Prioritization of Research Addressing Antipsychotics for Adolescents and Young Adults With Bipolar Disorder

Bipolar disorder is characterized by episodes of mania (mood elevation, delusions, and extreme behaviors) alternating with severe depressive symptoms. It may develop during childhood or adolescence, and symptoms seem to be more severe when onset occurs at a young age (1, 2). Adolescents and young adults (aged <25 years) with bipolar disorder have high rates of substance abuse, hospitalization, legal issues, academic and psychosocial functional impairment, and suicide. These outcomes may occur more frequently when bipolar disorder coexists with other psychiatric disorders, low socioeconomic status, or abuse. The disorder also affects relationships and the financial security of the families. Up to 2.7% of persons aged 12 to 21 years have bipolar disorder, although rates may approach 5% when those with subsyndromal manic symptoms, who are also at elevated risk for morbidity, are included in estimates (3). Diagnosing the disorder in adolescents and young adults is complex and requires longitudinal assessment. Bipolar disorder may be difficult to distinguish from other disorders affecting adolescents and young adults, such as attention-deficit hyperactivity disorder and behavioral disorders, and diagnosis is further complicated by the fact that bipolar disorder may coexist with these other disorders. Psychiatric interviews and rating scales can be used for screening by trained clinicians, and parent-report instruments have also been used (46). Recovery is achievable in most adolescents and young adults with bipolar disorder (710), but almost 80% of the affected population relapse within 2 to 5 years (9). Options for treating the disorder include medications (for example, antipsychotic drugs, lithium, and certain antiepileptic drugs), behavioral therapy interventions, and peer support. A lack of high-quality longitudinal studies comparing the effectiveness of different therapeutic options in adolescents and young adults complicates treatment of this population. The use of antipsychotic agents to treat bipolar disorder in adolescents and young adults has increased significantly during the past 20 years (11). Several factors have contributed to this occurrence. First, high-quality randomized, placebo-controlled trials have shown that second-generation antipsychotics are effective antimanic agents (12). On the basis of these data, aripiprazole, olanzapine, risperidone, and quetiapine have received regulatory approval for pediatric bipolar mania. Second, head-to-head trials have shown second-generation antipsychotics to be superior to valproic acid and lithium for treating mania in children and adolescents (1315). Finally, recent promotion by the pharmaceutical industry spurred by new indications for pediatric bipolar disorder has increased use of second-generation antipsychotics. However, use of antipsychotics in adolescents and young adults remains controversial because of the paucity of population-specific data on which to base practice recommendations (16) and existing concern that bipolar disorder diagnosis may be applied too broadly, including for patients with chronic mood dysregulation (17). The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, includes a new diagnosisdisruptive mood dysregulation disorderto reduce premature bipolar disorder assignment, but concerns about the validity of this new diagnosis have been raised (18, 19). Antipsychotic medications may also produce significant adverse effects (16, 20). First-generation antipsychotics can cause extrapyramidal symptoms, dry mouth, sedation, and the neuroleptic malignant syndrome, whereas second-generation antipsychotics can cause weight gain, diabetes, dyslipidemia, and hyperprolactinemia. Because antipsychotic use among adolescents and young adults with bipolar disorder is increasing despite significant clinical uncertainty, further research exploring the comparative effectiveness of antipsychotics on patient-centered outcomes in these populations is needed. Using a process described on the Patient-Centered Outcomes Research Institute (PCORI) Web site and in our companion paper (21), a PCORI advisory panel has identified this topic as being of high interest for potential targeted funding. Accordingly, PCORI tasked the Duke Evidence Synthesis Group with creating a prioritized agenda for research in this area that would incorporate the perspectives of relevant stakeholders. Methods The Appendix Figure and the companion paper (21) detail the methods used to prioritize future research and develop recommendations. We surveyed existing literature with a focus on systematic reviews (2008 to 2013), particularly an Agency for Healthcare Research and Quality report identifying future research needs for antipsychotic use in children and young adults with various psychiatric conditions (22, 23). On the basis of recommended areas for future research from these sources, we developed a draft list of 