Exclusion Criteria for Bipolar Trials Cast Doubt on Generalizability

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Patients with bipolar disorder may have psychiatric comorbidities and medical conditions that preclude their participation in clinical trials.
Patients with bipolar disorder may have psychiatric comorbidities and medical conditions that preclude their participation in clinical trials.

Clinical trials investigating the pharmacologic treatment of bipolar disorder typically use eligibility criteria that preclude the participation of the majority of affected patients, casting doubt about the generalizability and clinical relevance of the trial results.

Traditionally, researchers conducting trials on treatments for psychiatric disorders rigorously control patient variables in order to ensure that any symptoms and impairments can be confidently ascribed to the disorders under investigation and to increase the likelihood that patients will demonstrate treatment responses in a homogeneous fashion. However, the use of restrictive eligibility criteria can result in the evaluation of treatments in a study population that differs substantially from patients seen in everyday clinical practice.

Many patients with bipolar disorder have psychiatric comorbidities and medical conditions that preclude their participation in clinical trials. Patients who do not meet eligibility criteria are frequently older and face more socioeconomic challenges, including lower income, less education, unemployment, and unstable housing.1 Yet when researchers draw conclusions from their findings, their statements typically do not acknowledge the impact of eligibility criteria on the generalizability of their results to all or most patients diagnosed with bipolar disorder.1

In a recent review, Jessie J. Wong, PhD, of the Center for Innovation to Implementation at VA Palo Alto Health Care System, California, and colleagues analyzed studies of eligibility criteria in clinical trials for bipolar disorder and their impact on sample representativeness or study results. Across the 8 identified studies, the percentage of patients ineligible for clinical trials ranged from 55% to 96%. The criteria that accounted for the greatest percentage of exclusion across studies were comorbid substance use disorder, suicide risk, major medical disorders, and failure to meet requirements for minimum symptom severity.2

In another review, Mark Zimmerman MD, of Brown University School of Medicine in Providence, Rhode Island, and colleagues examined the inclusion and exclusion criteria used in all placebo-controlled trials of medications for bipolar depression published over a 20-year span between January 1995 and December 2014. Results showed that patients with suicidal ideation, a history of substance abuse disorders, or psychiatric comorbidities were excluded from the majority of trials.3

For more perspective on the generalizability of clinical trial results in bipolar disorder, Psychiatry Advisor interviewed Nicolas Hoertel, MD, MPH, PhD, of the department of psychiatry at Corentin-Celton Hospital, Issy-les-Moulineaux, France. Dr Hoertel has been involved in several studies analyzing the generalizability of clinical trial results in bipolar disorder and other psychiatric conditions.4-7

Psychiatry Advisor: In their recent review, Wong and colleagues concluded that 3 of 4 patients with bipolar disorder would not be eligible for clinical trials. Given this, can findings from clinical trials be safely and confidently applied in clinical practice?

Dr Hoertel: Results from this important review support the idea that pharmacologic trials for bipolar disorder typically include unrepresentative samples because they tend to exclude bipolar patients with psychiatric or general medical comorbidities. However, most patients with bipolar disorder do have such comorbidities. Therefore, these exclusionary practices can reduce the confidence of clinicians that findings from these trials can be translated to frontline practice in patients with bipolar disorder with psychiatric or general medical comorbidities. This highlights the importance of observational studies and postmarketing surveillance to monitor drug safety in these patients.

Psychiatry Advisor: How can researchers broaden eligibility criteria for clinical trials without confounding the results?

Dr Hoertel: For clinical trials to adequately inform clinical practice, the eligibility fraction must be increased by a progressive broadening of eligibility criteria. First, the use of exclusion criteria in response to concerns about patient safety such as pregnancy or significant medical conditions, study feasibility, and interpretability of results is justified and necessary. However, the use of certain criteria such as substance use disorders or anxiety disorders may mostly reflect a tradition that has evolved over time, resulting in progressive, unnecessary narrowing of the population of eligible patients. This is particularly true for pharmacologic trials the generalizability of which has not increased in recent years, in contrast to psychotherapy trials. In this context, there is a need to carefully consider the advantages and disadvantages of applying each exclusion criterion that is not dedicated to increasing patient safety. Second, conducting trials in the subpopulations typically excluded from trials, such as individuals with substance use disorders, may help inform clinical practice. Finally, developing integrated forms of pharmacotherapy and psychotherapy that can simultaneously target several psychiatric disorders may yield even more informative results.

Psychiatry Advisor: What would be the likely impact of broadening the eligibility criteria for clinical trials in bipolar disorder? Would this typically result in findings of greater or lesser efficacy for the treatments being evaluated?

Dr Hoertel: The inclusion of narrowly defined uncomplicated subjects may lead to greater treatment effects. Indeed, comorbid psychiatric disorders and medical conditions are an important source of heterogeneity in treatment response, and prior research suggests that patients with psychiatric or general medical comorbidities tend to have poorer treatment outcomes. This incentive may be greater since the current US Food and Drug Administration (FDA) labelling does not reflect the study subject selection process. Specifically, the FDA indication drawn from these trials is for “bipolar disorder,” not “uncomplicated bipolar disorder.” There is an inherent tension between the wish of investigators and manufacturers to obtain positive trial results and the clinical interests of patients and their providers who seek information from broadly representative studies. In this context, there is a need to carefully balance internal validity (the extent to which a causal conclusion based on a study is warranted) and external validity (the applicability of clinical trial results to routine clinical settings) while ensuring participant safety.


  1. Humphreys K, Williams LM. What can treatment research offer general practice?The Lancet Psychiatry. 2018;5:295-297.
  2. Wong JJ, Jones N, Timko C, Humphreys K. Exclusion criteria and generalizability in bipolar disorder treatment trials.Contemp Clin Trials Commun. 2018;9:130-134.
  3. Zimmerman M, Holst CG, Clark HL, et al. The psychiatric inclusion and exclusion criteria in placebo-controlled monotherapy trials of bipolar depression: an analysis of studies of the past 20 years.CNS Drugs. 2016;30:1209-1218.
  4. Blanco C, Hoertel N, Franco S, et al. Generalizability of clinical trial results for adolescent major depressive disorder.Pediatrics. 2017;140.
  5. Hoertel N, Le Strat Y, Lavaud P, Dubertret C, Limosin F. Generalizability of clinical trial results for bipolar disorder to community samples: findings from the National Epidemiologic Survey on Alcohol and Related Conditions.J Clin Psychiatry. 2013;74:265-270.
  6. Franco S, Hoertel N, McMahon K, et al. Generalizability of pharmacologic and psychotherapy clinical trial results for posttraumatic stress disorder to community samples.J Clin Psychiatry. 2016;77:e975-981.
  7. Hoertel N, López S, Wang S, González-Pinto A, Limosin F, Blanco C. Generalizability of pharmacological and psychotherapy clinical trial results for borderline personality disorder to community samples.Personal Disord. 2015;6:81-87.
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