Comparative Effectiveness Review Number 43. Off-Label Use of Atypical Antipsychotics: An Update

Transcription

1 Comparative Effectiveness Review Number 43 Off-Label Use of Atypical Antipsychotics: An Update

2 Comparative Effectiveness Review Number 43 Off-Label Use of Atypical Antipsychotics: An Update Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD Contract No. HHSA Prepared by: Southern California Evidence-based Practice Center Santa Monica, CA Authors: Evidence-based Practice Center Associate Director Margaret Maglione, M.P.P. Literature Reviewers/Content Experts Alicia Ruelaz Maher, M.D. Jianhui Hu, M.P.P. Zhen Wang, M.S. Librarian Roberta Shanman, M.L.S. Evidence-based Practice Center Director Paul G. Shekelle, M.D., Ph.D. Programmers Beth Roth, M.A. Lara Hilton, M.P.H. Statisticians Marika J. Suttorp, M.S. Brett A. Ewing, M.S. Project Assistants Aneesa Motala, B.A. Tanja Perry, B.H.M. AHRQ Publication No. 11-EHC087-EF September 2011

3 This report is based on research conducted by the Southern California Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA ). The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. 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. The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products or actions may not be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted, for which further reproduction is prohibited without the specific permission of copyright holders. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Maglione M, Ruelaz Maher A, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ, Ewing BA, Motala A, Perry T. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43. (Prepared by the Southern California Evidence-based Practice Center under Contract No. HHSA ) Rockville, MD: Agency for Healthcare Research and Quality. September Available at: ii

4 Preface The Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health Care Program as part of its mission to organize knowledge and make it available to inform decisions about health care. As part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices, and health care services to meet the needs of Medicare, Medicaid, and the Children s Health Insurance Program (CHIP). AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce Evidence Reports/Technology Assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care. The EPCs now lend their expertise to the Effective Health Care Program by conducting Comparative Effectiveness Reviews (CERs) of medications, devices, and other relevant interventions, including strategies for how these items and services can best be organized, managed, and delivered. 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 are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about systematic reviews, see AHRQ expects that CERs will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. In addition, AHRQ is committed to presenting information in different formats so that consumers who make decisions about their own and their family s health can benefit from the evidence. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site ( to see draft research questions and reports or to join an list to learn about new program products and opportunities for input. Comparative Effectiveness Reviews will be updated regularly. We welcome comments on this CER. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by to epc@ahrq.hhs.gov. Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Director Evidence-based Practice Program Center for Outcomes and Evidence Agency for Healthcare Research and Quality Jean Slutsky, P.A., M.S.P.H. Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Sonia Tyutyulkova, M.D., Ph.D. Task Order Officer Center for Outcomes and Evidence Agency for Healthcare Research and Quality iii

5 Acknowledgments This study was supported by the Agency for Healthcare Research and Quality. The investigators deeply appreciate the considerable support, commitment and contributions of Di Valentine. Technical Expert Panel Evelyn Attia, M.D. Columbia University Medical Center New York, NY Tami Eide, Pharm.D., B.C.P.S., FASHP Idaho Dept of Health & Welfare Boise, ID Carol Eisen, M.D., County of Los Angeles Department of Mental Health Los Angeles, CA David Sultzer, M.D. Greater Los Angeles Healthcare System Los Angeles, CA Bruce Kagan, M.D., Ph.D. UCLA Psychiatry and Biobehavioral Sciences Los Angeles, CA Syed Naqvi, M.D. Cedars-Sinai Medical Center Los Angeles, CA Cheryl A. Sadowski, B.Sc., Pharm.D. University of Alberta Edmonton, Alberta, Canada Charles Schultz, M.D. University of Minnesota Minneapolis, MN Peer Reviewers Peter Rabins, M.D., M.P.H. Johns Hopkins Hospital Baltimore, MD Julie Kreyenbuhl, Pharm.D., Ph.D. University of Maryland School of Medicine Baltimore, MD Steven Bagley, M.D. Palo Alto Veterans Administration Hospital Palo Alto, CA Mark Olfson, M.D. Columbia University Medical Center New York, NY Daniel J. Safer, M.D. Johns Hopkins Medicine Baltimore, MD iv

