Treatment for Bipolar Disorder in Adults

683 Pages·2017·14.89 MB·English

Comparative Effectiveness Review
Number 208
Treatment for Bipolar
Disorder in Adults: A
Systematic Review
e
Comparative Effectiveness Review
Number 208
Treatment for Bipolar Disorder in Adults: A
Systematic Review
Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
5600 Fishers Lane
Rockville, MD 20857
www.ahrq.gov
Contract No. 290-2012-00016-I
Prepared by:
Minnesota Evidence-based Practice Center
Minneapolis, MN
Investigators:
Mary Butler, Ph.D., M.B.A.
Snezana Urosevic, Ph.D., L.P.
Priyanka Desai, M.H.P.
Scott R. Sponheim, Ph.D.
Jonah Popp, M.S., M.A.
Victoria A. Nelson, M.Sc.
Viengneesee Thao, M.P.H.
Benjamin Sunderlin, M.P.H.
AHRQ Publication No. 18-EHC012-EF
August 2018
Key Messages
Purpose of Review
• To assess the effectiveness of drug and nondrug therapies for treating acute mania or
depression symptoms and preventing relapse in adults with bipolar disorder (BD) diagnoses,
including bipolar I disorder (BD-I), bipolar II disorder (BD-II), and other types.
Key Messages
• Acute mania treatment: Lithium, asenapine, cariprazine, olanzapine, quetiapine,
risperidone, and ziprasidone may modestly improve acute mania symptoms in adults with
BD-I. Participants on atypical antipsychotics, except for quetiapine, reported more
extrapyramidal symptoms, and those on olanzapine reported more weight gain, compared
with placebo.
• Maintenance treatment: Lithium may prevent relapse into acute episodes in adults with
BD-I.
• Depression treatment: Evidence was insufficient for drug treatments for depressive
episodes in adults with BD-I and BD-II.
• For adults with any BD type, cognitive behavioral therapy may be no better than other
psychotherapies for improving acute bipolar symptoms and systematic/collaborative care
may be no better than other behavioral therapies for preventing relapse of any acute
symptoms.
• Stronger conclusions were prevented by high rates of participants dropping out.
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This report is based on research conducted by the Minnesota Evidence-based Practice Center
(EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville,
MD (Contract No. 290-2012-00016-I). The findings and conclusions in this document are those
of the authors, who are responsible for its contents; the findings and conclusions do not
necessarily represent the views of AHRQ. Therefore, no statement in this report should be
construed as an official position of AHRQ or of the U.S. Department of Health and Human
Services.
None of the investigators have any affiliations or financial involvement that conflicts with
the material presented in this report.
The information in this report is intended to help health care decisionmakers—patients and
clinicians, health system leaders, policymakers, and others—make well-informed decisions and
thereby improve the quality of health care services. This report is not intended to be a substitute
for the application of clinical judgment. Anyone who makes decisions concerning the provision
of clinical care should consider this report in the same way as any medical reference and in
conjunction with all other pertinent information, i.e., in the context of available resources and
circumstances presented by individual patients.
This report is made available to the public under the terms of a licensing agreement between the
author and the Agency for Healthcare Research and Quality. This report may be used and
reprinted without permission except those copyrighted materials that are clearly noted in the
report. Further reproduction of those copyrighted materials is prohibited without the express
permission of copyright holders.
AHRQ or U.S. Department of Health and Human Services endorsement of any derivative
products that may be developed from this report, such as clinical practice guidelines, other
quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.
This report may periodically be assessed for the currency of conclusions. If an assessment is
done, the resulting surveillance report describing the methodology and findings will be found on
the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the
title of the report.
Persons using assistive technology may not be able to fully access information in this report. For
assistance contact [email protected].
Suggested citation: Butler M, Urosevic S, Desai P, Sponheim SR, Popp J, Nelson VA, Thao V,
Sunderlin B. Treatment for Bipolar Disorder in Adults: A Systematic Review. Comparative
Effectiveness Review No. 208. (Prepared by the Minnesota Evidence-based Practice Center
under Contract No. 290-2012-00016-I.) AHRQ Publication No. 18-EHC012-EF. Rockville, MD:
Agency for Healthcare Research and Quality; August 2018. Posted final reports are located on
the Effective Health Care Program search page.
DOI: https://doi.org/10.23970/AHRQEPCCER208.
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Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and
private-sector organizations in their efforts to improve the quality of health care in the United
States. These reviews provide comprehensive, science-based information on common, costly
medical conditions, and new health care technologies and strategies.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews can help clarify whether assertions about the value of the intervention are
based on strong evidence from clinical studies. For more information about AHRQ EPC
systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that these systematic reviews will be helpful to health plans, providers,
purchasers, government programs, and the health care system as a whole. Transparency and
stakeholder input are essential to the Effective Health Care Program. Please visit the Web site
(www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an
email list to learn about new program products and opportunities for input.
If you have comments on this systematic review, they may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane,
Rockville, MD 20857, or by email to [email protected].

