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Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder

Published online by Cambridge University Press:  21 November 2018

Marco Solmi*
Department of Neurosciences, University of Padua, Padua, Italy Neuroscience Center, University of Padua, Padua, Italy
Michele Fornaro
Section of Psychiatry–Unit on Treatment Resistant Psychosis, and Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy New York State Psychiatric Institute (NYSPI), Columbia University, New York, New York
Kuniyoshi Toyoshima
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Andrè F. Carvalho
Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
Cristiano A. Köhler
Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
Nicola Veronese
National Research Council, Aging Section, Padua, Italy
Brendon Stubbs
Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, United Kingdom
Andrea de Bartolomeis
Section of Psychiatry–Unit on Treatment Resistant Psychosis, and Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy
Christoph U. Correll
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York Hofstra Northwell School of Medicine, Hempstead, New York Feinstein Institute for Medical Research, Manhasset, New York
*Address for correspondence: Marco Solmi, Department of Neurosciences, University of Padua, via Giustiniani, 2, 35128 Padua, Italy. (Email:



Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia.


We undertook a systematic review, searching PubMed/Scopus/ for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented.


We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10–1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=−1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in β-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone–mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6).


No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

© Cambridge University Press 2018 

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MS and MF contributed equally to the article. All authors contributed equally to all stages of the article preparation.

No funding was directly involved in this paper’s preparation.


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