Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis

Abstract

Objective: Major depressive disorder (MDD) affects about 10–15% of the general population in a lifetime. A considerable number of patients fail to achieve full symptom remission despite adequate treatment and are considered treatment resistant (TRD). The current study compared the relative efficacy and tolerability of pharmacological and somatic TRD interventions by means of a Bayesian network meta-analysis.

Research design and methods: An electronic literature search of MEDLINE, MEDLINE In-Process, EMBASE, PsycInfo, EconLit and Cochrane Library databases for trials published between September 2003 and September 2014 was conducted. Key outcomes extracted were disease severity change from baseline, response and remission rates at various timepoints and discontinuation due to adverse events.

Results: Of the 3876 abstracts identified, 31 publications/randomised controlled trials (RCTs) were included in the analysis; 19 RCTs investigating 13 pharmacological interventions and 12 RCTs investigating electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). The evidence synthesis investigating efficacy outcomes of TRD treatments demonstrated superior efficacy for ketamine compared to pharmacological and somatic interventions at 2 weeks after treatment initiation. At 4, 6 and 8 weeks, quetiapine augmentation (800 mg/day) and risperidone augmentation were found to be the first and second best treatments, respectively. Networks were small for response rate and remission rate outcomes at most timepoints. The most tolerable treatment was lamotrigine augmentation showing a comparable profile to placebo/sham.

Conclusions: This analysis revealed scarcity of long-term data on sustained remission that would allow a comparative long-term efficacy assessment. Key limitations of the analysis can be considered the search timeframe and the use of mapping formula for the depression scores.

Keywords:

• Antidepressant effect
• Bayesian hierarchical model
• Disease severity
• Network meta-analysis
• Ranking
• Treatment-resistant depression

Transparency

Declaration of funding

This study was conducted by Mapi on behalf of Janssen Pharmaceutica NV who funded the study and the writing of this manuscript.

Author contributions: All authors were involved in defining the scope of the project. K.P., C.V. and A.K. conducted the systematic review and analyzed the data. C.K. and N.K. contributed material. K.P., C.V. and A.K. wrote the manuscript and C.D. and N.K. were involved in critical revision and final approval of the manuscript.

Christina Donatti^b

Nicole Kubitz^c

Declaration of financial/other relationships

K.P., C.V. and A.K. have disclosed that they are employees of Mapi and served as paid consultants to Janssen Pharmaceutica NV during the conduct of this study and the preparation of this manuscript. CD is an employee of Janssen UK, High Wycombe, UK and NK an employee of Janssen-Cilag GmbH, Neuss, Germany.

CMRO peer reviewer 1 has disclosed that he has been a recipient of grants or research funding from Servier and Eli Lilly; has been a consultant or advisor to Servier, Eli Lilly, AstraZeneca, sanofi aventis, Jannsen-Cilag and Lundbeck; and has been a member of the speakers bureau for Bristol Myers Squibb, Eli Lilly, Lundbeck and AstraZeneca. CMRO peer reviewer 2 has no relevant financial or other relationships to disclose.

Acknowledgements

The authors would like to thank the reviewers for their valuable comments.