6 Off-Label Use of Atypical Antipsychotics: An Update Structured Abstract Objectives. Antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia, bipolar disorder, and for some drugs, depression. We performed a systematic review on the efficacy and safety of atypical antipsychotic drugs for use in conditions lacking FDA approval. Data Sources. We searched PubMed, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane DARE (Database of Abstracts of Reviews of Effects), and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception to May We included only English-language studies. Review Methods. Controlled trials comparing an atypical antipsychotic (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, paliperidone) to either placebo, another atypical antipsychotic drug, or other pharmacotherapy, for the off-label conditions of anxiety disorder, attention deficit hyperactivity disorder, dementia and severe geriatric agitation, major depressive disorder, eating disorders, insomnia, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), personality disorders, substance abuse, and Tourette s syndrome were included. Observational studies with sample sizes greater than 1,000 were included to assess rare adverse events. Two investigators conducted independent article review, data abstraction, and study quality assessment. Results. One hundred seventy trials contributed data to the efficacy review. Among the placebocontrolled trials of elderly patients with dementia reporting a total/global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effect sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, pooled analysis of three large trials showed that quetiapine was associated with a 26 percent greater likelihood of responding, defined as at least 50 percent improvement on the Hamilton Anxiety Scale, compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of responding, defined as a 25 to 35 percent improvement on the Yale Brown Obsessive Compulsive Scale (YBOCS) compared with placebo. We identified 6 trials on eating disorders, 12 on personality disorder, an existing metaanalysis and 10 trials of risperidone or olanzapine for PTSD, 36 trials for depression of which 7 assessed drugs without an FDA-approved indication, and 33 trials of aripiprazole, olanzapine, quetiapine, or risperidone for treating substance abuse disorders. We identified one small trial (N=13) of atypical antipsychotics for insomnia which was inconclusive. For eating disorder patients specifically, evidence shows that atypicals are do not cause significant weight gain. The level of evidence is mixed regarding personality disorders and moderate for an association of risperidone with improving post-traumatic stress disorder. Evidence does not support efficacy of atypical antipsychotics for substance abuse. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH]=87), stroke (for risperidone, NNH=53), extrapyramidal symptoms (for olanzapine (NNH=10) and risperidone (NNH=20), and urinary symptoms (NNH= from 16 to 36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, v

7 sedation, akithisia (for aripiprazole) and extrapyramidal symptoms. Direct comparisons of different atypical antipsychotics for off-label conditions are rare. Conclusions. Benefits and harms vary among atypical antipsychotics for off-label usage. For symptoms associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of OCD; however, adverse events were common. vi

8 Contents Executive Summary... ES-1 Introduction... 1 Background... 1 Off-label Conditions... 2 Scope and Key Questions... 6 Key Questions... 6 Scope... 7 Methods... 8 Topic Development... 8 Analytic Framework... 8 Search Strategy... 9 Technical Expert Panel Study Selection Data Extraction Quality Assessment Applicability Rating the Body of Evidence Data Synthesis Efficacy Adverse Events Peer Review and Public Commentary Results Key Question 1. What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials? Key Points Detailed Analysis Discussion Key Question 2. What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications? Sub-Key Question 2: How do atypical antipsychotic medications compare with other drugs, including first generation antipsychotics, for treating off-label indications? Key Points Detailed Analysis Discussion Key Question 3. What subset of the population would potentially benefit from off-label uses? Do effectiveness and harms differ by race/ethnicity, gender, and age group? By severity of condition and clinical subtype? Key Points Detailed Analysis Discussion Key Question 4. What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions? Key Points vii

9 Detailed Analysis Discussion Key Question 5. What is the effective dose and time limit for off-label indications? Key Points Detailed Analysis Discussion Summary and Discussion Future Research References Abbreviations and Acronyms Tables Table A. Summary of Strength of Evidence of Efficacy, by Drug and Condition... ES-4 Table B. Summary Update: Efficacy of Atypical Antipsychotics for Off-Label Use... ES-5 Table C. Summary Update: Safety of Atypical Antipsychotics for Off-Label Use... ES-11 Table 1. Grading the Strength of a Body of Evidence: Required Domains and Their Definitions Table 2. Large Utilization Studies in the United States Table 3. Atypical Antipsychotics for ADHD Table 4. Generalized Anxiety Disorder PCTs Contributing to Meta-Analysis Table 5. Dementia PCTs Contributing to Meta-Analyses Table 6. Dementia Atypical Versus Haloperidol PCTs Contributing to Analysis Table 7. Dementia Head-to-Head Studies Contributing to Analysis Table 8. Depression Placebo-Controlled Augmentation Trials Contributing to HAM-D Meta-Analysis Table 9. Depression Placebo-Controlled Augmentation Trials Contributing to MADRS Meta-Analysis Table 10: Placebo-Controlled Monotherapy Trials Contributing to MADRS Meta-Analyses Table 11. Eating Disorder PCTs Contributing to Meta-Analysis Table 12. Atypical Antipsychotics for Insomnia, Observational Studies Olanzapine Table 13. Atypical Antipsychotics for Insomnia, Observational Studies Quetiapine Table 14. OCD PCTs Contributing to Meta-Analysis Table 15. PCTs for Personality Disorder Table 16. PTSD PCTs Contributing to Meta-Analyses Table 17. Alcohol Abuse PCTs Contributing to Meta-Analyses Table 18. Cocaine PCTs Contributing to Meta-Analysis Table 19. Atypical Antipsychotics for Tourette s Syndrome Table 20. Summary of Strength of Evidence of Efficacy, by Drug and Condition Table 21. Analysis of Publication Bias Table 22. Cardiovascular Adverse Events Among Dementia Patients Atypical Antipsychotics Compared With Placebo Table 23. Neurological Adverse Events Among Dementia Patients Atypical Antipsychotics Compared With Placebo Table 24. Endocrine Adverse Events Among Dementia Patients Atypical Antipsychotics Compared With Placebo Table 25. Urinary Symptoms Among Dementia Patients Atypical Antipsychotics Compared With Placebo viii

