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Review
. 2025 Sep;27(6):411-423.
doi: 10.1111/bdi.70048. Epub 2025 Aug 13.

Defining Treatment-Resistant Bipolar Depression: Recommendations From the ISBD Task Force

Eduard Vieta  1   2   3   4 , Roger S McIntyre  5 , Trisha Suppes  6 , Tamsyn E Van Rheenen  7   8 , Balwinder Singh  9 , Kamilla Woznica Miskowiak  10 , Allan H Young  11 , Lakshmi N Yatham  12 , Kyooseob Ha  12 , Michael Berk  13 , Holly A Swartz  14 , Chantal Henry  15   16 , Maja Pantovic Stefanovic  17   18 , Gerard Anmella Diaz  1   2   3   4 , Aysegul Ozerdem  9 , Wiesław J Cubała  19 , Diego Hidalgo-Mazzei  1   2   3   4 , Mauricio Tohen  20 , Isabella Pacchiarotti  1   2   3   4 , Paula Villela Nunes  21   22 , Carlos Lopez-Jaramillo  23 , Ana Gonzalez-Pinto  24 , Paolo Brambilla  25   26 , Robert Post  27 , Jair C Soares  28 , Michael Bauer  29 , Ana C Andreazza  30 , Xavier Justes Fradera  31 , Montserrat Cosials-Lopez  31 , Giovanna Fico  1   2   3   4
Affiliations
Review

Defining Treatment-Resistant Bipolar Depression: Recommendations From the ISBD Task Force

Eduard Vieta et al. Bipolar Disord. 2025 Sep.

Abstract

Objective: Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment-resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies.

Methods: The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD.

Results: TRBD was defined as the failure to achieve a significant and sustained clinical response after at least two approved and adequately dosed pharmacological treatments, administered for a sufficient duration with treatment adherence. For bipolar I (BD-I) depression, approved treatments included quetiapine (300-600 mg/day for ≥ 8 weeks), lurasidone (20-120 mg/day for ≥ 6 weeks), the combination of olanzapine (6-12 mg/day) and fluoxetine (25-75 mg/day for ≥ 8 weeks), cariprazine (1.5-3 mg/day for ≥ 6 weeks), and lumateperone (42 mg/day for ≥ 6 weeks). For bipolar II (BD-II) depression, approved treatments included quetiapine (300-600 mg/day for ≥ 8 weeks) and lumateperone (42 mg/day for ≥ 6 weeks).

Conclusion: This consensus definition aims to provide clarity for clinical trials, improve consistency in research, and guide treatment approaches and inform regulatory pathways. It represents a foundational step in addressing the unmet needs in TRBD and promoting the development of innovative therapeutic strategies. Future efforts will focus on adapting the definition to better align with real-world clinical challenges and optimize patient care.

Keywords: bipolar depression; bipolar disorder; clinical trial; depression; mental health; psychiatry; treatment response; treatment‐resistant bipolar depression.

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Conflict of interest statement

Dr. Vieta has received grants and served as a consultant, advisor, or CME speaker for AB‐Biotics, Abbott, AbbVie, Aimentia, Angelini, Biogen, Biohaven, Boehringer Ingelheim, Casen‐Recordati, Celon, Compass, Dainippon Sumitomo, Ethypharm, Ferrer, Gedeon Richter, GH Research, GSK, Idorsia, Janssen, Lundbeck, Novartis, Organon, Otsuka, Rovi, Sage, Sanofi‐Aventis, Sunovion, Takeda, and Viatris. Dr. Fico has received grants and served as a paid consultant, adviser, or CME speaker for Angelini, Janssen, Lundbeck, and Sanofi‐Aventis. Dr. Singh has received research grant support from Mayo Clinic, the National Network of Depression Centers (NNDC), Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and NIH. He has received honoraria from Elsevier for editing a Clinical Overview on Treatment‐Resistant Depression, and he is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the National Center for Advancing Translational Science. Dr. Tohen has received honoraria or consulted for multiple entities, including Abbott, AbbVie, AstraZeneca, Alkermes, Biohaven Pharmaceuticals, Lilly, Johnson & Johnson, and others. He was formerly employed by Lilly, and his spouse was also employed at Lilly. Dr. Swartz has received honoraria or consulted for Intracellular Therapies, Physician Postgraduate Press, Medscape/WebMD, Mediflix, and Clinical Education Alliance. Dr. Ozerdem has received research grant support from TÜBİTAK and Mayo Clinic, and honoraria from Carnot Laboratories. Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China's Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra‐Cellular, NewBridge Pharmaceuticals, and AbbVie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Hidalgo‐Mazzei has received CME‐related honoraria and served as a consultant for Abbott, Angelini, Ethypharm Digital Therapy, and Janssen‐Cilag. Dr. Gonzalez‐Pinto has received grants and served as a consultant, advisor, or CME speaker for Janssen‐Cilag, Lundbeck, Otsuka, Angelini, Novartis, and Takeda. Dr. Anmella has received CME‐related honoraria or consulting fees from Adamed, Angelini, Casen Recordati, Janssen‐Cilag, Lundbeck, Rovi, and Viatris. Dr. Cubala has received consultation or advisory fees from Alfred E. Tiefenbacher GmbH, COMPASS Pathfinder Ltd., GH Research, MedEd‐Link Inc., Janssen‐Cilag, and others, as well as speaking fees from Janssen‐Cilag and Biogen. Dr. Bauer has received competitive grant support from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), European Commission, Sächsische Aufbaubank (SAB), and served as an advisor to Alfred E. Tiefenbacher GmbH Co. KG, COMPASS Pathfinder Ltd., GH Research, MedEd‐Link Inc., Janssen Global Services LLC, Livanova, Mindforce Game Lab AB, Novartis Switzerland, Sunovion, and has received lecture fees from MedTrix GmbH and Streamedup GmbH. Dr. Cubała received CME‐related honoraria from Acadia, Angelini, Beckley Psytech, GH Research, HMNC Brain Health, IntraCellular Therapies, Janssen, MSD, Neumora, Novartis, Otsuka, Recognify Life Sciences. Honoraria: Angelini, Janssen, Novartis. Advisory Boards: Douglas Pharmaceuticals, GH Research, Janssen, MSD, Novartis. Dr. Van Rheenen was supported by an Al and Val Rosenstrauss Fellowship from the Rebecca L Cooper Medical Research Foundation (relationships reported within the last 3 years). The remaining authors declare no conflicts of interest related to the subject matter of this article.

Figures

FIGURE 1
FIGURE 1
Algorithm for diagnosis and management of TRBD—BDI.
FIGURE 2
FIGURE 2
Algorithm for diagnosis and management of TRBD—BDII.
See this image and copyright information in PMC

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