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. 2024 Jan 1;81(1):25-33.
doi: 10.1001/jamapsychiatry.2023.3555.

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression

Suvi Virtanen  1 , Tyra Lagerberg  1   2 , Christine Takami Lageborn  1 , Ralf Kuja-Halkola  1 , Isabell Brikell  1 , Anthony A Matthews  3 , Paul Lichtenstein  1 , Brian M D'Onofrio  1   4 , Mikael Landén  1   5 , Zheng Chang  1
Affiliations

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression

Suvi Virtanen et al. JAMA Psychiatry. .

Abstract

Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome.

Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania.

Design, setting, and participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included.

Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days.

Main outcomes and measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline.

Results: The cohort included 43 677 patients (28 885 [66%] girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks.

Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Matthews receives funding from the Swedish Research Council for Health, Working Life and Welfare and the Strategic Research Area in Epidemiology and Biostatistics at Karolinska Institutet outside the submitted work. Dr Landén reports receiving grants from the Swedish Research Council Swedish Brain Foundation (Hjärnfonden) and the Swedish Government under the LUA/ALF agreement during the conduct of the study and lecture honoraria from Lundbeck Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Estimated Cumulative Incidence of Mania/Hypomania During 12 Weeks of Follow-Up
Data were weighted by the treatment propensity weights. Shaded areas represent 95% CIs; the gray shaded area indicates overlapping 95% CIs.
See this image and copyright information in PMC

Comment in

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