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Recurrence rates in bipolar disorder: Systematic comparison of long-term prospective, naturalistic studies versus randomized controlled trials
Open accessAbstract
Bipolar disorder (BD) is a recurrent, lifelong illness with high risks of disability and excess mortality. Despite many treatment options with demonstrated short-term efficacy, evidence concerning long-term treatment effectiveness in BD remains limited and the relative value of naturalistic studies versus randomized, controlled trials (RCTs) in its assessment, uncertain. Systematic computer-searching yielded 10 naturalistic studies and 15 RCTs suitable for analysis of recurrence rates and their association with treatments and selected clinical factors. In naturalistic studies (3904 BD subjects, 53.3% women, 85.8% BD-I, mean onset age 29.1, followed up to 2.1 years), the pooled recurrence rate was 55.2% (26.3%/year). In RCTs (4828 subjects, 50.9% women, 96.0% BD-I, mean onset age 23.1, followed up to 1.9 years), the pooled recurrence rate was 39.3% (21.9%/year) with mood-stabilizing drug-treatment versus 60.6% (31.3%/year) with placebo; drug-versus-placebo outcomes favored antipsychotics over lithium, and disfavor an approved anticonvulsant. Depressive episode-polarity increased from 27.7% at intake to 52.0% at first-recurrence (p<0.0001). Recurrence rate (%/year) did not differ by study-type, was greater with younger onset and rapid-cycling, and paradoxically declined with longer observation. In short, recurrences of major affective episodes up to two years during putative mood-stabilizing treatment of BD patients in prospective, naturalistic studies and RCTs were substantial and similar (26.3 vs. 21.9%/year). Episode-polarity shifted strongly toward depressive first-recurrences. These findings support the value of naturalistic studies to complement long-term RCTs, and add to indications that control of depression in BD remains particularly unsatisfactory.
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“Risk factors for recurrence include younger age of onset,332 psychotic features,212 rapid cycling,331 more (and more frequent) previous episodes,333 comorbid anxiety,334 and comorbid SUDs.335”
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“With treatment, 19%‐25% of patients will experience a recurrence every year, compared to 23%‐40% of those on placebo.331”
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Metadata
- Authors
- Vázquez, G. H., Holtzman, J. N., Lolich, M., Ketter, T. A., & Baldessarini, R. J.
- Affiliations
- McLean Hospital (US)
- Stanford Medicine (US)
- University of Palermo (AR)
- Harvard University (US)
- Corresponding author
- Vázquez, Gustavo H.
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 25
- Issue
- 10
- Pages
- 1501-1512
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W1960912647
- Cited by
- 102
- References
- 53
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 15 · 2016: 4
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-nd)
- Funders
- Bruce J. Anderson Foundation
- McLean Private Donors Research Fund (RJB)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Psychology › Clinical Psychology › Personality Disorders and Psychopathology
- Keywords
- bipolar disorder, recurrence rate, naturalistic study, randomized controlled trials, mood stabilizers, lithium, antipsychotic drugs, antiepileptic drugs, rapid cycling bipolar disorder, age of onset, long-term treatment effectiveness
- MeSH terms
- Bipolar Disorder, Humans, Recurrence, Randomized Controlled Trials as Topic, Treatment Outcome
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