10 Table 26. Adverse Events in Large Observational Studies of Elderly Patients Table 27. Appetite Or Weight Increase in Other Conditions Atypical Antipsychotics Compared With Placebo Table 28. Endocrine and Other Metabolic Lab Abnormalities in Other Conditions Atypical Antipsychotics Compared With Placebo Table 29. Neurological Adverse Events in Other Conditions Atypical Antipsychotics Compared With Placebo Table 30. Summary Update: Efficacy of Atypical Antipsychotics for Off-Label Use Table 31. Summary Update: Safety of Atypical Antipsychotics for Off-Label Use Figures Figure 1. Analytic Framework for Comparative Effectiveness Review: Off-Label Uses of Atypical Antipsychotics... 9 Figure 2. Literature Flow Figure 3. Anxiety % Responders on Hamilton Anxiety Scale Figure 4. Dementia Placebo Comparisons Total/Global Scores Figure 5. Dementia Placebo Comparisons Psychosis Figure 6. Dementia Placebo Comparisons Agitation Figure 7. Dementia: Atypical Versus Haloperidol Total/Global Scores Figure 8. Dementia: Atypical Versus Haloperidol Agitation Figure 9. Dementia Head-to-Head Studies Olanzapine or Quetapine Versus Risperidone Total/Global Scores Figure 10. Head-to-Head Studies: Olanzapine or Quetapine Versus Risperidone Psychosis Figure 11. Dementia Head-to-Head Studies: Olanzapine or Quetapine Versus Risperidone Agitation Figure 12. Depression HAM-D % Remitted, Augmention Figure 13. Depression HAM-D % Responded, Augmentation Figure 14. Depression MADRS % Remitted, Augmentation Figure 15. Depression MADRS % Responded, Augmentation Figure 16. Depression MADRS % Remitted, Monotherapy Figure 17. Depression MADRS % Responded, Monotherapy Figure 18. Eating Disorders BMI Figure 19. OCD Responders Improving 25 35% on Y-BOCS Figure 20. PTSD by Drug Difference in CAPS Score Figure 21. PTSD by Combat Status Difference in CAPS Score Figure 22. PTSD by Time Difference in CAPS Score Figure 23. Substance Abuse Alcohol Complete Abstinence Figure 24. Cocaine ASI Drug Composite Figure 25. Dementia: PCTs With Dose Comparisons Total/Global Scores Figure 26. Dementia: PCTs With Dose Comparisons Psychosis Figure 27. Dementia: PCTs With Dose Comparisons Agitation Figure 28. Depression MADRS % Remitted Dose Figure 29. Depression MADRS % Responded Dose ix

11 Appendixes Appendix A. Literature Search Strategies Appendix B. Data Collection Forms Appendix C. Previously Published Meta-Analyses Appendix D. Evidence Tables Appendix E. Excluded Studies Appendix F. Adverse Events Analyses x

12 Executive Summary Background Antipsychotics medications are approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia and bipolar disorder. These medications are commonly divided into two classes, reflecting two waves of historical development: the conventional antipsychotics and the atypical. The conventional antipsychotics served as the first successful pharmacologic treatment for primary psychotic disorders such as schizophrenia. Having been widely used for decades, the conventional antipsychotics also produced various side effects requiring additional medications, which spurred the development of the atypical antipsychotics. Currently, nine atypical antipsychotic drugs have been approved by FDA: aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. These drugs have been used off-label (i.e., for indications not approved by FDA) for the treatment of various psychiatric conditions. While it is legal for a physician to prescribe drugs in such a manner, it is illegal for the manufacturer to actively promote such use. A 2006 study on Efficacy and Comparative Effectiveness of Off-label Use of Atypical Antipsychotics reviewed the scientific evidence on the safety, efficacy, and effectiveness for offlabel uses. (Clozapine was excluded because of its association with a potentially fatal blood disorder of bone marrow suppression, and it requires frequent blood tests for safety monitoring.) The 2006 study examined 84 published studies on atypicals and found that the most common off-label uses of the drugs were for treatment of depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette s syndrome, autism, and agitation in dementia. It concluded that with few exceptions, there was insufficient high-strength evidence to reach conclusions about the efficacy of any off-label uses of these medications. It also found strong evidence that atypicals are associated with increased risk of adverse events such as significant weight gain, sedation, and, among the elderly, increased mortality. Future research areas suggested by the report include safe treatment for agitation in dementia, association between the increased risk of death and antipsychotics drugs, and comparison of the development of adverse effects between patients taking atypical antipsychotics and those taking conventional antipsychotics. Since publication of that report, important changes have occurred that make the report out of date. Studies have been published on new off-label uses, such as treatment of eating disorders, insomnia, attention-deficit hyperactivity disorder (ADHD), anxiety, and substance abuse. New or increased adverse effects of off-label indications have been observed and new atypicals (asenapine, iloperidone, and paliperidone) have been approved by FDA for the treatment of schizophrenia and bipolar disorder. In addition, the following previously off-label uses have been approved for on-label use by the FDA: Quetiapine and quetiapine ER (extended release) as monotherapy in bipolar depression Quetiapine ER as augmentation for major depressive disorder (MDD) Aripiprazole as augmentation for MDD Olanzapine/fluoxetine combination for MDD Olanzapine/fluoxetine combination for bipolar depression Risperidone and aripiprazole for autism spectrum disorders ES-1

