Decoglurant well-tolerated but may not produce antidepressant effects

Decoglurant appeared well-tolerated but did not produce any antidepressant or procognitive effects among patients with partially refractory major depressive disorder, according to study results published in Journal of Clinical Psychiatry.

“While classic antidepressants mediate their effect primarily through monoamines, growing evidence supports the treatment of MDD through modulation of dysregulated glutamate neurotransmission,” Daniel Umbricht, MD, of Roche Pharmaceutical Research and Early Development in Switzerland, and colleagues wrote. “Of specific interest, as therapeutic targets in MDD, are the metabotropic glutamate receptor type 2 (mGlu₂) receptors — presynaptic autoinhibitory receptors that are highly expressed in the PFC, hippocampus, amygdala, and nucleus accumbens — with preclinical research suggesting that mGlu₂ antagonists have antidepressant and procognitive effects.”

One such antagonist, decoglurant (Roche), might restore normal glutamate transmission and reduce depressive and cognitive symptoms, the researchers hypothesized. Specifically, they sought to test it as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) among patients with partially refractory MDD according to DSM-IV-TR criteria. They conducted a randomized, placebo-controlled, double-blind, multicenter phase 2 trial that included 4 weeks of screening, 6 weeks of treatment and 8 weeks of follow-up. Inclusion criteria were Montgomery-Åsberg Depression Rating Scale (MADRS) score of 25 or greater and Clinical Global Impressions-Severity of Illness scale score of four or lower, as well as history of up to two adequate SSRI/SRNI trials and compliance confirmed by positive SSRI/SNRI blood levels. Umbricht and colleagues randomly assigned 101 participants to decoglurant 5 mg, 102 15 mg and 55 to 30 mg daily, and 99 to placebo, all in addition to ongoing treatment with one SSRI/SNRI. MADRS total score from baseline to end of treatment served as the primary outcome variable.

A total of 310 participants completed 6 weeks of treatment. Results showed no significant differences at 6 weeks between placebo and any active treatment arm in reducing MADRS total score or remission or response rates. Further, the researchers observed no significant effects of decoglurant on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores, nor on secondary functioning and mood measures. However, they did observe a relatively high placebo response, which may have limited efforts to detect treatment effects. Participants reported few serious adverse events, and no deaths occurred.

“Comparison of the placebo response rate to rates in studies with additional safeguards for patient selection suggests that improvements might be achieved by blinded, independent diagnosis of treatment-resistant MDD and assessment of the appropriateness of adjunctive treatment to SSRI/SNRI therapy as well as prospective testing of treatment nonresponse to background therapy before administration of study drug,” the researchers wrote. “A double- or single-blind placebo run-in period may also be beneficial. Nonetheless, while it is clear that the aforementioned improvements should be implemented for future trials, the absence of any signal of a treatment effect in our study across multiple endpoints in the subgroup analyses supports our conclusion that decoglurant does not exert any antidepressant effects.”