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In the absence of treatment consensus guidelines, this PRISMA-compliant meta-analysis (PROSPERO: CRD42024613967) evaluated efficacy and clinical significance of interventions targeting this dimension. Web of Science\/PsycInfo databases were searched from inception to December 2024. Five categories (antipsychotics, other pharmacological agents, brain stimulation, psychosocial, and lifestyle interventions) were analyzed across short\/middle\/long follow-up times. Categories were divided into 27 subcategories (e.g., \u2018other pharmacological agents\u2019 divided in 14 subcategories including antidepressants, antibiotics, immunomodulators) regardless of follow-up, assessing evidence with GRADE criteria. The primary outcome was the change in negative symptom severity, measured with validated scales (PANSS\/SANS\/BPRS\/CAINS\/BNSS) as standardized mean differences (SMD). A clinically meaningful SMD threshold was estimated from the regression between SMD and one-point reductions on the Clinical Global Impression-Severity (CGI-S) scale. This study meta-analyzed 451 trials (n\u2009=\u200942566). The clinically meaningful threshold, obtained from 122 trials reporting CGI-S, was SMD\u2009\u2265\u20090.457. In 214 high-quality studies (n\u2009=\u200919746), 2 category-by-follow-up combinations and 16 subcategories showed significant improvements. Clinically meaningful SMDs for subcategories were antibiotics (0.95; CI: 0.18\u20131.71; moderate-GRADE), integrated psychosocial interventions (0.93; CI: 0.53\u20131.33; very-low-GRADE), antidepressants (0.76; CI: 0.33\u20131.19; moderate-GRADE), physical activity (0.68; CI: 0.39\u20130.96; very-low-GRADE), transcranial current stimulation (0.52; CI: 0.17\u20130.86; low-GRADE), and immunomodulators (0.47; CI: 0.26\u20130.67; high-GRADE), typically as adjuncts to antipsychotics. Heterogeneity was the main limitation. While selected interventions may yield meaningful improvements, more rigorous designs are needed to identify reliable, personalized and scalable treatment options.<\/jats:p>","DOI":"10.1038\/s41380-026-03543-1","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:25:02Z","timestamp":1774275902000},"page":"4259-4269","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Interventions for negative symptoms in schizophrenia: efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled 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