13 An update is needed to better understand the trends in off-label use and the associated risks and benefits. Further, a number of issues remain unclear due to insufficient information in the previous report: subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dose, and time needed to see clinical improvement. This update will try to address these issues. This report covers the following off-label uses of atypical antipsychotic medications: anxiety, ADHD, dementia and severe geriatric agitation, major depressive disorder (MDD), eating disorders, insomnia, OCD, PTSD, personality disorders, substance abuse, and Tourette s syndrome. Autism, included in the original systematic review, is now reviewed in a study on the comparative effectiveness of typical and atypical antipsychotics for on-label indications, conducted by another organization. This report addresses the following Key Questions: Key Question 1. What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials? Key Question 2. What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications? Sub-Key Question 2. How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for treating off-label indications? Key Question 3. What subset of the population would potentially benefit from off-label uses? Do effectiveness and harms differ by race/ethnicity, gender, and age group? By severity of condition and clinical subtype? Key Question 4. What are the potential adverse effects and/or complications involved with offlabel prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions? Key Question 5. What is the effective dose and time limit for off-label indications? Conclusions Key Question 1. What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials? Atypicals have been studied as off-label treatment for the following conditions: ADHD, anxiety, dementia in elderly patients, depression, eating disorders, insomnia, OCD, personality disorder, PTSD, substance use disorders, and Tourette s syndrome. Off-label use of atypical antipsychotics in various settings has increased rapidly since their introduction in the 1990s; risperidone, quetiapine, and olanzapine are the most common atypicals prescribed for off-label use. ES-2

14 One recent study indicated that the 2005 regulatory warning from the FDA and Health Canada was associated with decreases in the overall use of atypical antipsychotics, especially among elderly dementia patients. Use of atypicals in the elderly is much higher in long-term care settings than in the community. Atypicals are frequently prescribed to treat PTSD in the U.S. Department of Veterans Affairs health system. At least 90 percent of antipsychotics prescribed to children are atypical, rather than conventional antipsychotics. The majority of use is off-label. No off-label use of the newly approved atypicals (asenapine, iloperidone, and paliperidone) was reported in the utilization literature. Key Question 2. What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics, for off-label indications? Sub-Key Question 2: How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for treating off-label indications? The efficacy results are summarized in Table A. It is important to note that no trials of the three most recently FDA-approved atypicals (asenapine, iloperidone, and paliperidone) were found for off-label use. Cells shaded in green indicate areas with the strongest evidence of efficacy, followed by the areas in blue. White areas containing circles indicate areas where no clinical trials exist. Brown and pink areas indicate areas where evidence of inefficacy exists. Table B shows how our current efficacy findings compare with those of our original Comparative Effectiveness Review (CER) submitted to the Agency for Healthcare Research and Quality (AHRQ) in The evidence that atypicals have efficacy in treating symptoms of dementia has increased in the past few years; this evidence must be weighed against possible harms described in Key Question 4 below. Evidence of efficacy as augmentation for MDD and OCD patients who have not responded adequately to selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) has also increased. Table B is organized as follows: First, all conditions dealt with in our original CER, in alphabetical order; second, all the new off-label indications in alphabetical order. ES-3

