Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis
Ben Carter, Rebecca Strawbridge, Muhammad Ishrat Husain, Brett D. M. Jones, Roxanna Short, Anthony J. Cleare, Dimosthenis Tsapekos, Fiona Patrick, Lindsey Marwood, R. Taylor, Tim Mantingh, Valeria de Angel, Viktoriya L. Nikolova, André F. Carvalho, Allan H. Young
International Review of Psychiatry June 5, 2020 DOI: 10.1080/09540261.2020.1765748 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and network meta-analysis Randomized Peer reviewed |
|---|---|
| Population | Adults meeting common clinical criteria for treatment-resistant depression |
| Interventions | antipsychotics mood stabilizers NMDA-targeting medications |
| Topics | Depression |
| Keywords | Meta-analysis Placebo Depression economics Clinical trial Randomized controlled trial Psychological intervention Mood Systematic review Medline Alternative medicine |
| Citations | 45 |
| Key findings | NMDA-targeting medications are markedly superior to placebo and have the highest chance of being an effective augmentation treatment for treatment-resistant depression. |
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.
Comparable studies
Other systematic reviews and meta-analyses on depression, most cited first.
Citations in the library
Cited by 5
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials. Neuropsychopharmacology May 1, 2025
- Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial BJPsych Open July 1, 2023
- Effectiveness of mindfulness based interventions in reducing depressive symptoms across mental disorders: A meta-analysis of randomized controlled trials. Psychiatry Research June 1, 2025
- Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence. The World Journal of Biological Psychiatry January 22, 2026
Cites 4
- A Randomized Controlled Trial of Mindfulness-Based Cognitive Therapy for Treatment-Resistant Depression Psychotherapy and Psychosomatics 2016
- Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. Journal of Affective Disorders 2019
- Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study The British Journal of Psychiatry September 24, 2018
- Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression. Neuropsychopharmacology December 2017