The Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression: A Phase IIa...

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.

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.

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 (pFDR<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.

The findings suggest potential central nervous system engagement through proxy biomarkers and increased glutamatergic tone, but this did not translate to clinical improvement.