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

Transcription

1 Supplementary Data for Prioritization of Research Addressing Antipsychotics for and Young Adults With Bipolar Disorder Data Supplement Table 1. Initial list of evidence gaps based on prior topic brief PICO Element Potential Future Research Need Population 1. How do psychiatric and medical comorbidities affect the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder? Intervention and Comparator Outcome 2. How do demographic differences (such as age, race, sex) affect the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder? 3. How do health risk behaviors (such as diet, exercise, substance abuse, nonadherence) affect the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder? 4. How do genetic differences affect the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder? 5. What are the comparative safety and effectiveness of using specific antipsychotic classes/agents in adolescents/young adults with bipolar disorder? 6. What are the comparative safety and effectiveness of differences in dose and dosing interval of antipsychotic drug treatment in adolescents/young adults with bipolar disorder? 7. What are the comparative safety and effectiveness of alternative medication classes (such as lithium or antiepileptic drugs like lamotrigine or valproic acid) compared with conventional antipsychotic drugs in adolescents/young adults with bipolar disorder? 8. What are the comparative safety and effectiveness of monotherapy compared to combination medical therapy with antipsychotic drugs in adolescents/young adults with bipolar disorder? 9. What are the comparative safety and effectiveness of monotherapy with antipsychotic drugs compared to combination antipsychotic drug plus psychotherapy in adolescents/young adults with bipolar disorder? 10. What are the comparative safety and effectiveness of concurrent psychiatric medications (such as antidepressants, anxiolytics, stimulants) given as adjuncts to antipsychotic drugs in adolescents/young adults with bipolar disorder? 11. What are the comparative effects of antipsychotic treatment of adolescents/young adults with bipolar disorder on patient- and family-centered outcomes, and what is the relative importance of these outcomes? 12. What are the comparative effects of antipsychotics on core disease features in adolescents/young adults with bipolar disorder? 13. What are the comparative effects of antipsychotics on physical, cognitive, and emotional development in adolescents/young adults with bipolar disorder? 14. What are the comparative effects of antipsychotics on commonly associated comorbidities and behavioral features in adolescents/young adults with bipolar disorder? 15. What are the comparative effects of antipsychotics on social/academic/occupational functioning in adolescents/young adults with bipolar disorder? 16. What are the comparative effects of antipsychotics on outcomes related to high risk behaviors in adolescents/young adults with bipolar disorder? 17. What are the comparative effects of antipsychotics on suicide-related behavior in adolescents/young adults with bipolar disorder? 18. What are the comparative effects of antipsychotics on utilization and costs in adolescents/young adults with bipolar disorder? 1

2 PICO Element Potential Future Research Need 19. What are the comparative effects antipsychotic classes/agents on adherence and persistence with drug therapy in adolescents/young adults with bipolar disorder? 20. What are the short-term adverse effects of medication exposure between and within antipsychotic classes for adolescents/young adults with bipolar disorder? 21. What are the long-term risks of medication exposure between and within antipsychotic classes for adolescents/young adults with bipolar disorder? 2

3 Data Supplement Table 2. Stakeholder organizations and roles Organization Stakeholder Perspective Purpose American Academy of Child and Adolescent Psychiatrists (AACAP) American Academy of Pediatrics (AAP) American Psychiatric Association (APA) American Society of Clinical Psychopharmacology (ASCP) National Federation of Families for Children s Mental Health Professional societies/researchers Professional societies/researchers Professional societies/researchers Professional societies/researchers Consumer and patient advocacy The AACAP seeks to promote the healthy development of children, adolescents, and families through research, training, advocacy, prevention, and comprehensive diagnosis and treatment, and to meet the professional needs of child and adolescent psychiatrists throughout their careers. The AAP is a professional membership organization of 60,000 primary care pediatricians, pediatric medical subspecialists, and pediatric surgical specialists dedicated to the health, safety, and well-being of infants, children, adolescents and young adults. The APA, founded in 1844, is the world s largest psychiatric organization. It is a medical specialty society representing more than 33,000 psychiatric physicians from the United States and around the world. Its member physicians work together to ensure humane care and effective treatment for all persons with mental disorders, including intellectual disabilities and substance use disorders. APA is the voice and conscience of modern psychiatry. The ASCP was founded in 1992 to advance the science and practice of clinical psychopharmacology. Its nearly 800 members are physicians who study and practice psychopharmacology, and doctoral-level investigators of clinical psychopharmacology or of pharmacology. ASCP members are advocates for clinical psychopharmacology and clinical research. The National Federation of Families for Children s Mental Health is a national family-run organization linking more than 120 chapters and state organizations focused on the issues of children and youth with emotional, behavioral, or mental health needs and their families. The National Federation works to develop and implement policies, legislation, funding mechanisms, and service systems that utilize the strengths of families. Its emphasis on advocacy offers families a voice in the formation of national policy, services, and supports for children with mental health needs and their families. Patient Advocate Consumer and patient advocacy We identified a patient advocate to represent the research priorities and issues from the patient (and family) perspective. 3

