. 2026 Mar 4:e261327.

doi: 10.1001/jama.2026.1327. Online ahead of print.

A Decision-Support System to Personalize Antidepressant Treatment in Major Depressive Disorder: A Randomized Clinical Trial

Andrea Cipriani^{1

2

3}, Karen Barros Parron Fernandes^{4

5}, Benoit H Mulsant^{6

7

8}, Orestis Efthimiou^{9

10}, Nicola Williams¹¹, Sam Mort¹¹, Rania Elgarf^{1

2}, Qiang Liu^{1

2

12}, Nyla Haque^{1

2}, Jennifer Potts^{1

2}, Roger Ede³, Robin Fox¹¹, Marcos Liboni¹³, Diego A Nesi Cavicchioli¹³, Judit Simon^{1

14}, Katharine A Smith^{1

2

3}, Caroline Zangani^{1

2

3}, Zhenpeng Li^{1

2}, Ursula Taylor¹⁵, M Ishrat Husain^{6

7}, Maddalena Cipriani¹⁶, Paulo V Carpaneze Dalaqua⁴, Eduardo Fernandes Leite¹³, Gustavo Aliano Gâmbaro^{4

5}, Diogo Nabhan Silveira⁴, Luísa Manfredin Vila¹³, Fernanda Liboni Cavicchioli⁴, Toshi A Furukawa¹⁷, Huseyin Naci¹⁸, Edoardo G Ostinelli^{1

2}; PETRUSHKA Team

Collaborators, Affiliations

Collaborators

PETRUSHKA Team:
Arradea Triesty Adinda, Nadeem Ahmed, Rosario Aronica, Eduarda Batista, Jithen Benjamin, Ian Binnian, Ruth Carson, Helen Collins, Johanna Cook, Rachel Delahay, Franco De Crescenzo, Lazarina Engonidou, Simon Gilbody, James Hong, Owen Hughes, Matt Jaquiery, Benjamin Johnston, Gemma Lewis, Andrea Paggi, Nicola Rizzopesci, Pippa Sealy, Neetul Shah, Rachel Shaw, Ilina Singh, Katherine Stevens, Jaimini Tanna, Anneka Tomlinson, Laurence Wainwright, Nick Wooding, Ly-Mee Yu, Stefan Kloiber, Daniel Mueller, Helena K Kim, Brett D M Jones, Abigail Ortiz, Daniel Blumberger, Georgia Salanti, Stéphanie P Araújo, Paulo R Bignardi, Bruna G Camargo, Andréa N Colado Simões, João Pedro de Vasconcelos, Bianca B P Fernandes, Isadora L Gobbi, Rafael S A Haber, Renato C Jacovetti, Augusto B Liboni, Caio C S Martins, Amanda P Oliveira, Giulia G A Ramos, Carolina B N Rodrigues, Raul H M Santos, Letícia F R Silva, Gabriela G Tassi, Vitor F Tomazini

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, England.
² Oxford Precision Psychiatry Lab, NIHR Oxford Health Biomedical Research Centre, Oxford, England.
³ NIHR Oxford Health Clinical Research Facility, Oxford Health NHS Foundation Trust, Oxford, England.
⁴ School of Medicine, Pontifícia Universidade Católica do Paraná, Londrina, Brazil.
⁵ Graduate Program of Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil.
⁶ Department of Psychiatry, Temerty School of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁸ Royal Ottawa Hospital, Ottawa, Ontario, Canada.
⁹ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
¹⁰ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
¹¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, England.
¹² School of Engineering, Mathematics, and Technology, University of Bristol, Bristol, England.
¹³ Health Sciences Center, Londrina State University, Londrina, Brazil.
¹⁴ Department of Health Economics, Medical University of Vienna, Vienna, Austria.
¹⁵ NIHR South Central Regional Research Delivery Network, Southampton, England.
¹⁶ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
¹⁷ Office of Institutional Advancement and Communications, Kyoto University, Kyoto, Japan.
¹⁸ Department of Health Policy, London School of Economics and Political Science, London, England.

PMID: 41779422
PMCID: PMC12961600 (available on 2026-09-04)
DOI: 10.1001/jama.2026.1327

A Decision-Support System to Personalize Antidepressant Treatment in Major Depressive Disorder: A Randomized Clinical Trial

Andrea Cipriani et al. JAMA. 2026.