Gopal Khanna, M.B.A. Arlene S. Bierman, M.D., M.S.
Director Director
Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement
Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Aysegul Gozu, M.D., M.P.H.
Director Task Order Officer
Evidence-based Practice Center Program Center for Evidence and Practice Improvement
Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality
Agency for Healthcare Research and Quality

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Acknowledgments
We wish to thank Kaci Parson, who helped as a research assistant; Jeannie Ouellette and
Cheryl Cole-Hill for their help with editing and producing this report; James D. Neaton for his
expertise in clinical trials and biostatics with regard to antipsychotics; and Aysegul Gozu and her
colleagues at AHRQ for their helpful comments during the writing process. Special gratitude for
Robert L. Kane in memoriam.
Key Informants
In designing the study questions, the EPC consulted several Key Informants who represent
the end-users of research. The EPC sought the Key Informant input on the priority areas for
research and synthesis. Key Informants are not involved in the analysis of the evidence or the
writing of the report. Therefore, in the end, study questions, design, methodological approaches,
and/or conclusions do not necessarily represent the views of individual Key Informants.
Key Informants must disclose any financial conflicts of interest greater than $5,000 and any
other relevant business or professional conflicts of interest. Because of their role as end-users,
individuals with potential conflicts may be retained. The TOO and the EPC work to balance,
manage, or mitigate any conflicts of interest.
The list of Key Informants who provided input into this report follows:

Benjamin G. Druss, M.D., M.P.H.
Rosalynn Carter Chair in Mental Health
Department of Health Policy and Management
Atlanta, GA

Brian Jost
NAMI Minnesota
St. Paul, MN

Amy M. Kilbourne, Ph.D., M.P.H.*
Director, VA Quality Enhancement Research Initiative (QUERI)
Professor of Psychiatry, University of Michigan Medical School
Ann Arbor, MI

Elinore F. McCance-Katz, M.D.
Chief Medical Officer
Substance Abuse and Mental Health Services
Washington, DC

Susan Carr Sonne, Pharm.D., B.C.P.P.
MUSC/Institute of Psychiatry
Charleston, SC

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Lauren M. Weinstock, Ph.D.*
Associate Professor
Alpert Medical School of Brown University
Providence, RI
Technical Expert Panel
In designing the study questions and methodology at the outset of this report, the EPC
consulted several technical and content experts. Broad expertise and perspectives were sought.
Divergent and conflicted opinions are common and perceived as healthy scientific discourse that
results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design,
methodologic approaches, and/or conclusions do not necessarily represent the views of
individual technical and content experts.
Technical Experts must disclose any financial conflicts of interest greater than $5,000 and
any other relevant business or professional conflicts of interest. Because of their unique clinical
or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC
work to balance, manage, or mitigate any potential conflicts of interest identified.
The list of Technical Experts who provided input to this report follows:

Mark S. Bauer, M.D.
Professor of Psychiatry
Harvard Medical School
Boston, MA

Laura J. Fochtmann, M.D., M.B.I.*
Distinguished Service Professor
Departments of Psychiatry, Pharmacological Sciences and Biomedical Informatics
Stony Brook University School of Medicine
Stony Brook, NY