15 Table A. Summary of strength of evidence of efficacy, by drug and condition Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Anxiety generalized anxiety disorder O Anxiety social phobia O + - O O Attention Deficit/Hyperactivity Disorder -no co-occurring disorders O O O + O Attention Deficit/Hyperactivity Disorder -bipolar children - O O O O Attention Deficit/Hyperactivity Disorder -mentally retarded children O O O + O Dementia overall O Dementia psychosis O Dementia agitation O Depression -MDD augmentation of SSRI/SNRI Depression -MDD: Monotherapy O - ++ O O Eating Disorders O -- - O O Insomnia O O - O O Obsessive Compulsive Disorder -augmentation of SSRI O Obsessive Compulsive Disorder -augmentation of citalopram O O + + O Personality Disorder -borderline O - Personality Disorder -schizotypal O O O +- O Post Traumatic Stress Disorder O O Substance Abuse alcohol O O Substance Abuse cocaine O - O - O Substance Abuse methamphetamine - O O O O Substance Abuse methadone clients O O O - O Tourette s Syndrome O O O : moderate or high evidence of efficacy + : low or very low evidence of efficacy +- : mixed results - : low or very low evidence of inefficacy -- : moderate or high evidence of inefficacy O : no trials : Approved by FDA for the indication MDD = major depressive disorder; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitors Note: Symbols denote strength of evidence, not size of portential effect. For example in dementia ++ indicates moderate-to-high strength of evidence that there is a beneficial effect, however the size of the effect is small. ES-4

16 Table B. Summary update: efficacy of atypical antipsychotics for off-label use Usage Strength of 2006 Findings 2011 Findings 2011 Conclusions Evidence Dementia High A published meta-analysis of 15 placebocontrolled trials (PCTs) found small but statistically significant effects favoring treatment with risperidone and aripiprazole. Overall In our meta-analysis of PCTs, aripiprazole, olanzapine, and risperidone were superior to placebo as treatment of behavioral symptoms as measured by total scores on BEHAVE-AD, BPRS, and NPI. Effect sizes were Aripiprazole, olanzapine, and risperidone have efficacy as treatment generally considered to be small in magnitude. for behavioral symptoms of dementia. Depression MDD: augmentation of SSRI/SNRI Moderate - risperidone, aripiprazole, quetiapine Low olanzapine, ziprasidone There were effects that favored treatment with olanzapine for the BPRS and the NPI, but these differences were not statistically significant. Three studies of quetiapine were considered too clinically dissimilar to pool and results for the individual studies showed, with one exception, trends favoring treatment with quetiapine that did not reach conventional levels of statistical significance. Three trials assessed the combination of olanzapine and fluoxetine, one trial each assessed augmentation of various SRIs with risperidone, ziprasidone, and quetiapine, and one study assessed adding risperidone versus olanzapine to SSRI. The combination of olanzapine and fluoxetine was no better than fluoxetine alone in improvement of depressive symptoms at 8 weeks, but three trials reported more rapid improvement in depressive symptoms (at 2 4 weeks) with combination therapy using olanzapine or quetiapine. The one trial that directly compared augmentation therapy between olanzapine and risperidone reported no differences in outcome. Psychosis In our meta-analysis risperidone was superior to placebo, as measured by the psychosis subscales of the BEHAVE-AD, BPRS, and NPI. Results for aripiprazole did not meet conventional levels of statistical significance. Agitation In our meta-analysis, aripiprazole, olanzapine and risperidone were superior to placebo, as measured by the agitation subscales of the BEHAVE-AD, BPRS, NPI, and CMAI. Three head to head trials compared atypicals; none was found superior. We conducted a meta-analysis using response to treatment and remission as outcome. Pooling trials that reported the HAM-D as outcome, the relative risk of responding for participants taking quetiapine or risperidone was significantly higher than for placebo. Olanzapine had only two trials, so pooling was not performed; the trials reported olanzapine superior to placebo. Other trials reported MADRS scores; the relative risk of responding for participants taking aripiprazole was significantly higher than those taking placebo. Risperidone and ziprasidone were included in two trials and one trial, respectively. These reported the drug superior to placebo. One trial compared ziprasidone at differing levels augmenting sertraline to sertraline alone. This trial found a greater improvement in CGI-S and MADRS scores augmenting with ziprasidone at 160mg than either augmentation with ziprasidone at 80mg or sertraline alone. However, there was no significant difference in HAMD-17, CGI-I or HAM-A scores. Aripiprazole, quetiapine, and risperidone have efficacy as augmentation to SSRIs/SNRIs for major depressive disorder. Olanzapine and ziprasidone may also have efficacy. ES-5