. 2026 Mar 4:e261327.

doi: 10.1001/jama.2026.1327. Online ahead of print.

Authors

Collaborators

PETRUSHKA Team:
Arradea Triesty Adinda, Nadeem Ahmed, Rosario Aronica, Eduarda Batista, Jithen Benjamin, Ian Binnian, Ruth Carson, Helen Collins, Johanna Cook, Rachel Delahay, Franco De Crescenzo, Lazarina Engonidou, Simon Gilbody, James Hong, Owen Hughes, Matt Jaquiery, Benjamin Johnston, Gemma Lewis, Andrea Paggi, Nicola Rizzopesci, Pippa Sealy, Neetul Shah, Rachel Shaw, Ilina Singh, Katherine Stevens, Jaimini Tanna, Anneka Tomlinson, Laurence Wainwright, Nick Wooding, Ly-Mee Yu, Stefan Kloiber, Daniel Mueller, Helena K Kim, Brett D M Jones, Abigail Ortiz, Daniel Blumberger, Georgia Salanti, Stéphanie P Araújo, Paulo R Bignardi, Bruna G Camargo, Andréa N Colado Simões, João Pedro de Vasconcelos, Bianca B P Fernandes, Isadora L Gobbi, Rafael S A Haber, Renato C Jacovetti, Augusto B Liboni, Caio C S Martins, Amanda P Oliveira, Giulia G A Ramos, Carolina B N Rodrigues, Raul H M Santos, Letícia F R Silva, Gabriela G Tassi, Vitor F Tomazini

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, England.
² Oxford Precision Psychiatry Lab, NIHR Oxford Health Biomedical Research Centre, Oxford, England.
³ NIHR Oxford Health Clinical Research Facility, Oxford Health NHS Foundation Trust, Oxford, England.
⁴ School of Medicine, Pontifícia Universidade Católica do Paraná, Londrina, Brazil.
⁵ Graduate Program of Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil.
⁶ Department of Psychiatry, Temerty School of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁸ Royal Ottawa Hospital, Ottawa, Ontario, Canada.
⁹ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
¹⁰ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
¹¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, England.
¹² School of Engineering, Mathematics, and Technology, University of Bristol, Bristol, England.
¹³ Health Sciences Center, Londrina State University, Londrina, Brazil.
¹⁴ Department of Health Economics, Medical University of Vienna, Vienna, Austria.
¹⁵ NIHR South Central Regional Research Delivery Network, Southampton, England.
¹⁶ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
¹⁷ Office of Institutional Advancement and Communications, Kyoto University, Kyoto, Japan.
¹⁸ Department of Health Policy, London School of Economics and Political Science, London, England.

PMID: 41779422
PMCID: PMC12961600 (available on 2026-09-04)
DOI: 10.1001/jama.2026.1327

Abstract

Importance: Antidepressants for moderate to severe major depressive disorder may be discontinued prematurely because the prescribed antidepressant is not always the most appropriate medication for an individual. Guidelines have recommended more precise targeting of antidepressant treatment.

Objective: To evaluate the efficacy of a web-based tool to personalize antidepressant treatment.

Design, setting, and participants: This multicenter, randomized clinical trial included persons between the ages of 18 and 74 years with major depressive disorder. The trial was conducted at 47 sites in 3 countries (Brazil, Canada, and the UK). The first participant was screened on November 29, 2022, and the last follow-up visit occurred on January 15, 2025.

Intervention: A total of 540 participants were randomized (1:1) to an evidence-based clinical decision-support system (PETRUSHKA tool; n = 271) or usual care (n = 269).

Main outcomes and measures: The primary outcome was treatment discontinuation due to any cause at 8 weeks. The secondary outcomes included treatment discontinuation up to 24 weeks due to adverse events and changes in depressive symptoms (measured with the 9-item Patient Health Questionnaire [PHQ-9]; range, 0-27; higher scores indicate more severe depression) and anxiety symptoms (measured with the 7-item Generalized Anxiety Disorder [GAD-7] questionnaire; range, 0-21; higher scores indicate more severe symptoms).