21 possible evidence gaps (Table 1 of the Supplement). Appendix Figure. Overview of prioritization process. Adapted from reference 27 ESG = Evidence Synthesis Group; PCORI = Patient-Centered Outcomes Research Institute. Supplement. Supplementary Data for Prioritization of Research Addressing Antipsychotics for Adolescents and Young Adults With Bipolar Disorder We then engaged a group of 9 stakeholders, which included clinical experts and researchers in bipolar disorder, representatives from federal and nongovernmental funding agencies, representatives from relevant professional societies, health care decision makers and policymakers, and representatives from related consumer and patient advocacy groups (Table 2 of the Supplement). In each of these categories, we identified a person with clinical or methodological expertise. We received feedback on potential stakeholders from the Research Triangle Institute-University of North Carolina Evidence-based Practice Center, which wrote the aforementioned future research needs report on antipsychotic use in children and young adults (23), and from PCORI's patient engagement group. Potential stakeholders completed a statement of disclosure and were screened for conflicts of interest. We sought input from these stakeholders on our draft list of possible evidence gaps, and we modified certain gaps and added others on the basis of their feedback, which led to a finalized list. From this list, we constructed an analytic framework (Figure) by adapting a previously used framework and incorporating the stakeholder-refined list of possible evidence gaps (23). By using a forced-ranking prioritization method (24), stakeholders then prioritized the list of possible evidence gaps through Web-based surveys. We used this input to rank the finalized list of possible evidence gaps into 3 tiers of priority. Figure. Analytic framework. For topics related to the 10 highest-priority (top-tier) evidence gaps, we did a horizon scan for recent and ongoing studies by searching PubMed and ClinicalTrials.gov (2008 to 2013) for projects that presented original data or secondary analysis of data from a randomized, controlled trial (RCT), prospective or retrospective observational study, or registry; included data on first- and second-generation antipsychotic medications; included adolescents or young adults with bipolar disorder; and included outcomes that could be categorized according to the identified list of research priorities. Our search strategy is presented in Table 3 of the Supplement. We then determined the most appropriate study designs for the 10 stakeholder-ranked research areas of highest priority. Role of the Funding Source Funding for this work was provided by PCORI. The funding source stipulated the topic for prioritization but did not participate in the literature search, determination of study eligibility criteria, data analysis or interpretation, or preparation and approval of the manuscript for publication. The funding source did review a draft version of the manuscript and provided suggestions to clarify language describing the process in selecting this topic for prioritization. Results Expansion of Evidence Gaps Through Stakeholder Engagement All 9 invited stakeholders participated in teleconferences to refine and expand the initial list of 21 evidence gaps (Table 1 of the Supplement). Three themes emerged during these discussions, which informed our expansion of the list. First, stakeholders highlighted how uncertainty in distinguishing bipolar disorder from attention-deficit hyperactivity disorder and other behavioral disorders can complicate diagnosis and interpretation of existing research in younger patients. This uncertainty often necessitates treatment in the absence of a firm diagnosis, which may confound outcome ascertainment. In addition to diagnostic uncertainty, stakeholders pointed to uncertainty in how phase and severity of illness are best measured and how these factors affect treatment choices. Second, our stakeholders discussed how our focus on adolescents and young adults requires consideration of a broad set of patient-centered outcomes in potential studies. These include outcomes measured over long periods; developmental outcomes; functional status outcomes; outcomes relating to parents, caregivers, or family members, including economic outcomes; and outcomes related to offspring in women of childbearing age (such as pregnancy, neonatal, and childhood outcomes). Finally, although the specific clinical domain addressed by this project focused on antipsychotic drug therapy, our stakeholders emphasized that the efficacy of such therapy for bipolar disorder in adolescents and young adults compared with alternative drug classes remains uncertain for many subgroups of patients. As such, stakeholders believed that attention needed to be given to research comparing antipsychotics with alternative treatment strategies, including lithium, antiepileptic drugs, and adjunctive nonpharmacologic treatments (such