17 Table B. Summary update: efficacy of atypical antipsychotics for off-label use (continued) Usage Strength of 2006 Findings 2011 Findings 2011 Conclusions Evidence Depression MDD: Monotherapy Moderate In our meta-analysis of five placebo-controlled trials, quetiapine was superior according to relative risk of both responding and remitted as measured by MADRS. Obsessivecompulsive disorder augmentation of SSRI Obsessivecompulsive disorder augmentation of citalopram Moderate risperidone Low - olanzapine Low- quetiapine Very low - risperidone The three olanzapine studies (above) also assessed its efficacy as monotherapy. Olanzapine alone was no better than placebo in improving symptoms at 6 or 12 weeks. Outcomes were too heterogeneous to allow pooling. 12 trials used risperidone, olanzapine, or quetiapine as augmentation therapy in patients who were resistant to treatment with SSRI. Nine trials were sufficiently similar clinically to pool. Atypical antipsychotics had a clinically important benefit (measured by the Yale-Brown Obsessive-Compulsive Scale) when used as augmentation therapy. Relative risk of responding significant for augmentation with quetiapine and risperidone. There were too few studies of olanzapine augmentation to permit separate pooling of this drug. One trial of risperidone reported no differences between groups in achieving a response to therapy, but patients maintained on risperidone had a significantly longer period of time to relapse compared with placebo (102 days vs. 85 days) Our updated meta-analysis found risperidone superior to placebo, as measured by changed in the Yale Brown Obsessive Compulsive Scale (Y-BOCS). There were too few studies (two) to permit separate pooling for olanzapine; both trials reported olanzapine superior to placebo. One new head to head trial found no difference in effect between olanzapine and risperidone as SSRI augmentation. One new head to head trial found quetiapine more effective than ziprasidone as SSRI augmentation. One new trial compared quetiapine to clomipramine as SSRI augmentation. Quetiapine produced a significant reduction in Y-BOCS score, while clomipramine did not. Two new trials found quetiapine superior to placebo as augmentation for citalopram, according to Y-BOCS and CGI-I scores. Olanzapine does not have efficacy as monotherapy for major depressive disorder. Quetiapine has efficacy as monotherapy for major depressive disorder. Risperidone has efficacy in improving OCD symptoms when used as an adjunct to SSRI in treatment refractory patients. Olanzapine may also have efficacy. Quetiapine is more efficacious than ziprasidone and clomipramine for this purpose. Quetiapine and risperidone may be efficacious as augmentation to citalopram in OCD patients. ES-6

18 Table B. Summary update: efficacy of atypical antipsychotics for off-label use (continued) Usage Strength of 2006 Findings 2011 Findings 2011 Conclusions Evidence Post-traumatic stress disorder Moderate risperidone Personality disorders borderline Personality disorders schizotypal Tourette s syndrome Olanzapine Low Quetiapine very low Low aripiprazole Very low quetiapine, olanzapine Low Low Four trials of risperidone and two trials of olanzapine, each of at least 6 week duration, treated patients with PTSD. Three trials enrolled men with combat-related PTSD; these showed a benefit in sleep quality, depression, anxiety, and overall symptoms when risperidone or olanzapine was used to augment therapy with antidepressants or other psychotropic medication. Three trials of olanzapine or risperidone as monotherapy for abused women with PTSD were inconclusive regarding efficacy. Three trials provide evidence that olanzapine is superior to placebo and may be superior to fluoxetine. The benefit of adding olanzapine to dialectical therapy in one trial was small. Aripiprazole was superior to placebo in one small trial. Risperidone was superior to placebo in one small trial. Risperidone was superior to placebo in one small trial, and it was at least as effective as pimozide or clonidine for 8 to 12 weeks of therapy in the three other trials. One trial of ziprasidone showed variable efficacy compared with placebo. Three new trials of risperidone were found, allowing us to conduct a meta-analysis using the Clinician Administered PTSD Scale (CAPS) as outcome. Risperidone was superior to placebo. There were too few olanzapine studies (two) to pool; one reported olanzapine superior to placebo, while one did not. A new trial found a 3-fold decline in CAPS scores in patients treated with quetiapine monotherapy compared with placebo. Exact scores were not reported. We also conducted a meta-analysis by condition; atypicals were efficacious for combat-related PTSD but not PTSD in abused women. One new trial found aripiprazole superior to placebo in improving SCL-90, HAM-D, and HAM-A scores at 8 months and less self-injury at 18 months. One new trial of ziprasidone found no significant difference in CGI-BPD, depressive, anxiety, psychotic or impulsive symptoms compared with placebo at 12 weeks. Two new trials of olanzapine found no difference from placebo in any outcomes, while another new trial of olanzapine found greater change in ZAN-BPD scores at 12 weeks, compared with placebo. One new trial found quetiapine superior to placebo on BPRS, PANSS scales. Due to heterogeneity of outcomes, we could not perform a meta-analysis. One new small trial of risperidone found no difference from placebo on a cognitive assessment battery. Risperidone is efficacious in reducing combat-related PTSD symptoms when used as an adjunct to primary medication. Olanzapine had mixed results in 7 trials, aripiprazole was found efficacious in two trials, quetiapine was found efficacious in one trial, and ziprasidone was found not efficacious in one trial. Risperidone had mixed results when used to treat schizotypal personality disorder in two small trials. No additional trials. Same as 2006: Risperidone is at least as efficacious as pimozide or clonidine for Tourette s syndrome. ES-7

