RESIDENT: Beyond the Infusion: Glutamatergic Strategies to Prolong Ketamine's Antidepressant Effects
Presenting Author(s): Kal Samarasinghe
Co-Author(s): Jennifer Swainson
Date and time: 21 Mar 2026 from 14:55 to 15:10
Location: Saddleback & Glacier
Learning Objectives
1. Identify major classes of glutamatergic agents studied as adjuncts to ketamine and summarize the current human evidence for each;
2. Explain the key components of ketamine's neuroplasticity cascade, including glutamate surge timing, AMPA activation, BDNF release, and mTOR signaling; and
3. Evaluate which adjunctive strategies may extend ketamine's antidepressant effects and why certain agents fail due to mechanistic interference with ketamine-induced plasticity.
Abstract
Background: Ketamine produces rapid antidepressant effects in treatment-resistant depression, yet benefits are short-lived and repeated dosing raises safety, cost, and tolerability concerns. Adjunctive glutamatergic strategies are being explored to extend ketamine's durability, but evidence is scattered and difficult to interpret clinically.
Objective: To synthesize current human data on glutamate-modulating agents used alongside ketamine and identify mechanistic principles that may determine which adjuncts meaningfully extend response.
Methods: A narrative review was conducted integrating recent clinical trials with mechanistic insights from preclinical studies. Agents were grouped by glutamatergic target (NMDA partial agonists/antagonists, glutamate release inhibitors, mTOR modulators, mood stabilizers, glycine-site agonists, mGlu receptor modulators, and AMPA potentiators). Emphasis was placed on alignment with ketamine's known plasticity cascade, including glutamate surge timing, AMPA engagement, BDNF release, and mTOR signaling.
Results: Most adjuncts, including memantine, riluzole, lamotrigine, and lithium, did not prolong ketamine's antidepressant effect and may suppress plasticity processes ketamine initiates. Two strategies show preliminary promise. First, the fixed-dose combination NRX-101 (D-cycloserine plus lurasidone) extended antidepressant and anti-suicidal effects, by supporting NMDA-AMPA-BDNF pathways without dampening early glutamate signaling. Second, low-dose rapamycin prolonged response up to two weeks, suggesting later-phase modulation of mTOR may stabilize ketamine-induced plasticity. Signals also support glycine-site agonists and mGlu2/3 antagonists as mechanistically synergistic.
Conclusion: Durability of ketamine's antidepressant response likely depends on selecting adjuncts that reinforce, rather than inhibit, the AMPA-BDNF-mTOR cascade and that are timed appropriately to ketamine's transient plasticity window. Mechanistically informed adjunct design represents a promising direction for improving the scalability of ketamine-based treatments.
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