Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study
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Objective Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing depressive relapse in bipolar II disorder.Methods Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium monotherapy for 12 weeks. Responders with a ≥50% reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy. Primary outcome was depressive relapse during continuation monotherapy. Secondary outcomes included sustained response rate from initiation of treatment to study end-point, relapse hazard, time to relapse, change in mania ratings, and frequency of treatment-emergent sub-syndromal hypomania and/or depressive episodes.Results Venlafaxine produced greater sustained response rate versus lithium (p<0.0001); however, there was no difference in relapse rate for venlafaxine (7.5%) versus lithium (26.7%) (p=0.079); relapse hazard (p=0.073), or time to relapse (p=0.090) between treatment conditions during continuation monotherapy. There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes. There were more sub-syndromal depressive episodes during lithium monotherapy (p=0.03).Limitations Sample size was limited by the lower sustained response rate for lithium versus venlafaxine; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups.Conclusion Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium, with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring. Larger, prospective trials are needed to confirm these observations.
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Head-to-head comparisons with antidepressants found that lithium was not as effective in preventing depressive relapse as fluoxetine or venlafaxine.
“In contrast, head‐to‐head comparisons with antidepressants (reviewed below) found that lithium was not as effective in preventing depressive relapse as fluoxetine or venlafaxine.469, 497”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [497]
The Results (‘Depressive relapse’) report a numerically higher relapse rate with lithium than venlafaxine, but the difference was not statistically significant (p=0.079). The Discussion concludes that the two treatments appeared similarly effective in preventing depressive relapse, contrary to the claimed finding of lower effectiveness for lithium. This paper does not compare lithium with fluoxetine. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredIn that venlafaxine RCT, no hypomanic episodes occurred in either group.
“No hypomanic episodes occurred in either group.”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [497]
The Results (Treatment-emergent mood symptoms) state that no subject met DSM-IV criteria for hypomania, supporting the claim if it means full-syndrome episodes. But the same section reports sub-syndromal hypomania in 10.9% of subjects, so the unqualified claim that no hypomanic episodes occurred omits an important distinction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a small 6-month RCT in patients with BDII who responded acutely to venlafaxine or lithium without hypomanic switch, there was a trend for lower rates of relapse into depression for patients treated with venlafaxine.
“In a small 6‐month RCT in patients with BDII who responded acutely to venlafaxine or lithium without hypomanic switch, there was a trend for lower rates of relapse into depression for patients treated with venlafaxine.”
From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [497]
Methods > Treatment describes six months of continuation therapy for acute responders, and Results > Enrollment reports a small continuation sample of 55. Results > Depressive relapse reports fewer relapses with venlafaxine than lithium (7.5% versus 26.7%, p=0.079), consistent with a trend rather than a significant difference. The paper’s response criteria do not state that absence of an acute hypomanic switch was required, so that qualification is not established. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn that venlafaxine RCT, the rate of sustained response was significantly greater in those who continued venlafaxine compared to those who continued lithium.
“Further, the rate of sustained response was significantly greater in those who continued venlafaxine compared to those who continued lithium.497”
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“, 2015) whereas continuation of antidepressant monotherapy in BD II provides prophylaxis with only minimal risk of switching (Amsterdam et al., 2015).”
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- Authors
- Amsterdam, J. D., Lorenzo-Luaces, L., Soeller, I., Li, S. Q., Mao, J. J., & DeRubeis, R. J.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Amsterdam, Jay D.
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 185
- Pages
- 31-37
- ISSN
- 0165-0327 (ISSN-L)
- PMC
- PMC4540653
- OpenAlex
- W1564492230
- Cited by
- 57
- References
- 42
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 12 · 2015: 2
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH080097, R01MH060353)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- bipolar II depression, depressive relapse prevention, venlafaxine, lithium, mania
- MeSH terms
- Venlafaxine Hydrochloride, Adult, Antidepressive Agents, Bipolar Disorder, Double-Blind Method, Female, Humans, Male, Prospective Studies, Antipsychotic Agents, Treatment Outcome, Lithium Compounds, Secondary Prevention
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