Augmentation with glutamatergic modulators for schizophrenia: A network meta-analysis

This network meta-analysis evaluated the effects of glutamatergic modulators as augmentation treatments on schizophrenia. A systematic search of PubMed, Embase, Cochrane Library, and PsycInfo for randomized controlled trials was conducted until January 2025. A random-effects network meta-analysis was performed within a frequentist framework, and the certainty of evidence was evaluated using the GRADE approach. A total of 148 randomized controlled trials and 12,339 patients were included. Among add-on glutamatergic modulators with moderate to high certainty of benefit over placebo, piracetam 2400–4800 mg/day showed the greatest improvement in total psychopathology (standardized mean differences [SMD] −0.94, 95 % confidence interval [CI] −1.47 to −0.41), benzoate 1000–2000 mg/day was most effective for positive symptoms (SMD −0.43, 95 % CI −0.71 to −0.16), memantine 5–20 mg/day ranked highest for negative symptom reduction (SMD −0.64, 95 % CI −0.85 to −0.43), and the combination of sarcosine 2000 mg/day and benzoate 1000 mg/day showed the greatest enhancement in global cognitive function (SMD 1.08, 95 % CI 0.45 to 1.71). Other agents, including d-serine 2000–4000 mg/day, evenamide 30–60 mg/day, iclepertine 10–25 mg/day, lamotrigine, luvadaxistat 50 mg/day, minocycline 100–300 mg/day, N-acetylcysteine 2000 mg/day, sarcosine 2000 mg/day, and topiramate demonstrated benefits with moderate to high certainty in one or more domains. Notably, memantine, N-acetylcysteine, and sarcosine exhibited efficacy across multiple outcome domains. The effects of some novel agents within specific dose ranges on cognitive function improvement were also observed.