esketamine in treatment resistant depression

Treatment-resistant depression (TRD) refers to major depressive disorder (MDD) in which an individual does not achieve an adequate response despite receiving at least two different antidepressant medications at appropriate doses and for a sufficient duration (1):

• while there is no universally accepted definition of appropriate dosage and treatment duration, TRD is generally diagnosed when a patient shows less than a 50% improvement in depressive symptoms after four weeks of optimal treatment with at least two different prescribed antidepressants

Esketamine in TRD (1)

• esketamine is the S-enantiomer of ketamine
• exerts its antidepressant effects primarily through non-selective, noncompetitive antagonism of NMDA receptors, a subtype of ionotropic glutamate receptors
  • by blocking these receptors, esketamine indirectly triggers a temporary surge in glutamate levels, which in turn stimulates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors
    • this cascade enhances neurotrophic signalling and promotes synaptogenesis in brain regions responsible for mood regulation and emotional processing
  • esketamine is also believed to restore dopaminergic activity in motivation and reward-related brain circuits, contributing to its rapid therapeutic effects, such as alleviating anhedonia
  • its fast onset may also involve activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which plays a key role in protein synthesis and supports brain-derived neurotrophic factor (BDNF) production, further enhancing synaptic connectivity and plasticity
• in 2019, the US Food and Drug Administration approved esketamine nasal spray in conjunction with an oral antidepressant for patients with TRD
• a 2025 systematic review concluded “..Despite promising results, the available evidence for esketamine monotherapy in TRD remains limited..” (1)
• the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD was evaluated in a study by Janik et al:
  • the study authors conluded that “..esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants..”
• a review noted “..(es)ketamine may be appropriate for selected patients where rapid benefit is a priority and service infrastructure allows safe delivery and monitoring…” (3)

Reference:

1. Bhavya, Shetty S, Sadasivam B. A New Era for Esketamine in Managing Treatment-Resistant Depression: A Systematic Review of Its Use From Adjunct to First-Line Therapy. Cureus. 2025 Sep 8;17(9):e91829.
2. Janik A et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2025 Sep 1;82(9):877-887.
3. Strawbridge R, Nikolova VL, Browning M, et al. Pharmacological augmentation for people with treatment-resistant depression. The British Journal of Psychiatry. Published online 2026:1-2.