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September 8, 2026Journal of Clinical Psychopharmacology

The Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression

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Authors

MKMark D. KvartaMWMai WatanabeSOSatoshi Ozaki

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Overview

Randomized double-blind crossover trial finds no clinical benefit from mGlu2/3 antagonist TS-161 in treatment-resistant depression, suggesting target engagement fails to alleviate symptoms.

Key Points

  • To assess the antidepressant efficacy, safety, and central nervous system target engagement of the orthosteric mGlu2/3 receptor antagonist prodrug TS-161 in treatment-resistant depression.
  • Conducted a single-site, phase IIa randomized, placebo-controlled, double-blind, crossover trial in 11 unmedicated adults with treatment-resistant depression.
  • Participants were assigned to receive oral TS-161 (50 to 100 mg daily) or placebo for 3 weeks before crossing over to the alternate condition, though the trial was stopped early due to low recruitment.
  • Primary endpoint analysis using linear mixed models found no significant difference in Montgomery-Åsberg Depression Rating Scale scores between TS-161 and placebo across all timepoints, including day 21 (P = 0.91).
  • Response was observed in 1 of 11 participants on TS-161 by day 7 compared to 0 of 9 on placebo, with no participants achieving clinical remission.
  • Biomarker assessments demonstrated target engagement, showing increased lateral cortical gamma power via magnetoencephalography (pFDR < 0.01), a qualitative increase in glutamate metabolites on magnetic resonance spectroscopy, and a trend toward higher peripheral brain-derived neurotrophic factor (P = 0.055).

Cite This Study

Kvarta et al. (2026) studied this question.

synapsesocial.com/papers/6a9fd83b58e84d0ff5b47a3chttps://doi.org/10.1097/jcp.0000000000002246
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Also Consider

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