4 Data Supplement Table 3. Exact Search Strategy Set # Terms Results #1 bipolar disorder[mesh] OR "bipolar disorder"[tiab] OR "bipolar affective disorder"[tiab] #2 ( Adolescent [Mesh]) OR ( Young Adult [Mesh]) #3 social support[mesh] OR family[tiab] OR peer[tiab] OR "Nutrition Therapy"[Mesh] OR "Exercise"[Mesh] OR "Exercise Therapy"[Mesh] OR "Exercise Movement Techniques"[Mesh] OR diet therapy [mesh] OR exercise[tiab] OR "physical activity"[tiab] OR diet[tiab] OR diets[tiab] OR weight management [tiab] OR "Behavior Therapy"[Mesh] OR health education[mesh] OR health promotion[mesh] OR counsel*[tiab] OR counseling[mesh] OR disease management [mesh] OR cognitive behavioral therapy [tiab] OR lifestyle modification [tiab] OR ( life style [mesh] AND modification[tiab]) OR "Patient Compliance"[Mesh] OR adher*[tiab] OR self-monitoring [tiab] OR "Recurrence/prevention and control"[mesh] OR relapse prevention [tiab] OR skills training [tiab] OR motivational interviewing [tiab] OR educat*[tiab] #4 chlorpromazine[mesh] OR chlorpromazine[tw] OR thorazine[tw] OR fluphenazine[mesh] OR fluphenazine[tw] OR haloperidol[mesh] OR haloperidol[tw] OR haldol[tw] OR iloperidone[supplementary Concept] OR iloperidone[tw] OR fanapt[tw] OR loxapine[mesh] OR loxapine[tw] OR loxitane[tw] OR molindone[mesh] OR molindone[tw] OR moban[tw] OR chlorpromazine[mesh] OR chlorpromazine[tw] OR thorazine[tw] OR perphenazine[mesh] OR perphenazine[tw] OR pimozide[mesh] OR pimozide[tw] OR orap[tw] OR thioridazine[mesh] OR thioridazine[tw] OR thiothixene[mesh] OR thiothixene[tw] OR navane[tw] OR trifluoperazine[mesh] OR trifluoperazine[tw] OR stelazine[tw] OR clozapine[mesh] OR clozapine[tw] OR clozaril[tw] OR risperidone[mesh] OR risperidone[tw] OR risperidal[tw] OR olanzapine[supplementary Concept] OR olanzapine[tw] OR zyprexa[tw] OR quetiapine[supplementary Concept] OR quetiapine[tw] OR seroquel[tw] OR ziprasidone[supplementary Concept] OR ziprasidone[tw] OR geodon[tw] OR aripiprazole[supplementary Concept] OR aripiprazole[tw] OR abilify[tw] OR 9-hydroxy-risperidone[Supplementary Concept] OR "9-hydroxy-risperidone"[tw] OR paliperidone[tw] OR invega[tw] OR antipsychotic agents[mh] OR antipsychotic agents[pharmacological action] OR antipsychotic[tiab] OR antipsychotics[tiab] #5 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR clinical trial [tiab] OR clinical trials [tiab] OR "comparative study"[publication Type] OR "comparative study"[tiab] OR systematic[subset] OR "meta-analysis"[publication Type] OR "meta-analysis as topic"[mesh Terms] OR "meta-analysis"[tiab] OR "meta-analyses"[tiab]) OR (("Decision Support Techniques"[Mesh] OR "evaluation studies"[publication Type] OR "evaluation studies as topic"[mesh Terms] OR "evaluation study"[tiab] OR evaluation studies [tiab] OR "intervention studies"[mesh Terms] OR "intervention study"[tiab] OR "intervention studies"[tiab] OR "case-control studies"[mesh Terms] OR "case-control"[tiab] OR "cohort studies"[mesh Terms] OR cohort[tiab] OR "longitudinal studies"[mesh Terms] OR "longitudinal [tiab] OR longitudinally[tiab] OR "prospective"[tiab] OR prospectively[tiab] OR "retrospective studies"[mesh Terms] OR "retrospective"[tiab] OR "follow up"[tiab]) AND ("2000"[Date - Publication] : "3000"[Date - Publication])) NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp]) NOT (animals[mh] NOT humans[mh]) #6 (#1 AND #2) AND (#3 OR #4) AND # #7 Limits: English, Date: past 5 yrs (2008 to 3000) 580 4

5 Data Supplement Table 4. Published and ongoing studies potentially relevant to Research Question 11 [What are the comparative safety and effectiveness of antipsychotic monotherapy compared to combination therapy with medications from the mood stabilizing class in adolescents/young adults with bipolar disorder?] Study N Population Objective Systematic Reviews Ben Amor, 2012 (1) 36 studies To provide a comparative review of the safety data available for antipsychotic drug use in pediatric populations. Correll, 2010 (2) 9 studies To compare antipsychotic and mood stabilizer efficacy and tolerability in youth and adults with bipolar mania. Fraguas, 2011 (3) 34 studies To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with psychotic and bipolar spectrum disorders. RCTs Cohort Studies Duffy, 2009 (4) 21 To determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent diagnosed with bipolar disorder. Case-Control Studies Models Ongoing Studies (ClinicalTrials.gov) Efficacy Study of Quetiapine Plus Topiramate for Reducing Cannabis Consumption and Bipolar Mania (NCT ) Efficacy and Tolerability of Topiramate in Treatment of Bipolar Mania and Alcohol Use in and Young Adults (NCT ) 90, Young Adults 31, Young Adults Ongoing (estimated completion December 2013). To determine whether this treatment may be useful for reducing cannabis consumption; reducing symptoms of bipolar mania; and weight mitigation therapy for individuals on psychopharmacotherapy. Completed. To study the effects (both good and bad) of combining quetiapine and topiramate for treating symptoms of bipolar mania (an illness with periods of elation, excessive excitement, irritability, high energy, racing thoughts, poor sleep, poor judgment, reckless behavior) and to study the effects (both good and bad) of combining quetiapine and topiramate for reducing use of alcohol. 5

