor-modulating compound by Neurocrine Biosciences as a particularly promising pipeline agent. On the basis of tolerability, Kellogg identified neuroactive steroids as especially compelling, citing brexanolone and zuranolone as well-tolerated and relatively fast-acting agents for postpartum depression, while acknowledging that bioavailability limitations—analogous to challenges in testosterone replacement therapy—remain a practical constraint.

Kellogg then addressed the methodological problem of functional unblinding in psilocybin trials, noting that participants reliably detect whether they have received the active compound due to psychoactive effects, precluding true placebo control. He outlined several proposed solutions: use of active comparators such as midazolam or niacin, or very low doses of the active compound itself to induce some expectancy without full psychoactive effect. He emphasized that the unblinding problem extends beyond the treatment session itself, potentially biasing self-report across the entire trial period.

On opioid use disorder, Kellogg argued that stigma and access remain the primary barriers to buprenorphine treatment, noting that while the elimination of the X-waiver in December 2022 was intended to increase prescribing, a Pennsylvania-based study found no significant increase in buprenorphine dispensing following the policy change.² He drew an analogy between addiction and diabetes to underscore that disease status does not eliminate personal responsibility for engaging with treatment, and that stigma reduction requires continued emphasis.

Dr Alva is a board-certified psychiatrist and the Mood Disorders Section Editor for Psychiatric Times.

Dr Kellogg is founder and chief executive officer of Progyny Clinics in Orange County, California.

References

1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.

2. Bilden RC, Roberts MS, Stein BD, et al. Examining the impact of eliminating the X waiver on buprenorphine dispensation in 63 counties in Pennsylvania. Subst Use Addctn J. 2025;46(3):503-509.