Briefly describe a specific question, or set of related questions, about a health care test or treatment that this program should consider.

For adult patients with bipolar disorder (including bipolar I and bipolar II disorder), what is the comparative effectiveness of available treatments including psychotherapy, other psychosocial treatments, medications, and other somatic treatments (e.g., electroconvulsive therapy) in specific types of bipolar episodes (e.g., mania, depression) and phases of treatment (e.g., acute, maintenance)?

What are the safety risks and adverse effects of available treatments for bipolar disorder, compared with placebo, and what are the relative rates of occurrence and the severity of the effects when these treatments are compared with each other?

Does your question include a comparison of different health care approaches? (If no, your topic will still be considered.)

yes

If yes, explain the specific technologies, devices, drugs, or interventions you would like to see compared:

Examples of comparisons that would be relevant include the following:

For treatment of a manic episode:

• Lithium vs. valproate vs. antipsychotic vs. carbamazepine vs. olanzapine-fluoxetine combination
• Monotherapy with any of these medications vs. adjunctive benzodiazepine
• Monotherapy vs. the combination of any of these medications

For treatment of a manic episode following inadequate response:

• Addition of another mood-stabilizing medication vs. placebo vs. switch to a different mood-stabilizing medication vs. switch to ECT

For treatment of a depressive episode:

• Lithium vs. lamotrigine vs. antipsychotic vs. olanzapine-fluoxetine combination vs. ECT
• Antidepressant monotherapy vs. any mood-stabilizing medication

For treatment of a depressive episode following inadequate response:

• Switch to lithium, lamotrigine, antipsychotic, or olanzapine-fluoxetine combination vs. lithium + lamotrigine vs. addition of pramiprexole vs. addition of modafinil vs. valproate vs. addition of an antidepressant vs. addition of psychotherapy

For maintenance treatment aimed at prevention of recurrent manic, depressive, or mixed episodes:

• Antipsychotic vs. lithium vs. lamotrigine vs. valproate vs. discontinuation of pharmacotherapy
• Treatment with the combination of two mood-stabilizing medications vs. monotherapy
• Addition of a psychotherapy (i.e., psychoeducation, CBT, interpersonal and social rhythm therapy, family-focused therapy) vs. treatment with maintenance medication(s) alone

For treatment of bipolar disorder co-occurring with a substance use disorder:

• Addition of a specific psychotherapy (e.g., motivational enhancement, behavioral, or cognitive behavioral) vs. treatment with maintenance medication(s) alone
• Addition of pharmacotherapy targeting the substance use disorder(s) vs. treatment with maintenance medication(s) alone

For treatment of bipolar disorder in women who are pregnant or planning to become pregnant:

• Lithium vs. val

What patients or group(s) of patients does your question apply to? (Please include specific details such as age range, gender, coexisting diagnoses, and indications for therapy.)

Adult patients with bipolar disorder, including bipolar I and bipolar II disorder

Are there subgroups of patients that your question might apply to? (For example, an ethnic group, stage or severity of a disease.)

Yes:

• Patients with inadequate response
• Patients with co-occurring substance use disorders
• Patients with co-occurring anxiety or anxiety disorders, e.g., PTSD
• Women who are pregnant or planning to become pregnant

Describe the health-related benefits you are interested in. (For example, improvements in patient symptoms or problems from treatment or diagnosis.)

• Remission of bipolar episode *

• Reduced frequency and severity of bipolar episodes

• Prevention of recurrent bipolar episodes

• Reduced suicide risk

• Improved treatment adherence

• Improved social and occupational functioning

• Improved health-related quality of life

• Remission of co-occurring substance use disorder

• Reduced impact of side effects of mood-stabilizing medications

• Note: Most studies have looked at "response" rather than remission.

Describe any health-related risks, side effects, or harms that you are concerned about.

• Adverse effects and safety risks of treatments for bipolar disorder, including to the fetus of women who are pregnant or planning to become pregnant
• Morbidity and mortality from bipolar disorder including suicide

Appropriateness for EHC Program

Does your question include a health care drug, intervention, device, or technology available (or likely to be available) in the U.S.?

yes

Which priority area(s) and population(s) does this topic apply to? (check all that apply)

EHC Priority Conditions (updated in 2008)

• Depression and other mental health disorders
• Functional limitations and disability
• Pregnancy, including preterm birth
• Substance abuse

AHRQ Priority Populations

• Low income groups
• Minority groups
• Women
• Elderly
• Individuals with special health care needs, including individuals with disabilities or who need chronic care or end-of-life health care

Federal Health Care Program

• Medicaid
• Medicare

Importance

Describe why this topic is important.

Bipolar disorder is one of the most common mental illnesses and is one of the most severe. It is characterized by recurrent episodes of mania and depression, which generally occur over a patient's entire adult life and cause serious impairments in functioning. Patients with bipolar disorder often have contact with the social welfare and legal systems. They also suffer serious psychosocial morbidity. Like all severe and persistent mental illnesses, bipolar disorder is difficult and costly to treat. Frequent hospitalization is common, as is comorbid substance abuse.