6 Study N Population Objective Study of the Efficacy of Adjunctive Lithium Treatment for the Treatment of Psychotic Mania (NCT ) 40 Ongoing (estimated completion September 2015). The proposed pilot study is a placebocontrolled, parallel group, randomized clinical trial comparing two treatment strategies in adolescents with mania and prominent psychotic features. One group will receive a second generation antipsychotic (SGA) and placebo and the other will receive a SGA and Topiramate vs. Placebo in Preventing Weight Gain in Bipolar Disorder Treated With Olanzapine (NCT ) Treatment and Outcome of Early Onset Bipolar Disorder (NCT ) Comparison of Combination Olanzapine + Lithium or Chlorpromazine + Lithium in Treatment of First Manic Episode With Psychotic Features (NCT ) lithium. 31 Completed. To examine the efficacy of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder. The secondary objective is to examine the tolerability of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder. 40 Completed. To compare the effectiveness in the maintenance of continuing adjunctive atypical antipsychotic medication compared to traditional mood stabilizer(s) alone in the maintenance treatment of adolescents with bipolar disorder. 75, Young Adults Abbreviation: RCTs=randomized controlled trials Unknown. To compare the side-effect profile, the degree of adherence, and the subjective well-being, as well as the efficacy of two treatments: The standard treatment currently applied (lithium + chlorpromazine) and an alternative treatment more recently introduced (lithium + olanzapine). In addition, to study retrospectively the development of bipolar disorder and study prospectively the 6- and 12- month outcome of a cohort of presenting a first manic episode with psychotic features. Data Supplement Table 5. Published and ongoing studies potentially relevant to Research Question 19 [What are the comparative effects of antipsychotics on social, academic, and occupational functioning in adolescents/young adults with bipolar disorder?] Study N Population Objective Systematic Reviews Doey, 2012 (5) 140 studies, Young Adults RCTs Findling, 2013 (6) 210 To review existing literature and to summarize the experience with aripiprazole in youth with psychotic and mood disorders. To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar disorder. 6

7 Study N Population Objective Lunsford-Avery, 2012 (7) 53 To examine the longitudinal associations between sleep disruption, mood symptom severity, and psychosocial functioning in a 2- year followup of with adolescent bipolar spectrum disorder who were randomized to family-focused treatment for adolescents or to enhanced care, a briefer psychoeducational treatment; both treatments were administered with pharmacotherapy. West, 2011 (8) 65 To examine comorbid disruptive behavior disorders and aggression prospectively as predictors of pharmacotherapy outcome, as well as potential moderators of response to a specific medication (risperidone vs. divalproex), among children with pediatric bipolar disorder. Cohort Studies Duffy, 2009 (4) 21 To determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent diagnosed with bipolar disorder. Stewart, 2009 (9) 46 To examine global functioning, health-related quality of life, and clinical outcome in children and adolescents with bipolar disorder, schizophrenia, or schizoaffective disorder following ziprasidone treatment. Jerrell, 2008 (10) 82 To examine the services and medications received, and psychosocial functioning changes over time of children and adolescents with bipolar disorder in a public mental health system. Jerrell, 2008 (11) 82 To examine differences between children and adolescents with bipolar disorder in a public mental health system. Case-Control Studies Models Ongoing Studies (ClinicalTrials.gov) Abbreviation: RCTs=randomized controlled trials 7

8 Data Supplement Table 6. Published and ongoing studies potentially relevant to Research Question 15 [What are the key patient-centered and family-centered outcomes for adolescents/young adults with bipolar disorder and their families, and how are these outcomes affected by different antipsychotic classes/agents?] Study N Population Objective Systematic Reviews Ben Amor, 2012 (1) 36 studies To provide a comparative review of the safety data available for antipsychotic drug use in pediatric populations. Doey, 2012 (5) 140 studies, Young Adults RCTs Findling, 2009 (12) 296 Findling, 2013 (Findling, 2013 #8} 210 Olsen, 2012 (13) 160 To review existing literature and to summarize the experience with aripiprazole in youth with psychotic and mood disorders. To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar disorder, manic or mixed episode, with or without psychotic features. To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. To examine health-related quality of life in adolescents with bipolar disorder before and after double-blind treatment with olanzapine or placebo. Sullivan, 2012 (14) 58 To examine family functioning and its relationship to symptoms of adolescent bipolar disorder, using longitudinal measures of family cohesion, adaptability, and conflict. West, 2011 (15) 66 To evaluate the sensitivity of the Child Mania Rating Scale to detect symptom change over time in a treatment study for pediatric bipolar disorder. Cohort Studies Lee, 2013 (16) 29 Young Adults Findling, 2012 (17) 296 To determine if clinical symptoms and neuropsychological deficits are longitudinally associated with functional outcome in young and early-course psychiatric out, with the aim of identifying cognitive markers that predict later socio-occupational functioning. This was a post-hoc analysis of data from a 4- week, randomized, double-blind, placebocontrolled study to evaluate which informants, parents or subjects, detect a response to treatment with aripiprazole in pediatric subjects experiencing a mixed or manic episode associated with bipolar disorder. 8