Mark A. Frye, M.D.
Chair, Department of Psychiatry and Psychology
Mayo Clinic,
Rochester, MN

Susan Carr Sonne, Pharm.D., B.C.P.P.
MUSC/Institute of Psychiatry
Charleston, SC

Lauren M. Weinstock, Ph.D.*
Associate Professor
Alpert Medical School of Brown University
Providence, RI

*Provided input on Draft Report.
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Peer Reviewers
Prior to publication of the final evidence report, EPCs sought input from independent Peer
Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the
scientific literature presented in this report do not necessarily represent the views of individual
reviewers.
Peer Reviewers must disclose any financial conflicts of interest greater than $5,000 and any
other relevant business or professional conflicts of interest. Because of their unique clinical or
content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO
and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest
identified.

David J. Bond, M.D., Ph.D.
Associate Professor
University of Minnesota
Minneapolis, MN

Matthew V. Rudorfer, M.D.
Program Chief
National Institute of Mental Health
Bethesda, MD
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Treatment for Bipolar Disorder in Adults: A
Systematic Review
Structured Abstract
Objective. Assess the effect of drug and nondrug interventions for treating acute symptoms
associated with bipolar disorder (BD) and preventing relapse.

Data sources. Ovid MEDLINE® and PsycINFO®, the Cochrane Central Register of Controlled
Trials, and Ovid Embase® bibliographic databases; hand searches of references of relevant
systematic reviews through May 2017.

Review methods. Eligible studies included randomized controlled trials and prospective cohorts
with comparator arms enrolling adults with bipolar disorder (BD) of any type with 3 weeks
followup for acute mania, 3 months for depression, and 6 months for maintenance treatments.
We excluded acute mania and depression studies with greater than 50 percent attrition.

Results. We synthesized evidence from 157 unique studies, 108 studies for 28 drugs, 49 studies
for nondrug interventions. All drug study findings with at least low-strength evidence were based
almost exclusively on adults with bipolar I disorder (BD-I). Asenapine, cariprazine, quetiapine,
and olanzapine improved acute mania symptoms compared to placebo (low-strength evidence).
However, improvements were of modest clinical significance, with values that were less than the
minimally important difference, but still large enough that a reasonable proportion of participants
likely received a benefit. Unpooled evidence indicated an overall beneficial effect of risperidone
and ziprasidone on acute mania symptoms compared to placebo (low-strength evidence).
Participants using atypical antipsychotics, except quetiapine, reported more extrapyramidal
symptoms compared to placebo, and those using olanzapine reported more clinically significant
weight gain. Lithium improved acute mania in the short term and prolonged time to relapse in
the long term compared to placebo (low-strength evidence). No difference was found between
olanzapine and divalproex/valproate for acute mania (low-strength evidence). For drugs not
approved for BD, paliperidone improved acute mania compared to placebo (low-strength
evidence), while topiramate and allopurinol showed no benefit (low-strength evidence). Further,
lithium improved acute mania better than topiramate (low-strength evidence), although
withdrawals for adverse events were lower for topiramate. Only lithium reached a minimally
important difference for acute mania and maintenance treatment. All other drug comparisons to
placebo or active controls for acute mania, depression, and maintenance had insufficient
evidence. For psychosocial interventions, cognitive behavioral training (CBT) was no better for
depression or mania symptoms than psychoeducation or other active psychosocial comparators
(low-strength evidence). Systematic/collaborative care had no effect on relapse compared to
inactive comparators (low-strength evidence).

Conclusions. We found no high- or moderate-strength evidence for any intervention to
effectively treat any phase of any type of BD versus placebo or an active comparator. All
antipsychotics approved by the Food and Drug Administration, except aripiprazole, had low-
strength evidence for benefit for acute mania in adults with BD-I. Lithium improved short-term
for acute mania and resulted in longer time to relapse in the long term versus placebo in adults
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