Meta-analysis finds mGluR modulators show no significant efficacy for schizophrenia symptoms
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Key Takeaway
Note: mGluR modulators show no significant efficacy for schizophrenia symptoms in current evidence.
This meta-analysis of 10 randomized controlled trials evaluated the efficacy and safety of metabotropic glutamate receptor (mGluR) agonists and positive allosteric modulators—specifically pomaglumetad methionil (POMA) and AZD8529—in 3715 participants with schizophrenia. The primary outcome was change in PANSS-Total score, with secondary outcomes including PANSS subscales, Clinical Global Impressions-Severity (CGI-S), treatment-emergent adverse events, and discontinuation rates. The analysis compared these experimental agents against placebo or second-generation antipsychotics (SGAs).
The main results showed no significant improvement in PANSS-Total score for mGluR modulators compared to control (MD: 3.20; 95% CI: 0.64, 5.76). Similarly, there was no significant improvement on PANSS subscales or CGI-S. Discontinuation due to lack of efficacy was not significantly different between groups (OR: 1.24; 95% CI: 0.86, 1.77).
Regarding safety, the incidence of treatment-emergent adverse events was statistically nonsignificant in the experimental group (OR: 1.08; 95% CI: 0.93, 1.27). However, discontinuation due to adverse events was significantly higher in the experimental group (OR: 1.43; 95% CI: 1.08, 1.89). Key limitations were not reported, and the certainty of evidence ranged from high to low. The findings indicate that, based on current evidence, mGluR modulators do not demonstrate efficacy for improving symptom severity in schizophrenia and are associated with higher discontinuation due to adverse events.
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View Original Abstract ↓
OBJECTIVE: Metabotropic glutamate receptor(mGluR) agonists and allosteric modulators like pomaglumetad methionil(POMA) and AZD8529 offer a novel pharmacotherapeutic option in schizophrenia. The results of individual trials on these agents being inconclusive, this meta-analysis was planned to assess the safety and efficacy of mGluR modulators in schizophrenia.
METHODS: Following PRISMA guidelines, a systematic search was performed on MEDLINE/PubMed, Embase, Web of Science, Scopus, Cochrane, Google Scholar and WHO-ICTRP, and randomized controlled trials(RCTs) that compared POMA or AZD8529 with either a placebo or second-generation antipsychotics(SGAs) were included. Change in PANSS-Total score was the primary outcome, and PANSS subscales, Clinical Global Impressions-Severity(CGI-S), treatment-emergent adverse events(TEAE) and discontinuation rates were secondary outcomes. A random-effects model was used to estimate the effect size for pairwise and network meta-analysis, and the risk of bias done by RoB2 tool.
RESULTS: A total of ten RCTs (3715 participants) were included in the meta-analysis. mGluR modulators did not show significant improvement in PANSS-T (MD:3.20,95 %CI:0.64,5.76) or PANSS-subscales and CGI-S over the control group. The pooled odds ratio for TEAE (OR:1.08; 95 %CI:0.93,1.27) indicates a statistically nonsignificant incidence of adverse events in the experimental group. Discontinuation due to adverse events was higher in the experimental group (OR:1.43; 95 %CI:1.08,1.89), but discontinuation due to lack of efficacy was not significantly different between the groups (OR:1.24,95 %CI:0.86,1.77). Certainty of evidence ranged from high to low. None of the mGluR modulators were better than placebo or SGAs in network meta-analysis.
CONCLUSION: mGluR modulators did not show efficacy in terms of improving symptom severity in schizophrenia. However, their therapeutic potential in specific subgroups may be explored by employing strategic trial designs and relevant biomarkers.
PROSPERO ID: CRD420251066533.
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