Novel Therapeutic Targets for Major Depressive Disorder: In Conversation With Ginger Shupe, MD

CONFERENCE REPORTER

Ginger Shupe, MD, presented on the role of NMDA antagonists in the treatment of major depressive disorder (MDD) at the 2025 Southern Florida Psychiatry Conference in West Palm Beach, MD. She sat down with Psychiatric Times for a conversation on how typical antidepressants may not be enough for every patient to achieve remission, particularly those with treatment-resistant depression (TRD).

As she shared in her presentation, Shupe believes we are witnessing a shift from monoamines to neuroplasticity-focused approaches. Monoaminergic treatments may take weeks to show effect; Glutamatergic agents, on the other hand, can provide rapid relief, particularly for patients who are suicidal or experiencing anhedonia.

NMDA overactivation leads to excitotoxicity in MDD, but NMDA antagonists act as a "circuit breaker," shared Shupe, by interrupting the flow and allowing the brain to reset.¹

She shared insights on the following agents:

• AXS-05 (dextromethorphan-bupropion), which is FDA-approved for MDD
• Ketamine off-label IV use, which is not FDA-approved
• Esketamine, which is FDA-approved for TRD and MDD with suicidality
• In her presentation, Shupe also offered attendees her clinical pearls on each of these agents:
• AXS-05 is well tolerated and the ideal choice for patients who are open to a novel oral agent but may not yet meet the threshold for ketamine or esketamine.
• Ketamine is a good option for patients with severe anhedonia who have not responded to traditional treatments, as it has a rapid effect on motivation and pleasure.
• Esketamine can provide sustained effects and symptom relief to patients with intense suicidal thoughts.²

Shupe recommended letting the symptom profile and urgency guide the choice of agent.

Dr Shupe is the medical director of outpatient psychiatry at Larkin Community Hospital.

References

1. Krystal JH, Sanacora G, Blumberg H, et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002:7 Suppl 1:S71-80.

2. Fu DJ, Zhang Q, Shi L, et al. Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality. BMC Psychiatry. 2023;23(1):587.