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Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials

Published online by Cambridge University Press:  30 September 2016

Marco Solmi*
Department of Neurosciences, University of Padova, Padova, Italy Institute for Clinical Research and Education in Medicine, I.R.E.M., Padua, Italy
Nicola Veronese
Institute for Clinical Research and Education in Medicine, I.R.E.M., Padua, Italy Department of Medicine—DIMED, Geriatrics Section, University of Padova, Padova, Italy
Leonardo Zaninotto
Institute for Clinical Research and Education in Medicine, I.R.E.M., Padua, Italy Department of Biomedical and Neuro-Motor Sciences, University of Bologna, Bologna, Italy
Marc L. M. van der Loos
Department of Psychiatry, Isala Klinieken, Location Sophia, Zwolle, the Netherlands
Keming Gao
Mood & Anxiety Clinic, Mood Disorders Program, Department of Psychiatry, Case Western Reserve University School of Medicine/University Hospitals Case Medical Center, Cleveland, Ohio, USA
Ayal Schaffer
Mood & Anxiety Disorders Program, Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
Catherine Reis
Mood & Anxiety Disorders Program, Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
Claus Normann
Department of Psychiatry and Psychotherapy, University Medical Center, Freiburg, Germany
Ion-George Anghelescu
Dr. Kurt Fontheim’s Hospital for Mental Health, Department of Psychiatry, Liebenburg, Lower Saxony, Germany
Christoph U. Correll
Institute for Clinical Research and Education in Medicine, I.R.E.M., Padua, Italy The Zucker Hillside Hospital, Psychiatry Research, North Shore—Long Island Jewish Health System, Glen Oaks, New York, USA Hofstra North Shore LIJ School of Medicine, Department of Psychiatry and Molecular medicine, Hempstead, New York, USA The Feinstein Institute for Medical Research, Manhasset, New York, USA Albert Einstein College of Medicine, Department of Psychiatry and Behavioral Sciences, Bronx, New York, USA
*Address for correspondence: Dr. Marco Solmi, Department of Neurosciences, University of Padua, Via Giustiniani, 2, 35128 Padova, Italy. (Email:



To meta-analytically summarize lamotrigine’s effectiveness and safety in unipolar and bipolar depression.


We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs).


Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine’s efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=–0.15, 95% CI=–0.27, –0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13–1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85–0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons.


Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.

Original Research
© Cambridge University Press 2016 

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