9 Study N Population Objective Algorta, 2011 (18) 138 Case-Control Studies Macneil, 2012 (19) 40, Young Adults Models Ongoing Studies (ClinicalTrials.gov) Aripiprazole in Children and With Bipolar Disorder and Attention Deficit Hyperactivity Disorder (ADHD) (NCT ) Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder (P06107 AM4) (NCT ) (P06107 has an extension (P05898; NCT ) To examine the relationship between suicidal behavior, mood symptom presentation, family functioning, and quality of life in youth with pediatric bipolar disorder. To assess whether a manualized psychological intervention could be effective in reducing symptomatology and relapse, and improve functional outcome in a young, first-episode cohort. 50 Completed. This study aims to assess the efficacy of aripiprazole (a novel antipsychotic drug) for the treatment of children and adolescents with bipolar disorder comorbid with ADHD. 400 Ongoing (estimated completion September 2014). To evaluate efficacy and safety of asenapine for the treatment of bipolar disorder (manic or mixed episodes) in participants between 10 and 17 years old, who are either hospitalized or nonhospitalized. In this 3-week, double-blind, parallel design trial, eligible for participation will be randomized to receive one out of three fixed-dose levels of asenapine, or placebo. Abbreviations: ADHD=attention deficit hyperactivity disorder; RCTs=randomized controlled trials Data Supplement Table 7. Published and ongoing studies potentially relevant to Research Question 12 [What are the comparative safety and effectiveness of concurrent psychiatric medications not belonging to the mood stabilizing class given as adjuncts to antipsychotic drugs in adolescents/young adults with bipolar disorder?] Study N Population Objective Systematic Reviews RCTs Zeni, 2009 (20) 16 To conduct a randomized crossover trial with methylphenidate and placebo combined with aripiprazole in children and adolescents with juvenile bipolar disorder and ADHD who had a significant response in manic symptoms with aripiprazole but still presented clinically significant symptoms of ADHD. 9

10 Study N Population Objective Cohort Studies Chang, 2009(21) 12 To evaluate the effects of Atomoxetine on youth with a diagnosis of bipolar disorder I or II and ADHD. Case-Control Studies Models Ongoing Studies (ClinicalTrials.gov) Aripiprazole Associated With Methylphenidate in Children and With Bipolar Disorder and ADHD (NCT ) A Study for Assessing Treatment of Patients Ages With Bipolar Depression (NCT ) 20 Completed. To assess the efficacy of aripiprazole associated with methylphenidate for the treatment of children and adolescents with bipolar disorder comorbid with ADHD who improve in maniac symptoms while receiving aripiprazole but did not have an adequate response in ADHD symptoms. 291 Completed. To help answer the following research question(s): Can this study drug make children with bipolar depression feel better? Does this study drug work better than a placebo (sugar pill)? Does this study drug cause side effects in children who take it? Is this drug safe to use in children? (The study drug is a mixture of olanzapine and fluoxetine.) Abbreviations: ADHD=attention deficit hyperactivity disorder; RCTs=randomized controlled trials Data Supplement Table 8. Published and ongoing studies potentially relevant to Research Question 13 [What are the comparative safety and effectiveness of mood stabilizing medication classes (e.g., lithium or antiepileptic drugs like lamotrigine or valproic acid) compared with antipsychotic drugs in adolescents/young adults with bipolar disorder?] Study N Population Objective Systematic Reviews Correll, 2010 (2) 9 studies To compare antipsychotic and mood stabilizer efficacy and tolerability in youth and adults with bipolar mania. RCTs Geller, 2012 (22) 61 To investigate which medication to administer first to antimanic, medication-i children and adolescent subjects. Pavuluri, 2011 (23) 46 To determine the relative effects of risperidone and divalproex on brain function in pediatric mania. West, 2011 (15) 66 To evaluate the sensitivity of the Child Mania Rating Scale to detect symptom change over time in a treatment study for pediatric bipolar disorder. 10

11 Study N Population Objective West, 2011 (8) 65 To examine comorbid disruptive behavior disorders and aggression prospectively as predictors of pharmacotherapy outcome, as well as potential moderators of response to a specific medication (risperidone vs. divalproex), among children with pediatric bipolar disorder. Pavuluri, 2010 (24) 66 To determine the relative effects of risperidone and divalproex in pediatric mania. Cohort Studies Jerrell, 2008 (10) 82 To examine the services and medications received, and psychosocial functioning changes over time of children and adolescents with bipolar disorder in a public mental health system. Jerrell, 2008 (11) 82 To examine differences between children and adolescents with bipolar disorder in a public mental health system. MacMillan, 2008 (25) 28 To compare clinical responses of with pediatric bipolar disorder being treated with risperidone versus divalproex. Case-Control Studies Models Ongoing Studies (ClinicalTrials.gov) Olanzapine Compared to Lamotrigine in the Prevention of Depressive Episode in the Patients With Bipolar Disorder (OCTLPODEPWBD) (NCT ) 60, Young Adults Abbreviation: RCTs=randomized controlled trials 11 Completed. The investigators hypothesized that olanzapine will be superior to lamotrigine in the prevention of any kind of recurrence of bipolar disorder. On the other hand, lamotrigine group will have better prevention of depressive episode than olanzapine group. Meanwhile, the investigators supposed that there will be more concomitant medicine in Lamictal group than olanzapine group. The comorbidity will influence the measurement of outcome such as time period of recurrence of depressive episode in both groups. Data Supplement Table 9. Published and ongoing studies potentially relevant to Research Question 14 [What are the comparative safety and effectiveness of antipsychotic drugs alone compared with the combination of antipsychotic drugs plus other nonpharmacologic interventions (e.g., psychotherapy/counseling, peer and family support, supported employment, diet and physical activity interventions, assertive community treatment) in adolescents/young adults with bipolar disorder?] Study N Population Objective Systematic Reviews NA NA NA NA

