The Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression: A Phase IIa Proof-of-Concept Clinical Trial.
Mark D Kvarta, Mai Watanabe, Satoshi Ozaki et al.
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In 30 seconds
This phase IIa, randomized, placebo-controlled, double-blind crossover trial assessed oral TS-161 in 11 unmedicated adults with treatment-resistant depression. Participants received TS-161 (50 to 100 mg daily) and placebo for 3 weeks each; the single-site study stopped early because of low recruitment. Depression rating scores did not differ significantly between conditions at any timepoint, including day 21 (P =0.91). Biomarker findings suggested central nervous system engagement, but these were not accompanied by clinical improvement. Adverse events were mild and consistent with the prior phase I study.
Key findings
- There was no significant difference in depression rating scores between TS-161 and placebo at any timepoint, including day 21 (P =0.91).
- One of 11 participants responded to TS-161 by day 7, compared with 0/9 receiving placebo; no participants achieved remission.
- TS-161 increased gamma power relative to baseline and placebo in lateral cortical regions (p FDR <0.01), while other biomarker findings were suggestive or trends.
- Adverse events were mild and consistent with the prior phase I study.
Why it matters
The trial provides an early clinical test of a glutamatergic approach in treatment-resistant depression. Although biomarker changes suggest possible central nervous system engagement, the absence of a detectable clinical benefit means these signals should not be interpreted as evidence of antidepressant efficacy. The findings help distinguish target engagement from improvement in patient symptoms.
What to keep in mind
The single-site trial included only 11 participants and was halted early because of low recruitment, limiting its ability to detect clinical effects.