Results: Of the 520 eligible participants, 493 were included in the primary analysis (median age, 35 [IQR, 25 to 48] years; 58% female; PHQ-9 mean score, 16.6 [SD, 5.1]; GAD-7 mean score, 11.5 [SD, 4.1]). At 8 weeks, 41 of 241 participants (17%) in the PETRUSHKA group discontinued the prescribed antidepressant due to any cause vs 69 of 252 (27%) in the usual care group (adjusted relative risk, 0.62 [95% CI, 0.44 to 0.88]; P = .007). At 8 weeks, 22 of 241 participants (9%) in the PETRUSHKA group discontinued the prescribed antidepressant due to adverse events vs 39 of 252 (16%) in the usual care group (adjusted relative risk, 0.59 [95% CI, 0.36 to 0.97]; P = .04). For the assessment of depressive symptoms at 24 weeks, the mean PHQ-9 score was 7.1 (SD, 5.4) in the PETRUSHKA group vs 9.2 (SD, 6.5) in the usual care group (n = 129 in each group; adjusted between-group mean difference, -1.92 [95% CI, -3.06 to -0.78]; P < .001). For the assessment of anxiety symptoms at 24 weeks, the mean GAD-7 score was 4.6 (SD, 4.1) in the PETRUSHKA group (n = 133) vs 5.8 (SD, 4.9) in the usual care group (n = 126) (adjusted between-group mean difference, -1.39 [95% CI, -2.26 to -0.52]; P = .002).

Conclusions and relevance: Compared with usual care, use of the PETRUSHKA tool increased the number of patients still taking their antidepressant at 8 weeks and improved depressive and anxiety symptoms at 24 weeks. However, lack of a double-blind design and the large amount of missing data limit the validity of these results.

Trial registration: ClinicalTrials.gov Identifier: NCT05608330.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr A. Cipriani reported receiving grants from the National Institute for Health and Care Research (NIHR), NIHR Oxford and Thames Valley Applied Research Collaboration, NIHR Oxford Health Biomedical Research, Oxford Cognitive Health, Angelini Pharma, and Wellcome Trust and receiving personal fees from INCiPiT (Italian Network for Paediatric Trials), the CARIPLO Foundation, Lundbeck, Angelini Pharma, and Teva. Dr Mulsant reported receiving funding from the Labatt Family Chair in the Biology of Depression in Late Life (University of Toronto); receiving grants from the CAMH Foundation, Bell Canada, Brain Canada, the Canadian Institutes of Health Research, the Patient-Centered Outcomes Research Institute, the National Institutes of Health, the Medical Psychiatry Alliance (a Canadian collaborative partnership between the Centre for Addiction and Mental Health, the Hospital for Sick Children, Trillium Health Partners, and the University of Toronto), and HAPPYneuron (software used in a study founded by Brain Canada); and receiving personal fees from the University of Toronto. Dr Efthimiou reported receiving support from the Swiss National Science Foundation. Dr Williams reported receiving grants from the NIHR and the CAMH Foundation. Ms Elgarf reported receiving personal fees from Angelini Pharma. Dr Nesi Cavicchioli reported receiving personal fees from Adium and Apsen. Dr Simon reported receiving institutional grant support from the Vienna Science and Technology Fund, the European Commission, the NIHR, and the Austrian Science Fund and receiving personal fees from the European Brain Council. Dr Li reported having a patent pending for the PETRUSHKA tool. Dr Husain reported receiving grants from Compass Pathfinder Ltd and having stock options with Mindset Pharma Inc. Dr Furukawa reported receiving personal fees from Daiichi Sankyo, DT Axis, Micron, Shionogi, SONY, and UpToDate; receiving a grant from DT Axis; and having a patent pending, a patent issued, and having licensed intellectual properties for Kokoro app to DT Axis. Dr Naci reported receiving grants from the NIHR, UK Research and Innovation, the European Commission, the National Institute for Health Care Management Foundation, and the Commonwealth Fund and receiving personal fees from the World Health Organization, Arnold Ventures, and BMJ. Dr Ostinelli reported being supported by the NIHR Oxford and Thames Valley Applied Research Collaboration and receiving personal fees from Angelini Pharma. No other disclosures were reported.

Comment in

doi: 10.1001/jama.2026.0816

References

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A Decision-Support System to Personalize Antidepressant Treatment in Major Depressive Disorder: A Randomized Clinical Trial

Collaborators

Affiliations

A Decision-Support System to Personalize Antidepressant Treatment in Major Depressive Disorder: A Randomized Clinical Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Comment in

References

Associated data

LinkOut - more resources

Full Text Sources

Medical