12 Study N Population Objective RCTs Lunsford-Avery, 2012 (7) 53 To examine the longitudinal associations between sleep disruption, mood symptom severity, and psychosocial functioning in a 2- year followup of with adolescent bipolar spectrum disorder who were randomized to family-focused treatment for adolescents or to enhanced care, a briefer psychoeducational treatment; both treatments were administered with pharmacotherapy. Sullivan, 2012(14) 58 To examine family functioning and its relationship to symptoms of adolescent bipolar disorder, using longitudinal measures of family cohesion, adaptability, and conflict. Miklowitz, 2008 (26) 58 To examine the benefits of family-focused treatment for adolescents and pharmacotherapy in the 2-year course of adolescent bipolar disorder. Cohort Studies Case-Control Studies Macneil, 2012(19) 40, Young Adults Models Ongoing Studies (ClinicalTrials.gov) Effectiveness of Family- Focused Treatment Plus Pharmacotherapy for Bipolar Disorder in (NCT ) 150 Study in With Schizophrenia or Bipolar Disorder (NCT ) 200 Abbreviation: RCTs=randomized controlled trials To assess whether a manualized psychological intervention could be effective in reducing symptomatology and relapse, and improve functional outcome in a young, first-episode cohort. Unknown. To evaluate the effectiveness of family-focused treatment plus pharmacotherapy in treating adolescents with bipolar disorder. Completed. Open-label safety study of oral olanzapine treatment in adolescents, aged 13 to 17 years, with bipolar disorder (manic or mixed episodes) or schizophrenia. 12

13 Data Supplement Table 10. Published and ongoing studies potentially relevant to Research Question 23 [What are the adverse effects of short-term and long-term medication exposure between and within antipsychotic classes for adolescents/young adults with bipolar disorder, and how do these adverse effects vary based on patient characteristics?] Study N Population Objective Systematic Reviews Ben Amor, 2012 (1) 36 studies To provide a comparative review of the safety data available for antipsychotic drug use in pediatric populations. Doey, 2012 (5) 140 studies, Young Adults To review existing literature and to summarize the experience with aripiprazole in youth with psychotic and mood disorders. Maayan, 2011 (27) 34 studies To review randomized, cohort, and pharmacoepidemiologic studies of antipsychotic-related weight gain and metabolic adverse effects and of interventions for their reduction in youth. Correll, 2010 (2) 9 studies To compare antipsychotic and mood stabilizer efficacy and tolerability in youth and adults with bipolar mania. Kryzhanovskaya, 2009 (28) 4 studies To describe the safety of olanzapine treatment in adolescents (aged years) with schizophrenia or bipolar disorder, and to compare these data with those of olanzapinetreated adults. Fraguas, 2011 (3) 34 studies To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with psychotic and bipolar spectrum disorders. RCTs Findling, 2013 (6) 210 Youngstrom, 2013 (29) 296 To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar disorder. To compare different definitions of treatment response in a large sample of children and adolescents. Findling, 2012 (30) 96 This study evaluates the long-term efficacy of aripiprazole compared to placebo in children with bipolar disorders. Pathak, 2013 (31) 277 To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar disorder. Geller, 2012 (22) 61 To investigate which medication to administer first to antimanic, medication-i children and adolescent subjects. Robles, 2011 (32) 50 To compare changes in cognition in earlyonset psychosis after 6-months of treatment with quetiapine or olanzapine. 13

14 Study N Population Objective West, 2011 (8) 65 To examine comorbid disruptive behavior disorders and aggression prospectively as predictors of pharmacotherapy outcome, as well as potential moderators of response to a specific medication (risperidone vs. divalproex), among children with pediatric bipolar disorder. Karagianis, 2010 (33) 14 Young Adults To conduct exploratory analyses of the data from a multinational, randomised study to identify factors associated with weight change after 16 weeks of treatment with standard olanzapine tablets or sublingual orally disintegrating olanzapine. DelBello, 2009 (34) 32 To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar disorder. Findling, 2009 (12) 296 Haas, 2009 (35) 169 To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar disorder, manic or mixed episode, with or without psychotic features. To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar disorder. Tramontina, 2009 (36) 43 To assess response to treatment with aripiprazole in children and adolescents with bipolar disorder comorbid with ADHD. Cohort Studies Joshi, 2012 (37) 23 To assess the impact of comorbid autism spectrum disorders on the response to secondgeneration antipsychotics in pediatric bipolar disorder. Kozicky, 2012 (38) 75 Young Adults Wang, 2012 (39) 28, Young Adults To compare performance between receiving maintenance treatment with mood stabilizer monotherapy, adjunctive risperidone, or quetiapine, and a group of demographically matched healthy controls on tests of executive function (working memory, set shifting, and inhibition) and verbal learning. To evaluate the neurocognitive effects of aripiprazole in adolescents and young adults with bipolar disorder. Duffy, 2009 (4) 21 To determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent diagnosed with bipolar disorder. 14

15 Study N Population Objective Redden, 2009 (40) 109 To assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar disorder. DelBello, 2008 (41) 63 To characterize the tolerability of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. MacMillan, 2008 (25) 28 To compare clinical responses of with pediatric bipolar disorder being treated with risperidone versus divalproex. Case-Control Studies Models Ongoing Studies (ClinicalTrials.gov) Safety and Tolerability of Aripiprazole in With Schizophrenia or Children and With Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features. (ATTAIN 267) (NCT ) Study to Determine Whether There Are Any Cognitive or Motor Effects From Taking the Medicine Risperidone. (NCT ) Study in With Schizophrenia or Bipolar Disorder (NCT ) Comparison of Aripiprazole Versus Higher Metabolic Risk Antipsychotic Drugs on Adiposity Using MRI (CALM) (NCT ) 650 Ongoing (estimated completion January 2015). This is an open-label study consisting of a screening period, a conversion/titration phase (Phase 1), an open-label treatment phase (Phase 2), and a followup period. 30 Completed. To assess the effects of risperidone (Risperdal ) as compared with placebo on cognitive-motor performance (attention, memory, and hand steadiness) and body movements , Young Adults Completed. Open-label safety study of oral olanzapine treatment in adolescents, aged years, with bipolar disorder (manic or mixed episodes) or schizophrenia. Ongoing (estimated completion November 2014). To compare abdominal weight gain and fat distribution in people taking aripiprazole versus risperidone or quetiapine, to people not taking any of these antipsychotic medications. 15

