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

Background: Like ketamine, group II metabotropic glutamate receptor (mGluR2/3) antagonists increase glutamate release and monoaminergic signaling, promote synaptic plasticity, and show antidepressant-related activity in preclinical models. A recent phase I trial of the orthosteric mGluR2/3 antagonist prodrug TS-161 established its safety, tolerability, and pharmacokinetic profile. Methods: This phase IIa randomized, placebo-controlled, double-blind, crossover, proof-of-concept, single-site trial was designed to evaluate the antidepressant effects of TS-161. Eleven unmedicated adults with treatment-resistant depression received either oral TS-161 (50 to 100 mg daily) or a placebo for 3 weeks before crossing over to the other condition. The study was halted early due to low recruitment. Results: Adverse events were mild and consistent with the prior phase I study. Linear mixed models using drug×time interaction to estimate mean Montgomery-Åsberg Depression Rating Scale scores per treatment identified no significant difference between treatment conditions at any timepoint, including the primary endpoint, day 21 ( P =0.91). One of the 11 participants responded to TS-161 by day 7 (vs. 0/9 receiving placebo); no participants achieved remission. Magnetic resonance spectroscopy suggested a qualitative trend for increased glutamate metabolite values, and TS-161 increased gamma power during magnetoencephalography relative to baseline and placebo (p FDR <0.01) in lateral cortical regions. Peripheral brain-derived neurotrophic factor levels trended toward elevation (overall drug effect P =0.055). No advantages were seen in secondary clinical or cognitive outcomes. Conclusions: The findings suggest potential central nervous system engagement through proxy biomarkers and increased glutamatergic tone, but this did not translate to clinical improvement.