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Interventions for negative symptoms in schizophrenia : efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials

Damiani, Stefano ; Stefanelli, Riccardo ; Fortea, Lydia ; D'Imperio, Aldo LU orcid ; Calò, Matteo ; Casarini, Francesco ; Crippa, Andrea ; Esposito, Cecilia Maria ; Leggi, Roberto and Orlandi, Marika , et al. (2026) In Molecular Psychiatry p.1-11
Abstract

Negative symptoms (avolition, anhedonia, asociality, blunted affect, and alogia) are among the most disabling features of schizophrenia spectrum disorders. 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., 'other pharmacological agents' divided in 14 subcategories including... (More)

Negative symptoms (avolition, anhedonia, asociality, blunted affect, and alogia) are among the most disabling features of schizophrenia spectrum disorders. 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., 'other pharmacological agents' 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 = 42566). The clinically meaningful threshold, obtained from 122 trials reporting CGI-S, was SMD ≥ 0.457. In 214 high-quality studies (n = 19746), 2 category-by-follow-up combinations and 16 subcategories showed significant improvements. Clinically meaningful SMDs for subcategories were antibiotics (0.95; CI: 0.18-1.71; moderate-GRADE), integrated psychosocial interventions (0.93; CI: 0.53-1.33; very-low-GRADE), antidepressants (0.76; CI: 0.33-1.19; moderate-GRADE), physical activity (0.68; CI: 0.39-0.96; very-low-GRADE), transcranial current stimulation (0.52; CI: 0.17-0.86; low-GRADE), and immunomodulators (0.47; CI: 0.26-0.67; 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.

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publishing date
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Contribution to journal
publication status
epub
subject
in
Molecular Psychiatry
pages
1 - 11
publisher
Springer Nature
external identifiers
  • pmid:41872518
  • scopus:105034342879
ISSN
1359-4184
DOI
10.1038/s41380-026-03543-1
language
English
LU publication?
yes
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© 2026. The Author(s).
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377df057-e772-4013-9ede-cae076e5c2da
date added to LUP
2026-03-27 00:24:56
date last changed
2026-06-03 16:26:47
@article{377df057-e772-4013-9ede-cae076e5c2da,
  abstract     = {{<p>Negative symptoms (avolition, anhedonia, asociality, blunted affect, and alogia) are among the most disabling features of schizophrenia spectrum disorders. 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., 'other pharmacological agents' 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 = 42566). The clinically meaningful threshold, obtained from 122 trials reporting CGI-S, was SMD ≥ 0.457. In 214 high-quality studies (n = 19746), 2 category-by-follow-up combinations and 16 subcategories showed significant improvements. Clinically meaningful SMDs for subcategories were antibiotics (0.95; CI: 0.18-1.71; moderate-GRADE), integrated psychosocial interventions (0.93; CI: 0.53-1.33; very-low-GRADE), antidepressants (0.76; CI: 0.33-1.19; moderate-GRADE), physical activity (0.68; CI: 0.39-0.96; very-low-GRADE), transcranial current stimulation (0.52; CI: 0.17-0.86; low-GRADE), and immunomodulators (0.47; CI: 0.26-0.67; 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.</p>}},
  author       = {{Damiani, Stefano and Stefanelli, Riccardo and Fortea, Lydia and D'Imperio, Aldo and Calò, Matteo and Casarini, Francesco and Crippa, Andrea and Esposito, Cecilia Maria and Leggi, Roberto and Orlandi, Marika and Patron, Sara and Peviani, Alessandro and Piccolo, Alessandro and Provenzani, Umberto and Santilli, Fabrizio and Spallarossa, Cecilia and Papanastasiou, Evangelos and Cella, Matteo and Patel, Rashmi and Solmi, Marco and Galderisi, Silvana and Leucht, Stefan and Stahl, Daniel and Radua, Joaquim and Fusar-Poli, Paolo}},
  issn         = {{1359-4184}},
  language     = {{eng}},
  month        = {{03}},
  pages        = {{1--11}},
  publisher    = {{Springer Nature}},
  series       = {{Molecular Psychiatry}},
  title        = {{Interventions for negative symptoms in schizophrenia : efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials}},
  url          = {{http://dx.doi.org/10.1038/s41380-026-03543-1}},
  doi          = {{10.1038/s41380-026-03543-1}},
  year         = {{2026}},
}