16 Study N Population Objective Metabolic Effects of Antipsychotics in Children (MEAC) (NCT ) 240 Completed. To address clinically relevant questions concerning both the safety and efficacy of these agents in antipsychotic-naïve aggressive children with conduct disorder, with permitted comorbidity for a variety of psychiatric conditions including attention deficit disorder, bipolar disorder, high functioning pervasive developmental disorder, autism and schizophrenia. The project aims to describe and compare the outcome of 12 weeks of prospective, randomized treatment with olanzapine, risperidone or aripiprazole on insulin action in skeletal muscle, liver and adipose tissue, insulin secretion, abdominal fat mass, total body and fat-free mass, resting metabolic rates, efficacy for symptoms of A Study to Evaluate the Safety and the Effects of Risperidone Compared With Other Atypical Antipsychotic Drugs on the Growth and Sexual Maturation in Children (NCT ) A Study of the Safety and Tolerability of Oral Ziprasidone in Children and Teens With Psychotic Disorders (NCT ) Safety and Tolerability of Ziprasidone in Children and With Bipolar I Disorder (Manic or Mixed) (NCT ) Aripiprazole in Children and With Bipolar Disorder and Attention Deficit Hyperactivity Disorder (ADHD) (NCT ) Topiramate vs. Placebo in Preventing Weight Gain in Bipolar Disorder Treated With Olanzapine (NCT ) aggression and nonmetabolic adverse events. Completed. To evaluate the effects of risperidone compared with other atypical antipsychotic drugs on the physical maturity, growth and development of children, and the risk of prolactin-related adverse events (side effects) associated to these drugs. 63 Completed. To evaluate the safety and tolerability of oral ziprasidone in children and teens with psychotic disorders. 169 Completed. To assess the safety and tolerability of ziprasidone during long-term open-label administration in children and adolescents (ages 10 17) with bipolar disorder (manic or mixed). 50 Completed. To assess the efficacy of aripiprazole (a novel antipsychotic drug) for the treatment of children and adolescents with bipolar disorder comorbid with ADHD. 31 Completed. To examine the efficacy of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder. The secondary objective is to examine the tolerability of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder.

17 Study N Population Objective Aripiprazole Open- Label, Safety and Tolerability Study (APEX 241) (NCT ) 325 Completed. To test the long-term safety and tolerability of aripiprazole in adolescent with schizophrenia, and child and adolescent with bipolar disorder, manic or mixed episode. ½-MC4R Genotype and Pediatric Antipsychotic Drug- Induced Weight Gain (NCT ) 80 Ongoing (estimated completion April 2014). To compare usual care antipsychotic treatment (aripiprazole, quetiapine, risperidone) with ziprasidone in children and adolescents aged years old. Patients will have 10 days or less lifetime antipsychotic exposure and be in clinical need for antipsychotic treatment for a pediatric psychiatric disorder with FDA indication for antipsychotic use, i.e., bipolar mania, schizophrenia-spectrum disorders, and irritability associated with autistic disorder. Randomization will be stratified by high vs. low genetic risk for antipsychotic-induced weight gain based on MC4R genotype and the primary outcome will be weight change from baseline to endpoint between ziprasidone and usual care antipsychotic treatment in each of the two genotype groups. Abbreviations: FDA=Food and Drug Administration; RCTs=randomized controlled trials Data Supplement Table 11. Published and ongoing studies potentially relevant to Research Question 3 [How do the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder differ depending on demographic differences such as age group (e.g., under 18 vs ), rural versus urban, race/ethnicity, and sex?] Study N Population Objective Systematic Reviews RCTs Cohort Studies Castilla-Puentes, 2008(42) 8129 To delineate the prevalence, demographic characteristics, comorbidity, hospitalization, and medication use of a large cohort of children and adolescents ( 18 years of age) with bipolar disorders with and without multiple episodes per year. Jerrell, 2008(11) 82 To examine differences between children and adolescents with bipolar disorder in a public mental health system. Case-Control Studies Models 17

18 Study N Population Objective Ongoing Studies (ClinicalTrials.gov) Olanzapine Treated With Schizophrenia or Bipolar I Disorder (NCT ) 100 Abbreviation: RCTs=randomized controlled trials Completed. To characterize olanzapine pharmacokinetics: the inter- and intra- subject variabilities of olanzapine pharmacokinetics; and the potential influence of patient factors such as age, weight, gender, origin, and smoking status on olanzapine pharmacokinetics in adolescents with schizophrenia or bipolar disorder. This study will also assess the safety of olanzapine delivered orally. NOTE: From the PubMed search and ClinicalTrials.gov searches, we did not identify any studies that were potentially relevant Research Question 4 [How do the comparative safety and effectiveness of antipsychotic treatment in adolescents/young adults with bipolar disorder differ depending on socioeconomic factors such as income, insurance status, access to healthcare and to types of services, and level of caregiver/social support?] Data Supplement Table 12. Published and ongoing studies potentially relevant to Research Question Research Question 16 [What are the comparative effects of antipsychotics on core disease features in adolescents/young adults with bipolar disorder, both in the immediate and long-term?] Study N Population Objective Systematic Reviews Doey, 2012(5) 140 studies, Young Adults To review existing literature and to summarize the experience with aripiprazole in youth with psychotic and mood disorders. Correll, 2010(2) 9 studies To compare antipsychotic and mood stabilizer efficacy and tolerability in youth and adults with bipolar mania. Gentile, 2011(43) 18 studies To critically analyze findings from RCTs that have investigated the clinical utility of secondgeneration antipsychotics for the treatment of early-onset schizophrenia and bipolar disorders. RCTs Findling, 2013(6) 210 Pathak, 2013(31) 277 To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar disorder. To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar disorder. 18

