Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis

Abstract

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most common clinical criteria for TRD. The NMA compared the intervention effectiveness of depressive symptoms for TRD augmentation. Of 36 included trials, 27 were suitable for inclusion in NMA, and no psychological trials could be included in the absence of a common comparator. Antipsychotics (13 trials), mood stabilizers (three trials), NMDA-targeting medications (five trials), and other mechanisms (3 trials) were compared against placebo. NMDA treatments were markedly superior to placebo (ES = 0.91, 95% CI 0.67 to 1.16) and head-to-head NMA suggested that NMDA therapies had the highest chance of being an effective treatment option compared to other pharmacological classes. This study provides the most comprehensive evidence of augmenters’ effectiveness for TRD, and our GRADE recommendations can be used to guide guidelines to optimize treatment choices. Although conclusions are limited by paucity of, and heterogeneity between, trials as well as inconsistent reports of treatment safety. This work supports the use of NMDA-targeting medications such as ketamine.

Keywords:

• Treatment resistant depression
• antipsychotics
• mood stabilisers
• NMDA antagonists
• network meta-analysis

Author contributions

BC, RS, MIH, AY drafted the protocol. BC, RS, AY contributed to the first draft of the manuscript. RS and BJ carried out the searches and obtained unpublished data from pharmaceutical companies. BC, RS contributed to the methodology and statistical analysis plan. AY was the senior author and is the guarantor for the review. All authors approved the final manuscript.

Disclosure statement

RS has received an honorarium for speaking from Lundbeck. AY has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen, in the last 3 years. AJC has in the last 3 years received honoraria for speaking from Lundbeck; honoraria for consulting from Livanova, Lundbeck and Janssen; sponsorship for conference attendance from Janssen; and research grant support from Protexin Probiotics.

Additional information

Funding

This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.  This study’s design, data management (collection, analysis and interpretation), writing of the report and decision to submit for publication were undertaken by the authors, entirely independent of the funder.