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The Risk of Switch to Mania in Patients With Bipolar Disorder During Treatment With an Antidepressant Alone and in Combination With a Mood Stabilizer
Alexander Viktorin, M.Sc.; Paul Lichtenstein, Ph.D.; Michael E. Thase, M.D.; Henrik Larsson, Ph.D.; Cecilia Lundholm, M.Sc.; Patrik K.E. Magnusson, Ph.D.; Mikael Landén, M.D., Ph.D.
Am J Psychiatry 2014;171:1067-1073. doi:10.1176/appi.ajp.2014.13111501
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Dr. Thase has served as a consultant for Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Dey Pharma, Forest Laboratories (including PGx), Gerson Lehman Group, Guidepoint Global, Lundbeck, MedAvante, Merck (including Schering-Plough and Organon), Neuronetics, Ortho-McNeil (including Johnson & Johnson), Otsuka, Pamlab, Pfizer (including Wyeth-Ayerst Pharmaceuticals), PGx, Shire, Sunovion, Supernus, Takeda, and Transcept Pharmaceuticals; he has received grant support from the Agency for Healthcare Research and Quality, Alkermes, Eli Lilly, Forest Pharmaceuticals, NIMH, Otsuka, PharmaNeuroboost, and Roche; he has equity holdings in MedAvante and has received royalties from the American Psychiatric Foundation, Guilford Press, Herald House, and W.W. Norton; his spouse is employed by Peloton Advantage (Formerly Advogent and Embryon), which does business with Pfizer/Wyeth. Dr. Landén has received lecture honoraria from AstraZeneca, Bayer, Biophausia, Bristol-Myers Squibb, and Servier Sweden and has served on an advisory board for Lundbeck. The other authors report no financial relationships with commercial interests.

Supported by grants from the Swedish Medical Research Council (K2014-62X-14647-12-51 and K2010-61P-21568-01-4), the Swedish Foundation for Strategic Research, and the Swedish Brain Foundation.

From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; and the Department of Psychiatry, University of Pennsylvania, Philadelphia.

Address correspondence to Dr. Landén (mikael.landen@neuro.gu.se).

Copyright © 2014 by the American Psychiatric Association

Received November 15, 2013; Revised March 27, 2014; Accepted April 25, 2014.

Abstract

Objective  This study examined the risk of antidepressant-induced manic switch in patients with bipolar disorder treated either with antidepressant monotherapy or with an antidepressant in conjunction with a mood stabilizer.

Method  Using Swedish national registries, the authors identified 3,240 patients with bipolar disorder who started treatment with an antidepressant and had no antidepressant treatment during the previous year. Patients were categorized into those receiving antidepressant monotherapy and those receiving an antidepressant plus a mood stabilizer. A within-individual design was used to control for confounding by disorder severity, genetic makeup, and early environmental factors. Cox regression analyses conditioned on individual were used to compare the rate of mania 0–3 months and 3–9 months after the start of antidepressant treatment with a preceding non-treatment period.

Results  Nearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio=2.83, 95% CI=1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI=0.54, 1.15), and a decreased risk was observed during the period 3–9 months after treatment initiation (hazard ratio=0.63, 95% CI=0.42, 0.93).

Conclusions  In this national registry study, antidepressant monotherapy was associated with an increased risk of mania. However, no risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer. The results highlight the importance of avoiding antidepressant monotherapy in the treatment of bipolar disorder.

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FIGURE 1. Description of the Within-Individual Design of a National Registry Study of Patients With Bipolar Disordera

a The design allows for comparisons of mania after initiation of antidepressant treatment with a preceding non-treatment period within each subject. The follow-up time was split into 0–3 months and 3–9 months to assess acute (switch) effects and longer-term effects. By applying a within-individual design, confounding by differences in disorder severity, genetic makeup, and early environmental factors is reduced.

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TABLE 1.Baseline Characteristics of Patients With Bipolar Disorder in a National Registry Study (N=3,240)
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TABLE 2.Specific Antidepressants Dispensed to Patients With Bipolar Disorder in a National Registry Studya
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a The antidepressants and numbers listed here are those that were dispensed at the start of the treatment period. Because we applied strict inclusion criteria to classify patients as being on a concurrent mood stabilizer or not, 482 patients from the full sample with ambiguous mood stabilizer use were not classified as either receiving monotherapy or receiving concurrent mood stabilizer treatment. Therefore, the sum of the individuals in the antidepressant monotherapy group and mood stabilizer group do not add up to the full sample.

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TABLE 3.Mania Diagnoses Before and After Antidepressant Treatment Among Patients With Bipolar Disorder Treated With an Antidepressant in a National Registry Study (N=3,240)a
Table Footer Note

a Mania rate is computed as the number of mania diagnoses divided by number of patients. The hazard ratio for mania during an acute and a longer-term period after antidepressant treatment is based on comparison with a prior non-treatment period.

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TABLE 4.Mania Diagnoses Among Patients With Bipolar Disorder in a National Registry Study Who Received Antidepressant Monotherapy or an Antidepressant and a Concurrent Mood Stabilizera
Table Footer Note

a Mania rate is computed as the number of mania diagnoses divided by number of patients. The hazard ratio for mania during an acute and a longer-term period after antidepressant treatment is based on comparison with a prior non-treatment period. Because we applied strict inclusion criteria to classify patients as being on a concurrent mood stabilizer or not, 482 patients with ambiguous mood stabilizer use were excluded from the subsequent analyses.

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1.
A major hurdle in pharmacoepidemiological studies is confounding by indication, which is best described by which of the following?
2.
What is the most likely outcome of comparing the incidence of manic episodes in patients treated with antidepressant monotherapy or in combination with a mood stabilizer?
3.
One concern regarding antidepressant use in bipolar disorder is that they might induce a switch from depression to mania. In what group of antidepressants was this observation first noted?
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