19 Study N Population Objective Chang, 2012(44) 26 To examine the effects of quetiapine, an atypical antipsychotic, on brain concentrations of myoinositol and N-acetylaspartate, and potential predictors of response to quetiapine in adolescents with bipolar depression. Mankoski, 2011(45) 296 To evaluate the effects of aripiprazole treatment on individual Young Mania Rating Scale line items in pediatric subjects with manic or mixed episodes associated with bipolar disorder to better understand the discrete symptom improvements. DelBello, 2009(34) 32 To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar disorder. Findling, 2009(12) 296 To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar disorder, manic or mixed episode, with or without psychotic features. Tramontina, 2009(36) 43 To assess response to treatment with aripiprazole in children and adolescents with bipolar disorder comorbid with ADHD. Cohort Studies Jerrell, 2008(11) 82 To examine differences between children and adolescents with bipolar disorder in a public mental health system. Duffy, 2009(4) 21 To determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent diagnosed with bipolar disorder. Joshi, 2012(37) 23 To assess the impact of comorbid autism spectrum disorders on the response to secondgeneration antipsychotics in pediatric bipolar disorder. Redden, 2009(40) 109 To assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar disorder. Stewart, 2009(9) 46 To examine global functioning, health-related quality of life, and clinical outcome in children and adolescents with bipolar disorder, schizophrenia, or schizoaffective disorder following ziprasidone treatment. Case-Control Studies Models 19

20 Study N Population Objective Ongoing Studies (ClinicalTrials.gov) Olanzapine Treated With Schizophrenia or Bipolar I Disorder (NCT ) Open-Label Comparative Study of Risperidone Versus Olanzapine Versus Quetiapine for Mania in Children and With Bipolar I and Bipolar II Disorder (NCT ) Aripiprazole in Children and With Bipolar I Disorder (NCT ) Aripiprazole Open- Label, Safety and Tolerability Study (APEX 241) (NCT ) Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder (P06107 AM4) (NCT ) (P06107 has an extension (P05898; NCT ) Aripiprazole in Children and With Bipolar Disorder and Attention Deficit Hyperactivity Disorder (ADHD) (NCT ) Completed. To characterize olanzapine pharmacokinetics: the inter- and intra- subject variabilities of olanzapine pharmacokinetics; and the potential influence of patient factors such as age, weight, gender, origin, and smoking status on olanzapine pharmacokinetics in adolescents with schizophrenia or bipolar disorder. This study will also assess the safety of olanzapine delivered orally. Completed. To compare the safety and effectiveness of risperidone, olanzapine, and quetiapine in the treatment of mania in children and adolescents with Bipolar disorder over 8 weeks and then over an extension phase. This is an exploratory, open-label study, which seeks to determine if there is evidence for efficacy. Completed. To test the safety and efficacy of two doses of aripiprazole in child and adolescent with bipolar disorder, manic or mixed episode with or without psychotic features. Completed. To test the long-term safety and tolerability of aripiprazole in adolescent with schizophrenia, and child and adolescent with bipolar disorder, manic or mixed episode Ongoing (estimated completion September 2014). To evaluate the efficacy and safety of asenapine for the treatment of bipolar disorder (manic or mixed episodes) in participants between 10 and 17 years old, who are either hospitalized or nonhospitalized. In this 3-week, double-blind, parallel design trial, eligible for participation will be randomized to receive one out of three fixed-dose levels of asenapine, or placebo. 50 Completed. To assess the efficacy of aripiprazole (a novel antipsychotic drug) for the treatment of children and adolescents with bipolar disorder comorbid with ADHD. 20

21 Study N Population Objective Determining the Safety and Effectiveness of Olanzapine in Children and (NCT ) A Double-Blind Randomized Placebo Controlled Study of Quetiapine for the Treatment of Depression in With Bipolar Disorder (NCT ) Study to Determine the Effectiveness of Risperidone in Bipolar Disorder in Children and (NCT ) Clozapine vs. Placebo in Treatment-Refractory Bipolar Disorder in Children and (NCT ) Ziprasidone in Pediatric Bipolar Disorder (NCT ) Ziprasidone for the Treatment of Mania in Children and With Bipolar Disorder (NCT ) An Open-Label Trial of Aripiprazole in Children and With Bipolar Disorder (NCT ) 68 Unknown. To examine the safety and effectiveness of the antipsychotic drug olanzapine in children and adolescents with bipolar disorder or psychosis. 30 Completed. To test quetiapine for the possible treatment of bipolar disorder with an acute depressive episode in children and adolescents. 13 Completed. To determine the safety and effectiveness of risperidone compared with placebo in the treatment of bipolar disorder (manic or mixed type) in children and adolescents aged 10 to 17 years. 116 Completed. To determine the safety and effectiveness of clozapine in children and adolescents with treatment resistant bipolar disorder. This study will also explore how the brain functions in early-onset bipolar disorder. 45 Completed. This is a 6-week, open-label, blinded-rater, randomized, controlled, pilot study designed to determine the dosing, safety and efficacy of ziprasidone in the treatment of pediatric bipolar disorder. In this pilot study we are comparing the efficacy of rapid versus slow dose titration of ziprasidone in pediatric bipolar disorder. 20 Completed. To compare the safety and effectiveness of ziprasidone in the treatment of mania in children and adolescents with bipolar disorder over 8 weeks. This is an exploratory, open-label study, which seeks to determine if there is evidence for efficacy. 30 Completed. To determine the effectiveness of aripiprazole (Abilify ) in helping persons with symptoms of mania whose current medications do not completely control those symptoms. A secondary aim of this research is to explore whether CYP 2D6 polymorphisms are related to side effects with aripiprazole. The goal of this research is to identify individuals who metabolize aripiprazole more rapidly or slowly, which will potentially help the clinician make dosing adjustments and decrease the risk of adverse events. 21