19 Table B. Summary update: efficacy of atypical antipsychotics for off-label use (continued) Usage Strength of 2006 Findings 2011 Findings 2011 Conclusions Evidence Anxiety Moderate Not covered. Three placebo-controlled trials of quetiapine as Quetiapine has efficacy monotherapy for Generalized Anxiety Disorder (GAD) could as treatment for be pooled; relative risk of responding on HAM-A favored the quetiapine group. Generalized Anxiety Disorder Attention deficit/ hyperactivity disorder no cooccurring disorders Attention deficit/ hyperactivity disorder mentally retarded children Attention deficit/ hyperactivity disorder bipolar children Eating disorders Moderate olanzapine One head to head trial showed no difference between risperidone and paroxetine on HAM-A score improvement. One trial each found quetiapine equally effective as paroxetine and escitalopram. Low Not covered. One trial showed risperidone superior to placebo in reducing scores on the Children s Aggression Scale Parent version (CAS-P). Low Not covered. One trial showed risperidone led to greater reduction in SNAP-IV (Swanson, Nolan, and Pelham teacher & parent rating scale) scores than methylphenidate. Low Not covered. Two trials of aripiprazole showed no effect on SNAP-IV (Swanson, Nolan, and Pelham teacher & parent rating scale) scores than placebo. Low - quetiapine Not covered. Five trials of olanzapine were found; three reporting Body Mass Index (BMI) could be pooled. There was no difference in change in BMI at either one or three months compared with placebo. One trial of quetiapine reported no statistical difference from placebo in BMI increase at three months. Insomnia Very low. Not covered. In one small trial (N=13) of quetiapine, sleep outcomes were not statistically different from placebo. Risperidone may be efficacious in treating children with ADHD with no serious co-occurring disorders. Risperidone may be superior to methylphenidate in treating ADHD symptoms in mentally retarded children. Aripiprazole is inefficacious in reducing ADHD symptoms in children with bipolar disorder. Olanzapine and quetiapine have no efficacy in increasing body mass in eating disorder patients. Quetiapine may be inefficacious in treating insomnia. ES-8

20 Table B. Summary update: efficacy of atypical antipsychotics for off-label use (continued) Usage Strength of 2006 Findings 2011 Findings 2011 Conclusions Evidence Substance abuse alcohol Substance abuse cocaine Substance abuse methamphetamine Substance abuse methadone clients Moderate aripiprazole Low quetiapine Not covered. Two trials of aripiprazole and one of quetiapine reported % of patients completely abstinent during follow-up. In our pooled analysis, the effect versus placebo was insignificant. Low Not covered. Two trials of olanzapine and one of risperidone reported there was no difference in efficacy versus placebo as measured by the Addiction Severity Index (ASI). Low Not covered. One trial found aripiprazole inefficacious in reducing use of intravenous amphetamine, as measured by urinalysis. Another trial found aripiprazole inefficacious in reducing craving for methamphetamine. Low Not covered. One trial of methadone clients found no difference between risperidone and placebo in reduction of cocaine or heroin use. Aripiprazole is inefficacious in treating alcohol abuse /dependence. Quetiapine may also be inefficacious. Olanzapine is inefficacious in treating cocaine abuse /dependence. Risperidone may also be inefficacious. Aripiprazole is inefficacious in treating methamphetamine abuse/dependence. Risperidone is an inefficacious adjunct to methadone maintenance. ADHD = attention-deficit hyperactivity disorder; BEHAVE-AD = Behavioral Pathology in Alzheimer s Disease Scale; BPRS = Brief Psychiatric Rating Scale; CGI-BPD = Clinical Global Impression Scale for Borderline Personality Disorder; CGI-I = Clinical Global Impression Improvement; CGI-S = Clinical Global Impression-Severity; CMAI = Cohen-Mansfield Agitation Inventory; HAM-A = Hamilton Anxiety Scale; HAM-D = Hamilton Depression Rating Scale; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; NPI = Neuropsychiatric Inventory; OCD = obsessive-compulsive disorder; PANSS = Positive and Negative Syndrome Scale; PCT = placebo-controlled trial; PTSD = post-traumatic stress disorder; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitors; ZAN-BPD = Zanarini Rating Scale for Borderline Personality Disorder ES-9

21 Key Question 3. What subset of the population would potentially benefit from off-label uses? Do effectiveness and harms differ by race/ethnicity, gender, and age group? By severity of condition and clinical subtype? There are insufficient data regarding efficacy, effectiveness, and harms to determine what subset of the population would potentially benefit from off-label uses of atypicals. Only one study conducted a subgroup analysis by gender; there were no studies that stratified by racial or ethnic group. Although many studies specified age in their inclusion criteria, few studies stratified results by age. Examination of the literature for differing efficacy of atypicals by clinical subsets did not reveal studies reporting subgroup analyses. Our own meta-analysis found efficacy for combat-related PTSD in men but not for PTSD in civilian women, although these data come from separate literatures, and head-to-head comparison of gender effects within study have not been performed. Due to the varying measures utilized in determining severity of illness, it was not possible to analyze treatment effects by severity of illness across any other condition. Key Question 4. What are the potential adverse effects and/or complications involved with offlabel prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions? Table C compares the most important findings regarding adverse events, by age group and study design. ES-10

