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Published Online: 1 July 2024

A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression

Christopher Rohde, M.D., Ph.D., Søren Dinesen Østergaard, M.D., Ph.D., and Oskar Hougaard Jefsen, M.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 181, Number 7
https://doi.org/10.1176/appi.ajp.20230477
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Abstract

Objective:

Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period.

Methods:

The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation.

Results:

The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72–1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63–2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65–2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence.

Conclusions:

These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

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Supplementary Material

File (appi.ajp.20230477.ds001.pdf)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 181 • Number 7 • July 01, 2024
Pages: 630 - 638

History

Received: 14 June 2023
Revision received: 20 September 2023
Revision received: 3 November 2023
Accepted: 4 December 2023
Published online: 1 July 2024
Published in print: July 01, 2024

Keywords

  1. Antidepressants
  2. Bipolar and Related Disorders
  3. Epidemiology
  4. Mania
  5. Pharmacotherapy
  6. Target Trial Emulation

Authors

Affiliations

Christopher Rohde, M.D., Ph.D.
Department of Clinical Medicine, Aarhus University (Rohde, Østergaard, Jefsen), and Department of Affective Disorders (Rohde, Østergaard, Jefsen) and Psychosis Research Unit (Jefsen), Aarhus University Hospital–Psychiatry, Aarhus, Denmark.
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Søren Dinesen Østergaard, M.D., Ph.D.
Department of Clinical Medicine, Aarhus University (Rohde, Østergaard, Jefsen), and Department of Affective Disorders (Rohde, Østergaard, Jefsen) and Psychosis Research Unit (Jefsen), Aarhus University Hospital–Psychiatry, Aarhus, Denmark.
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Oskar Hougaard Jefsen, M.D. [email protected]
Department of Clinical Medicine, Aarhus University (Rohde, Østergaard, Jefsen), and Department of Affective Disorders (Rohde, Østergaard, Jefsen) and Psychosis Research Unit (Jefsen), Aarhus University Hospital–Psychiatry, Aarhus, Denmark.
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Notes

Send correspondence to Dr. Jefsen ([email protected]).

Competing Interests

The authors report no financial relationships with commercial interests.

Funding Information

Dr. Rohde has received funding from the Danish Diabetes Academy, the Lundbeck Foundation (grant R358-2020-2342), and the Novo Nordisk Foundation (grant NNF17SA0031406) and received the 2020 Lundbeck Foundation Talent Prize. Dr. Østergaard has received funding from the Central Denmark Region Fund for Strengthening of Health Science (grant 1-36-72-4-20), the Danish Agency for Digitization Investment Fund for New Technologies (grant 2020-6720), the Danish Cancer Society (grant R283-A16461), Independent Research Fund Denmark (grants 7016-00048B and 2096-00055A), the Lundbeck Foundation (grants R358-2020-2341 and R344-2020-1073), and the Novo Nordisk Foundation (grant NNF20SA0062874) and received the 2020 Lundbeck Foundation Young Investigator Prize. Dr. Jefsen has received funding from the Health Research Foundation of Central Denmark Region (grant R64-A3090-B1898).

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