Abstract
<jats:p>Abstract Background Negative symptoms are persistent determinants of disability in schizophrenia and often respond incompletely to antipsychotic treatment. Objective To compare the efficacy of pharmacological and non-pharmacological add-on treatments for prominent or persistent negative symptoms using network meta-analysis. Methods This systematic review followed PRISMA 2020 and PRISMA-NMA and was registered in PROSPERO (CRD420261422218). PubMed, Europe PMC, Semantic Scholar and Crossref were searched from inception to 29 July 2026, supplemented by citation chasing. Eligible studies were randomized controlled trials in adults with DSM/ICD schizophrenia or schizoaffective disorder, prominent or persistent negative symptoms, stable antipsychotic treatment and an adjunctive intervention. Outcomes were Positive and Negative Syndrome Scale negative subscale or Scale for the Assessment of Negative Symptoms scores. Random-effects frequentist networks estimated standardized mean differences (SMDs) with 95% confidence intervals (CIs); negative values favoured add-on treatment. Risk of bias was assessed with Cochrane RoB 2. Results Forty-nine unique RCTs met the clinical and design criteria, of which 28 (2,067 randomized; 1,933 analysable participants) contributed to the locked quantitative dataset. The primary connected network included 24 trials, 25 treatments and 31 comparison estimates. Fourteen add-ons had CIs excluding the null versus a broad control node. The highest P-scores were observed for mirtazapine (SMD −2.38, 95% CI −3.55 to −1.21), granisetron (−1.96, −2.74 to −1.17), tropisetron (−1.82, −2.59 to −1.05), minocycline (−1.78, −2.55 to −1.01) and memantine (−1.54, −2.28 to −0.80). Heterogeneity was low (τ = 0.119; τ2= 0.014), but the predominantly star-shaped network had zero inconsistency degrees of freedom. Overall RoB 2 judgements were low for eight trials, some concerns for 15 and high for five. Conclusions Several pharmacological and non-pharmacological add-ons showed potentially important efficacy signals. Because most nodes were informed by single small trials, direct active comparisons were scarce, inconsistency could not be evaluated and risk-of-bias concerns were common, the treatment hierarchy should be considered hypothesis-generating rather than a basis for firm clinical recommendations. Registration: PROSPERO CRD420261422218 Keywords: schizophrenia; negative symptoms; adjunctive treatment; network meta-analysis; randomized controlled trial; neurostimulation Key Points This review compares pharmacological and non-pharmacological adjuncts in adults selected for prominent or persistent negative symptoms while receiving stable antipsychotic medication. Mirtazapine, granisetron, tropisetron, minocycline and memantine had the highest P-scores, while tDCS, rTMS and body-oriented psychotherapy also showed efficacy signals versus broad control. The evidence network was sparse and star-shaped, most interventions were supported by one small trial, and inconsistency was not estimable; rankings therefore require cautious interpretation.</jats:p>