22 Study N Population Objective Aripiprazole for the Treatment of Mania in Children and With Bipolar Disorder (NCT ) 20 Completed. This is an open-labeled study of aripiprazole, testing its efficacy in the treatment of mania in children and adolescents with bipolar I, bipolar II and bipolar spectrum disorder over 8 weeks. This is an exploratory, pilot study, seeking to determine whether aripiprazole is efficacious and well tolerated in the treatment of youth with pediatric bipolar Quetiapine (Seroquel) Maintenance Treatment in Early Onset Bipolar Spectrum Disorders (NCT ) Olanzapine Versus Placebo in the Treatment of Mania in With Bipolar I Disorder (NCT ) Safety and Tolerability of Ziprasidone in Children and With Bipolar I Disorder (Manic or Mixed) (NCT ) Safety and Efficacy of Ziprasidone in Children and With Bipolar I Disorder (Manic or Mixed) (NCT ) A Study of the Safety and Tolerability of Oral Ziprasidone in Children and Teens With Psychotic Disorders (NCT ) Quetiapine Fumarate (SEROQUEL) Compared to Placebo in the Treatment of Children & With Bipolar I Mania (ANCHOR 149) (NCT ) , Young Adults and bipolar spectrum disorder. Completed. This is a single center, open prospective study to evaluate the effectiveness of quetiapine monotherapy in the maintenance treatment of adolescent with a bipolar spectrum disorder (bipolar I and bipolar II disorders, cyclothymia, and bipolar disorder not otherwise specified for a minimum of 48 weeks. Completed. To determine the efficacy (how well the drug works), safety, and any side effects of olanzapine compared to placebo in the treatment of mania in bipolar disorder in adolescents. Both the potential benefits and side effects of olanzapine will be evaluated throughout this trial. Completed. To assess the safety and tolerability of ziprasidone during long-term open-label administration in children and adolescents (ages 10 17) with bipolar disorder (manic or mixed). Completed. To determine if flexibly-dosed ziprasidone is safe and effective for the treatment of children and adolescents (ages 10 17) with bipolar disorder (manic or mixed). 63 Completed. To evaluate the safety and tolerability of oral ziprasidone in children and teens with psychotic disorders. 220 Completed. To demonstrate efficacy and safety of quetiapine fumarate (Seroquel ) compared with placebo in the treatment of children and adolescent with bipolar I mania. 22

23 Study N Population Objective Pediatric Bipolar Depression (NCT ) 193 Completed. To determine if quetiapine fumarate extended-release (quetiapine XR or Seroquel XR) 150 to 300 mg per day taken by itself is effective and safe in treating children or adolescents aged with bipolar depression and if so, how it compares with placebo (a nonactive tablet, like a sugar pill, that looks like quetiapine). Abbreviations: ADHD=attention deficit hyperactivity disorder; RCTs=randomized controlled trials 23

24 Data Supplement Table 13. Top tier research questions and potential study designs Research Area a 11) What are the comparative safety and effectiveness of antipsychotic monotherapy compared to combination therapy with medications from the mood stabilizing class in adolescents/young adults with bipolar disorder? 19) What are the comparative effects of antipsychotics on social, academic, and occupational functioning in adolescents/young adults with bipolar disorder? RCT? Yes: RCT would be an ideal strategy for evaluating this question, though potential limitations could include difficulty evaluating different potential drug combinations and achieving sufficiently longterm followup. Yes: Incorporation of bipolar-specific instruments measuring these outcomes into new RCTs could address this question, though achieving sufficiently longterm followup could be a limitation. Meta-analysis or data analysis across RCTs? helpful if sufficient data regarding different potential drug combinations exist to allow metaanalysis and data are obtainable. Would require cooperation between investigators. possible if existing RCTs have used appropriate instruments with enough consistency to allow synthesis. Meta-analysis of observational studies? helpful if sufficient data exist to allow meta-analysis and data are obtainable. Would require cooperation between investigators. No: Unlikely that existing observational studies have reported appropriate instruments with enough consistency to allow synthesis. Observational study new data collection? appropriate for long-term outcomes; potential limitations would include changes in treatment over time and resources needed for longterm studies. Yes: Relatively low-cost, and could be appropriate for long-term outcomes. Potential limitations would include changes in treatment over time and resources needed for longterm studies. Observational study existing data? Yes: Could facilitate long-term followup. Would depend on availability of relevant data, and confounding could be an issue. possible if existing studies have collected data using appropriate instruments. Model? Maybe: Modeling studies would be very valuable for integrating data from other study designs; using modeling to identify key decision drivers could be useful for informing study design, including sample size estimates. No: Though could have a role in defining clinically meaningful differences. 24