Therapeutic benefits of pharmacologic and nonpharmacologic treatments for depressive symptoms after traumatic brain injury: a systematic review and network meta-analysis

Therapeutic benefits of pharmacologic and nonpharmacologic treatments for depressive symptoms after traumatic brain injury: a systematic review and network meta-analysis

J Psychiatry Neurosci 2021;46(1):E196-E207 | PDF | Appendix

Yu-Shian Cheng, MD*; Ping-Tao Tseng, MD*; Yi-Cheng Wu, MD; Yu-Kang Tu, MD; Ching-Kuan Wu, MD; Chih-Wei Hsu, MD; Wei-Te Lei, MD; Dian-Jeng Li, MD; Tien-Yu Chen, MD; Brendon Stubbs, MD; Andre F. Carvalho, MD; Chih-Sung Liang, MD; Ta-Chuan Yeh, MD; Che-Sheng Chu, MD; Yen-Wen Chen, MD; Pao-Yen Lin, MD; Ming-Kung Wu, MD†; Cheuk-Kwan Sun, MD, PhD†

Background: Depression is a common morbidity after traumatic brain injury. This network meta-analysis investigated the efficacy and tolerability of pharmacologic and nonpharmacologic interventions for depression after traumatic brain injury.

Methods: We extracted randomized controlled trials examining pharmacologic or nonpharmacologic interventions with placebo- or active-controlled designs from PubMed, the Cochrane Library and ScienceDirect, from inception to October 30, 2018. We based study selection and extraction of a predefined list of variables on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, and conducted meta-analysis procedures using random effects modelling. Primary outcomes were changes in depressive symptom severity after pharmacologic or nonpharmacologic treatment; the secondary outcome was tolerability, reflected in overall patient dropout rates.

Results: Our analysis of 27 randomized controlled trials (10 pharmacologic, total n = 483, mean age = 37.9 yr; 17 nonpharmacologic, total n = 1083, mean age = 38.0 yr) showed that methylphenidate had significantly superior efficacy compared to placebo or control (standardized mean difference –0.91, 95% confidence interval [CI] –1.49 to –0.33). Sertraline was associated with significantly lower tolerability (i.e., a higher dropout rate) compared to placebo or control (odds ratio 2.65, 95% CI 1.27 to 5.54). No nonpharmacologic treatment was more effective than the others, and we found no significant differences in tolerability (i.e., dropout rates) among the nonpharmacologic treatments.

Limitations: Heterogeneity in participant characteristics (e.g., comorbidities), study designs (e.g., trial duration) and psychopathology assessment tools, as well as small trial numbers for some treatment arms, could have been confounders.

Conclusion: The present network meta-analysis suggests that methylphenidate might be the best pharmacologic intervention for depressive symptoms related to traumatic brain injury. None of the nonpharmacologic interventions was associated with better improvement in depressive symptoms than the others or than control conditions. None of the pharmacologic or nonpharmacologic treatments had inferior tolerability compared to placebo or controls except for sertraline, which had significantly lower tolerability than placebo.


*These authors contributed equally to this work.

†These authors contributed equally to this work.

Submitted Jun. 26, 2019; Revised Jul. 19, 2020; Accepted Sep. 4, 2020

Affiliations: From the Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Kaohsiung, Taiwan (Cheng, Wu); the Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung City, Taiwan (Cheng, Tseng); the WinShine Clinics in Specialty of Psychiatry, Kaohsiung, Taiwan (Tseng); the Prospect Clinic for Otorhinolaryngology & Neurology (Tseng, Chen); the Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan (Wu); the Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (Tu); the Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan (Hsu, Wu, Lin); the Division of Allergy, Immunology, Rheumatology Disease, Department of Pediatrics, Mackay Memorial Hospital, Hsinchu, Taiwan (Lei); the Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Lei Taiwan (Li); the Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan (Li); the Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Chen); the Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan (Chen); the Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK (Stubbs); Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, De Crespigny Park, London, UK (Stubbs); the Department of Psychiatry, University of Toronto, Toronto, ON (Carvalho); the Centre for Addiction & Mental Health (CAMH), Toronto, ON (Carvalho); the Department of Psychiatry, Beitou branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Liang); the Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan (Liang); the Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan (Yeh); the Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan (Chu); the Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Chu); the Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (Lin); the Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan (Wu); the Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan (Sun); the I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (Sun).

Competing interests: None declared.

Contributors: Y.-S. Cheng, P.-T. Tseng, M.-K.Wu and C.-K. Sun designed the study and acquired the data, which all authors analyzed. Y.-S. Cheng, P.-T. Tseng, M.-K. Wu and C.-K. Sun wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.190122

Correspondence to: C.K. Sun, Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan; lawrence.c.k.sun@gmail.com; ed105983@edah.org.tw