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Cited by 103Bipolar Disorder and TreatmentSchizophrenia research and treatmentTreatment of Major Depression

A 6-Month, Double-Blind, Maintenance Trial of Lithium Monotherapy Versus the Combination of Lithium and Divalproex for Rapid-Cycling Bipolar Disorder and Co-Occurring Substance Abuse or Dependence

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Kemp, David E., Gao, Keming, Ganocy, Stephen J., Elhaj, Omar, Bilali, Sarah R., Conroy, Carla, Findling, Robert L., Calabrese, Joseph R.·2009·The Journal of Clinical Psychiatry
DOI 10.4088/jcp.07m04022PMC PMC3587136
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Abstract

OBJECTIVE: To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder and comorbid substance abuse and/or dependence. METHOD: A 6-month, double-blind, parallel-group comparison was carried out in patients who met DSM-IV criteria for (1) bipolar I or II disorder; (2) alcohol, cannabis, or cocaine abuse within the last 3 months or dependence within the last 6 months; (3) rapid cycling during the 12 months preceding study entry; and (4) a history of at least 1 manic, hypomanic, or mixed episode within 3 months of study entry and who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy. The study was conducted at an outpatient mood disorders program between October 1997 and October 2006. RESULTS: Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%, nonresponse: 25%, intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% (N = 17) relapsed (24% [N = 4] into depression and 76% [N = 13] into a manic/hypomanic/mixed episode), 26% (N = 8) completed the study, and 19% (N = 6) were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (not significant). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% (N = 9) and 53% (N = 8), respectively. The rate of depressive relapse in both arms was 13% (N = 2), while the rate of relapse into a manic, hypomanic, or mixed episode was 44% (N = 7) for lithium monotherapy and 40% (N = 6) for the combination of lithium and divalproex. CONCLUSION: A small subgroup of patients in this study stabilized after 6 months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of rapid-cycling bipolar disorder in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00194129.

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Crossref · 10.4088/jcp.07m04022

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  • In a small RCT, there was a significant reduction in the number of drinks per drinking day, as well as per heavy drinking day, in the combination group compared to the group with lithium alone when adherence to treatment was added as a covariate.

    “In a small RCT, there was a significant reduction in the number of drinks per drinking day, as well as per heavy drinking day, in the combination group compared to the group with lithium alone when adherence to treatment was added as a covariate.”

    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 [682]

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  • Lithium and/or divalproex have level 3 evidence for cannabis use disorder in bipolar disorder.

    “Lithium and/or divalproex have level 3 evidence.617, 682, 685, 686, 687”

    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 [682]

    The Results section (Effects on Alcohol and Substance Use; page not available) reports that 8 of 15 participants with cannabis use disorders no longer met criteria for active abuse or had entered early full remission after open-label lithium-plus-divalproex treatment. This provides limited evidence relevant to the claim, but the paper does not assign it a “level 3” rating or establish a treatment effect on cannabis use against a control group. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A combination of divalproex and lithium is the only treatment for alcohol use disorder comorbid with bipolar disorder that meets criteria for level 2 evidence.

    “A combination of divalproex and lithium is the only treatment for alcohol use disorder comorbid with BD that meets criteria for level 2 evidence.682, 683”

    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 [682]

    The Results (Effects on Alcohol and Substance Use; page unavailable) report that some participants with alcohol abuse or dependence entered remission during open-label lithium-plus-divalproex treatment. The paper does not classify the combination as “level 2 evidence” or establish that it is the only treatment meeting that criterion. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Lithium or divalproex, either alone or in combination, were proven useful in small studies addressing cocaine use disorder (level 4).

    “Lithium or divalproex, either alone or in combination, were proven useful in small studies addressing cocaine use disorder682, 685, 686, 687, 707, 708 (level 4).”

    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 [682]

    The Results section (Effects on Alcohol and Substance Use; page unavailable) reports that 7 of 9 participants with cocaine use disorders no longer met criteria for active abuse or had entered early full remission after open-label lithium-plus-divalproex treatment. This supports a possible benefit of the combination in a small group with rapid-cycling bipolar disorder, but it does not prove efficacy for cocaine use disorder or establish a benefit from either drug alone. The same section reports no statistically significant difference in cocaine-use days between treatment responders and non-responders. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. [10]Swann A Garza-Trevino ES Practical management of depressive and manic episodes Medical Psychiatry: Theory and Practice Teaneck, NJ World Scientific 1989
  2. [24]First MB Spitzer RL Gibbon M Williams JBW 1997 Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders 4 Patient Version Washington, DC American Psychiatric Press

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Authors
Kemp, D. E., Gao, K., Ganocy, S. J., Elhaj, O., Bilali, S. R., Conroy, C., Findling, R. L., & Calabrese, J. R.
Affiliations
  • University Hospitals Cleveland Medical Center (US)
  • Louis Stokes Cleveland VA Medical Center (US)
ORCID
Venue
The Journal of Clinical Psychiatry
Publisher
Physicians Postgraduate Press, Inc
Published
2008-12-30
Volume
70
Issue
1
Pages
113-121
ISSN
0160-6689 (ISSN-L)
DOI
10.4088/jcp.07m04022
PMC
PMC3587136
OpenAlex
W2156493246
Cited by
103
References
38
Citations by year
2025: 5 · 2024: 3 · 2023: 5 · 2022: 10 · 2021: 6 · 2020: 1 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 2 · 2015: 5 · 2014: 10 · 2013: 6 · 2012: 11
FWCI
4.45
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5kl2rr024990-05)
  • National Institute of Mental Health (P 20 MH-66054, P20MH066054, R01 MH-50165, R01MH050165)
  • National Center for Research Resources (KL2-RR-024990, 1KL2 RR024990)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
rapid cycling bipolar disorder, lithium monotherapy, divalproex, maintenance therapy, relapse prevention, substance use comorbidity, alcoholism, cocaine dependence, cannabis use disorder, medication adherence, mood episode recurrence, depression relapse, treatment discontinuation, adverse effects
MeSH terms
Adolescent, Adult, Affect, Aged, Alcoholism, Anticonvulsants, Bipolar Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Valproic Acid, Comorbidity, Lithium Carbonate, Antimanic Agents, Substance-Related Disorders, Young Adult

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