Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials.
Johan Saelens, Anna Gramser, Victoria Watzal, Carlos A. Zarate, Rupert Lanzenberger, Christoph Kraus
Neuropsychopharmacology May 1, 2025 DOI: 10.1038/s41386-024-02044-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and network meta-analysis Randomized Peer reviewed |
|---|---|
| Sample size | 10,285 |
| Population | Adults with depression who had not responded to at least two antidepressant trials, excluding those with bipolar or psychotic depression |
| Interventions | electroconvulsive therapy minocycline theta-burst stimulation repetitive transcranial magnetic stimulation ketamine aripiprazole |
| Topics | Depression |
| Keywords | Depression treatment Electroconvulsive therapy Mental health interventions Brain stimulation |
| Citations | 47 |
| Key findings | Six treatments—ECT, minocycline, theta-burst stimulation, rTMS, ketamine, and aripiprazole—showed higher response rates than placebo or sham for treatment-resistant depression. |
Abstract
This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at least two antidepressant trials; all RCTs had ≥10 participants per study arm, and participants with bipolar or psychotic depression were excluded. The Cochrane Risk of Bias Tool-2 was used to assess study quality. Response rate was the primary outcome measure. Odds ratios (ORs) using a random effects NMA are reported. From 8234 records, 69 RCTs were included in this analysis, encompassing 10,285 participants (5662 F/4623 M) and 25 separate treatments. Six of the 25 treatments demonstrated a higher response rate versus placebo or sham treatment: electroconvulsive therapy (ECT), minocycline, theta-burst stimulation (TBS), repetitive transcranial magnetic stimulation (rTMS), ketamine, and aripiprazole. ORs ranged from 1.9 (95%CI = [1.25; 2.91]) for aripiprazole to 12.86 (95%CI = [4.07; 40.63]) for ECT. Moderate heterogeneity of the model was observed (I2 = 47.3% (95%CI [26.8-62%]). Of the included studies, 12.5% were rated as having high risk of bias, 28.13% as having low risk, and 59.38% as showing some concerns. Several effective treatments for TRD showed robust treatment effects across outcomes (ECT, TBS, rTMS, and ketamine), and others showed promising results for some, but not all, outcomes (minocycline, aripiprazole). These findings may help guide evidence-based treatment choices for TRD. Study Registration: PROSPERO (#CRD42023420584).
Comparable studies
Other systematic reviews and meta-analyses on depression, most cited first.
Citations in the library
Cited by 11
- Efficacy and safety of esketamine for "treatment resistant depression": registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials. BMC Medicine November 28, 2025
- Investigating novel pharmacological strategies for treatment-resistant depression: focus on new mechanisms and approaches Expert Opinion on Drug Discovery January 31, 2025
- Interdisciplinary, Delphi-driven consensus guidelines on the use of intravenous ketamine infusions for depressive disorders from the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3). Journal of Affective Disorders May 16, 2026
- Oral Ketamine for the Treatment of Depression: A randomized controlled trial and meta-analysis medRxiv Preprint Server March 21, 2025
- CSF galanin and noradrenaline downregulation by psilocybin therapy in major depressive disorder Neuropsychopharmacology July 7, 2026
and 6 more in the library
Cites 6
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
- Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine May 24, 2023
- Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression New England Journal of Medicine October 4, 2023
- Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT) The International Journal of Neuropsychopharmacology December 4, 2021
- Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis International Review of Psychiatry June 5, 2020
and 1 more in the library