SynthesisJournal of psychopharmacology (Oxford, England)2021
Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium.
Synthesis in Journal of psychopharmacology (Oxford, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05814640 (Sequenced Treatment Alternatives to Relieve Adolescent Depression), which is not on this map. Cited by 43 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Sequenced Treatment Alternatives to Relieve Adolescent Depression (STAR-AD): a Pragmatic Clinical Trial
Who cites it
43 citing papers in PubMed, 6 syntheses or guidelines pooled it, 85 citations in OpenAlex.
- Reappraising lithium, triiodothyronine and second-generation antipsychotic augmentation treatment for major depression: a systematic review and meta-analysis with bias-adjustment analyses.BMJ mental health · 2026Pooled it
- Efficacy and acceptability of psilocybin for primary or secondary depression: A systematic review and meta-analysis of randomized controlled trials.Frontiers in psychiatry · 2024Pooled it
- The use of esketamine in the treatment of patients with severe depression and suicidal ideation: systematic review and meta-analysis.Revista da Associacao Medica Brasileira (1992) · 2023Pooled it
- The use of esketamine in the treatment of patients with oral antidepressant-resistant depression: systematic review and meta-analysis.Revista da Associacao Medica Brasileira (1992) · 2023Pooled it
- Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis.Expert opinion on drug safety · 2022Pooled it
- Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis.Journal of affective disorders · 2022Pooled it
- Clinical evaluation of adjunctive magnesium therapy in patients receiving antidepressants for depression-open label, nonrandomized clinical trial.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression: 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial.Psychotherapy and psychosomatics · 2026Article
- Efficacy and Clinical Relevance of Adjunctive Cariprazine Treatment in Patients with Major Depressive Disorder: Post Hoc Analyses from a Phase III Study.Neuropsychiatric disease and treatment · 2026Article
- [Lithium and its impact on renal function. Recommendations for practice, especially for older patients].Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater · 2025Review
- Lithium Augmentation in Treatment-Resistant Depression: A Qualitative Review of the Literature.Pharmacotherapy · 2025Review
- Clinical prescription of lithium, anticonvulsants antipsychotics, and antidepressants for major mood disorders.International journal of bipolar disorders · 2025Article
- The augmentative efficacy of second-generation anti-psychotics (SGA) to anti-depressants in treating treatment-resistant depression: a network meta-regression analysis.BMC psychiatry · 2025Article
- Nutritional Strategies in Major Depression Disorder: From Ketogenic Diet to Modulation of the Microbiota-Gut-Brain Axis.Molecular neurobiology · 2025Review
- Treatment-resistant depression and intranasal esketamine: Spanish consensus on theoretical aspects.Frontiers in psychiatry · 2025Article
- The Impact of Esketamine on Depression: Targeting Oxidative Stress and Neuronal Apoptosis Through BDNF/TrkB/PI3K/AKT Pathway Activation.Neuropsychiatric disease and treatment · 2025Article
- Bibliometric Analysis of Antipsychotic-induced Metabolic Disorder from 2006 to 2021 Based on WoSCC Database.Current neuropharmacology · 2025Article
- Treatment-resistant depression: molecular mechanisms and management.Molecular biomedicine · 2024Review
- Antidepressant effects of activation of infralimbic cortex via upregulation of BDNF and β-catenin in an estradiol withdrawal model.Psychopharmacology · 2024Article
- Therapeutic Drug Monitoring in Psychiatry: Enhancing Treatment Precision and Patient Outcomes.Pharmaceuticals (Basel, Switzerland) · 2024Review
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSuccessful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their
methodsWe reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes.
resultsAnalyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9-15]); esketamine (7 [5-10]) and lithium (5 [4-10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4-6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4-6) for esketamine, and 9 (5-106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25-10.60) for lithium and much less favorable for esketamine (0.71 [0.60-0.80]) or SGAs (0.45 [0.17-0.77]).
conclusionsSeveral modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated. LIMITATIONS: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.