Epidemiologic studies indicate that approximately 1% of adults meet diagnostic criteria for bipolar I disorder at some point in their lifetime, and about 1% meet diagnostic criteria for bipolar II disorder (Merikangas et al. 2007), with other estimates from community samples yielding estimates of up to approximately 4% for both bipolar I and II (Kessler et al. 2005). These rates are consistent across diverse cultures and ethnic groups (Weissman et al. 1996). These estimates of prevalence are considered conservative, because of differences in diagnostic definitions and exclusion of persons who fall within the bipolar spectrum but do not meet all DSM-IV-TR criteria for bipolar I or bipolar II disorder (Akiskal et al. 2006; Angst et al. 2003).

Individuals with bipolar disorder have increased mortality rates compared with the general population as a whole (Osby et al. 2001), with higher than expected death from both natural and unnatural causes. They are 15 times more likely to die from suicide than persons in the general population (Osby et al. 2001; Harris & Barraclough 1997; Tondo et al. 2003). Suicide occurs in an estimated 7%–15% of individuals with bipolar disorder, with risk being generally higher early in the course of illness and for those with more severe illness (Goodwin & Jamison 2007).

The World Health Organization identified bipolar disorder as the fifth leading cause of years of life li

What specifically motivated you to ask this question? (For example, you are developing a clinical guideline, working with a policy with large uncertainty about the appropriate approach, costly intervention, new research you have read, items in the media you may have seen, a clinical practice dilemma you know of, etc.)

The American Psychiatric Association (APA) plans to develop clinical practice guidelines on the treatment of bipolar disorder. Since 1993, APA has published 24 evidence-based guidelines on 14 mental health topics, including two previous editions of guidelines on bipolar disorder, in 1994 and 2002. In 2011, APA revised its guideline development process in accordance with new standards recommended by the Institute of Medicine (2011).

Does your question represent uncertainty for clinicians and/or policy-makers? (For example, variations in clinical care, controversy in what constitutes appropriate clinical care, or a policy decision.)

yes

If yes, please explain:

Bipolar disorder is a difficult illness to treat. Available treatments have differential efficacy depending on polarity of episode (manic or depressive) and stage of illness (acute or chronic). Effectiveness is influenced by patient factors including general medical and psychiatric comorbidities such as substance use disorders. Moreover, all mood-stabilizing medications carry risks of adverse effects, some serious but rare (e.g., Stevens-Johnson syndrome with lamotrigine), others less serious but common (e.g., weight gain with antipsychotics). Because of the need to monitor for and manage adverse effects and because of the need to frequently change medication regimens, patient engagement and adherence is critical to treatment success, yet adherence is often compromised by the episodic nature of the illness and by psychosocial morbidity including social and occupational instability.

Uncertainty about how to best care for patients with bipolar disorder also results from the difficulty of interpreting evidence for available mood-stabilizing medications. Placebo-controlled studies have used different outcomes. Head-to-head studies are lacking or have used inadequate dosing of the comparator. Old studies of off-patent medications such as lithium did not use robust study designs. Newer industry-funded studies have used better designs have also tended to use selective comparators, populations, and outcomes. Long-term effectiveness studies in typical patients, e.g., patients with common psychiatric and general medical comorbidities, are lacking. Harms data are also lacking.

In a 2011 survey of more than 200 clinicians (with 67 responding), the American Psychiatric Association found that a majority "strongly agreed" or "agreed" that the usual treatment of patients with bipolar disorder is not aligned with best practice (APA unpublished data). Studies using claims data have come to similar conclusions: In a study of 1,864 patients, Lim et al. (2001) reported that a subs

Potential Impact

How will an answer to your research question be used or help inform decisions for you or your group?

A systematic review on the above research questions will be used to inform new APA practice guidelines on bipolar disorder.

Describe the timeframe in which an answer to your question is needed.

Guidelines can be initiated as soon as a systematic review is available. The American Psychiatric Association develops clinical practice guidelines using a defined process that is designed to meet standards recommended by the Insitute of Medicine. Experts are already appointed to a work group that is writing new guidelines across topics. Advisors to this group with specific expertise in bipolar disorder are available to begin work immediately.

Describe any health disparities, inequities, or impact on vulnerable populations your question applies to.

Numerous reports have documented racial, ethnic, and socioeconomic disparities in access to care and the quality of care received by individuals with mental illnesses (Office of the Surgeon General 2001; Institute of Medicine 2003; New Freedom Commission on Mental Health 2003; Agency for Healthcare Research and Quality 2012).

These reports have also highlighted inequalities in health care outcomes for individuals with severe mental illness, such as bipolar disorder. The lifespan of people with severe mental illness is shorter compared to the general population (de Hert et al. 2011), mainly because of co-occurring general medical illnesses and substandard care for these illnesses. For example, the largest number of excess deaths are from common physical illnesses including cardiovascular disease, cancers, and respiratory illnesses (Lawrence and Kisely 2010).

Studies have also found health disparities for patients with bipolar disorder specifically. McIntyre et al. (2007) found that chronic health problems in patients with bipolar disorder tend to be under-recognized and suboptimally treated. In a study of Medicaid claims data, Busch et al. (2009) found disparities in the use of antimanic medications by whites with bipolar I disorder vs. African Americans.

Nominator Information

Other Information About You: (optional)

Please choose a description that best describes your role or perspective: (you may select more than one category if appropriate)

A systematic review on the above research questions will be used to inform new APA practice guidelines on bipolar disorder.

Are you making a suggestion as an individual or on behalf of an organization?

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