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

Stefano Damiani; Riccardo Stefanelli; Lydia Fortea; Aldo D'Imperio; Matteo Calò; Francesco Casarini; Andrea Crippa; Cecilia Maria Esposito; Roberto Leggi; Marika Orlandi; Sara Patron; Alessandro Peviani; Alessandro Piccolo; Umberto Provenzani; Fabrizio Santilli; Cecilia Spallarossa; Evangelos Papanastasiou; Matteo Cella; Rashmi Patel; Marco Solmi; Silvana Galderisi; Stefan Leucht; Daniel Stahl; Joaquim Radua; Paolo Fusar-Poli

doi:10.1038/s41380-026-03543-1

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

Stefano Damiani
, Riccardo Stefanelli
, Lydia Fortea
, Aldo D'Imperio
, Matteo Calò
, Francesco Casarini
, Andrea Crippa
, Cecilia Maria Esposito
, Roberto Leggi
, Marika Orlandi
, Sara Patron
, Alessandro Peviani
, Alessandro Piccolo
, Umberto Provenzani
, Fabrizio Santilli
, Cecilia Spallarossa
, Evangelos Papanastasiou
, Matteo Cella
, Rashmi Patel
, Marco Solmi

Silvana Galderisi, Stefan Leucht, Daniel Stahl, Joaquim Radua, Paolo Fusar-Poli

University of Pavia
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
HMNC Brain Health
South London and Maudsley NHS Foundation Trust
King's College London
University of Cambridge
University of Ottawa
University of Campania Luigi Vanvitelli
Univ Munich, University of Munich, Klinikum Grosshadern

Research output: Contribution to journal › Review article › peer-review

3 Citations (Scopus)

16 Downloads (Pure)

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 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.

Original language	English
Pages (from-to)	4259-4269
Number of pages	11
Journal	Molecular Psychiatry
Volume	31
Issue number	8
Early online date	23 Mar 2026
DOIs	https://doi.org/10.1038/s41380-026-03543-1
Publication status	Published - Aug 2026

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Damiani, S., Stefanelli, R., Fortea, L., D'Imperio, A., Calò, M., Casarini, F., Crippa, A., Esposito, C. M., Leggi, R., Orlandi, M., Patron, S., Peviani, A., Piccolo, A., Provenzani, U., Santilli, F., Spallarossa, C., Papanastasiou, E., Cella, M., Patel, R., ... Fusar-Poli, P. (2026). Interventions for negative symptoms in schizophrenia: efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials. Molecular Psychiatry, 31(8), 4259-4269. https://doi.org/10.1038/s41380-026-03543-1

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

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 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.",

author = "Stefano Damiani and Riccardo Stefanelli and Lydia Fortea and Aldo D'Imperio and Matteo Cal{\`o} and Francesco Casarini and Andrea Crippa and Esposito, \{Cecilia Maria\} and Roberto Leggi and Marika Orlandi and Sara Patron and Alessandro Peviani and Alessandro Piccolo and Umberto Provenzani and Fabrizio Santilli and Cecilia Spallarossa and Evangelos Papanastasiou and Matteo Cella and Rashmi Patel and Marco Solmi and Silvana Galderisi and Stefan Leucht and Daniel Stahl and Joaquim Radua and Paolo Fusar-Poli",

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year = "2026",

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doi = "10.1038/s41380-026-03543-1",

language = "English",

volume = "31",

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Damiani, S, Stefanelli, R, Fortea, L, D'Imperio, A, Calò, M, Casarini, F, Crippa, A, Esposito, CM, Leggi, R, Orlandi, M, Patron, S, Peviani, A, Piccolo, A, Provenzani, U, Santilli, F, Spallarossa, C, Papanastasiou, E, Cella, M, Patel, R, Solmi, M, Galderisi, S, Leucht, S, Stahl, D, Radua, J & Fusar-Poli, P 2026, 'Interventions for negative symptoms in schizophrenia: efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials', Molecular Psychiatry, vol. 31, no. 8, pp. 4259-4269. https://doi.org/10.1038/s41380-026-03543-1

TY - JOUR

T1 - Interventions for negative symptoms in schizophrenia

T2 - efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials

AU - Damiani, Stefano

AU - Stefanelli, Riccardo

AU - Fortea, Lydia

AU - D'Imperio, Aldo

AU - Calò, Matteo

AU - Casarini, Francesco

AU - Crippa, Andrea

AU - Esposito, Cecilia Maria

AU - Leggi, Roberto

AU - Orlandi, Marika

AU - Patron, Sara

AU - Peviani, Alessandro

AU - Piccolo, Alessandro

AU - Provenzani, Umberto

AU - Santilli, Fabrizio

AU - Spallarossa, Cecilia

AU - Papanastasiou, Evangelos

AU - Cella, Matteo

AU - Patel, Rashmi

AU - Solmi, Marco

AU - Galderisi, Silvana

AU - Leucht, Stefan

AU - Stahl, Daniel

AU - Radua, Joaquim

AU - Fusar-Poli, Paolo

PY - 2026/8

Y1 - 2026/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105034342879

U2 - 10.1038/s41380-026-03543-1

DO - 10.1038/s41380-026-03543-1

M3 - Review article

C2 - 41872518

SN - 1359-4184

VL - 31

SP - 4259

EP - 4269

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 8

ER -

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

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