DOI: 10.1136/bmj-2026-100216 ISSN: 1756-1833

Evidence based interventions for bipolar disorder across phases and age groups: living umbrella review, evaluation, analysis, and communication hub (U-REACH) project

Michele De Prisco, Vincenzo Oliva, Alessandro Miola, Michele Fornaro, Elena Dragioti, Giovanni Croatto, Andre F Carvalho, Michael Berk, Katerina Nikolitch, Gayatri Saraf, Lakshmi N Yatham, Kamyar Keramatian, Risa Shorr, Mark A Frye, Balwinder Singh, Damir Krinitski, Mikkel Højlund, Alessandro Serretti, Giuseppe Fanelli, Fabiano A Gomes, Anne Sofie Hansen, Rene Ernst Nielsen, Paolo Fusar-Poli, Pasquale Paribello, Mirko Manchia, Anees Bahji, Gustavo Vazquez, Spyridon Siafis, Stefan Leucht, Ayşegül Yildiz, Richard Delorme, Ayal Schaffer, Brendon Stubbs, Ruby Rubaiyat, Eduard Vieta, Christoph U Correll, David Moher, Samuele Cortese, Jess G Fiedorowicz, Joaquim Radua, Corentin J Gosling, Marco Solmi
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Abstract

Objectives

To systematically evaluate the certainty of evidence for treatment strategies across age groups and mood phases in bipolar disorder, and develop an open access web platform to facilitate shared decision making.

Design

Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project.

Data sources

PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024.

Eligibility criteria for selecting studies

Systematic reviews with network or pairwise meta-analyses of randomised controlled trials of pharmacological, nutraceutical, psychosocial, brain stimulation, or circadian rhythm based treatments, administered as monotherapy (without concurrent interventions), augmentation treatment (interventions added to an ongoing treatment regimen), or combination treatment (simultaneous initiation of two different interventions), examining any age group, bipolar disorder phase (ie, acute bipolar depression, mania or mixed episodes, or maintenance), treatment, control, or outcome.

Results

77 studies met the inclusion criteria (21 network meta-analyses and 56 pairwise meta-analyses), including 116 unique pharmacological (n=74), brain stimulation (n=18), nutraceutical (n=13), psychosocial (n=8), and circadian rhythm based (n=3) treatments as monotherapy, augmentation, or combination therapy, along with five control interventions. These studies covered 133 unique outcomes (45 efficacy outcomes and 88 safety outcomes) resulting in 2510 meta-analyses with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings of the certainty of the evidence as high (n=236), moderate (n=827), low (n=986), and very low (n=461). A communication hub, the Evidence Based Interventions for Bipolar Disorder (EBI-BD) platform, was developed and the full results are freely available ( https://ebibd-database.org ), including the preference based tool (12 interventions and 17 safety outcomes). Interventions effective across outcomes varied by phases. For bipolar depression, effective interventions in adults were cariprazine, divalproex or valproate, fluoxetine, ketamine (augmentation), lamotrigine, lumateperone, lurasidone, olanzapine, olanzapine with fluoxetine, and quetiapine, whereas effective interventions in children and adolescents were lurasidone and olanzapine with fluoxetine. For mania episodes, effective interventions in adults were aripiprazole, asenapine, carbamazepine, cariprazine, divalproex or valproate, haloperidol, lithium, olanzapine, paliperidone, quetiapine (also augmentation), risperidone (also as augmentation), tamoxifen, and ziprasidone, whereas effective interventions in children and adolescents were aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. For maintenance, interventions effective across outcomes in adults were aripiprazole (also the long acting injectable formulation), asenapine, divalproex or valproate, lithium, olanzapine, group psychoeducation (augmentation), quetiapine, and risperidone long acting injectable formulation. Interventions effective across phases were aripiprazole (also as augmentation and as a long acting injectable formulation), asenapine, cariprazine, cognitive behavioural therapy (augmentation), divalproex or valproate, lamotrigine, lithium, olanzapine (also as augmentation), paliperidone, quetiapine (also as augmentation), and risperidone (also as augmentation and the long acting injectable formulation) (adults). Treatment effects by neuroscience based nomenclature classes are also reported.

Conclusions

The EBI-BD tool can help clinicians make evidence based, personalised treatment decisions for bipolar disorder. This resource can inform clinical guidelines and provides a foundation for continuously improving bipolar disorder care as new evidence emerges.

Trial registration

Open Science Framework https://osf.io/pjmvn/

Readers’ note

This is a living systematic review and may be updated in the next two years if additional evidence emerges.

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