22 Table C. Summary update: safety of atypical antipsychotics for off-label use Adverse Event Head-to-Head Comparisons Active Comparisons Placebo Comparisons Weight gain Elderly patients Weight gain Adults Weight gain Children & adolescents Mortality Elderly patients In one large trial (CATIE-AD) patients who were treated with olanzapine, quetiapine, or risperidone averaged a monthly gain of 1.0, 0.7, and 0.4 lbs respectively, compared with a monthly weight loss of 0.9 lbs for placebo patients. More common in olanzapine patients than ziprasidone patients in one trial. No head-to-head studies No difference between olanzapine and risperidone according to a meta-analysis of six trials of olanzapine published in More common in patients taking olanzapine than risperidone or conventional antipsychotics, particularly if their BMI was less than 25 at baseline, according to a large cohort study. More common among patients taking olanzapine than patients taking conventional antipsychotics in three trials. More common in patients taking aripiprazole than patients taking conventional antipsychotics in one trial. More common among patients taking olanzapine than patients taking mood stabilizers in two trials. No difference between clonidine and risperidone in one trial. Six large cohort studies compared mortality in elderly patients taking atypical and conventional antipsychotics. Four of these studies found a significantly higher rate of death with conventional antipsychotics, while two found no statistical difference in mortality between the drug classes. More common in patients taking olanzapine and risperidone than placebo according to our metaanalysis. More common in patients taking aripiprazole, olanzapine, quetiapine, and risperidone than placebo according to our meta-analysis. More common in patients taking risperidone in two PCTs. No difference in one small PCT of ziprasidone. The difference in risk for death was small but statistically significant for atypicals, according to a 2006 metaanalysis which remains the best available estimate. Sensitivity analyses found no difference between drugs in the class. Patients taking atypicals had higher odds of mortality than those taking no antipsychotics in the two cohort studies that made that comparison. There are no trials or large observational studies of ziprasidone in this population; therefore, we cannot make conclusions regarding safety here. ES-11

23 Table C. Summary update: safety of atypical antipsychotics for off-label use (continued) Adverse Event Head-to-Head Comparisons Active Comparisons Placebo Comparisons Endocrine/ diabetes Elderly patients No evidence reported. No evidence reported. No difference in endocrine events in risperidone patients in one PCT. Regarding diabetes, risk was elevated but not statistically significant in one industry-sponsored cohort study of olanzapine patients. Endocrine/ diabetes Adults CVA Elderly patients Diabetes more common in patients taking olanzapine than patients taking risperidone in one trial. No evidence reported. No evidence reported. Hospitalization for CVA was increased in the first week after initiation of conventional antipsychotics, but not for initiation of atypicals in a large cohort study. Endocrine events more common in patients taking quetiapine, risperidone, and ziprasidone in one PCT each. More common in olanzapine in two pooled PCTs. Diabetes more common in patients taking quetiapine in six pooled PCTs; however, the pooled odds ratio was elevated at 1.47 but not statistically significant. More common in olanzapine patients in one PCT; the odds ratio of 5.14 was not statistically significant, with very wide confidence intervals (0.6 to 244). Lower odds of diabetes in risperidone patients in one large observational study More common in risperidone patients than placebo according to four PCTs pooled by the manufacturer. In our new meta-analysis of PCTs, risperidone was the only drug associated with an increase. More common in olanzapine than placebo according to five PCTs pooled by the manufacturer. ES-12

24 Table C. Summary update: safety of atypical antipsychotics for off-label use (continued) Adverse Event Head-to-Head Comparisons Active Comparisons Placebo Comparisons EPS Elderly patients No evidence reported. EPS Adults Sedation Elderly patients Sedation Children and adolescents Sedation Adults More common in patients taking aripiprazole and risperidone patients than patients taking quetiapine in one large trial (CATIE-AD). No evidence reported. More common in elderly patients taking olanzapine or quetiapine than risperidone according to our analysis, but not quite statistically significant. No head-to-head trials. More common in patients taking quetiapine than risperidone in two trials. No difference in one trial of risperidone versus olanzapine. Less likely in patients taking quetiapine than mood stabilizers in one small trial. Less likely in patients taking olanzapine or aripiprazole than patients taking conventional antipsychotics in one trial each. No difference in one trial of olanzapine versus benzodiazepines. No difference in three trials of olanzapine and three of risperidone versus conventional antipsychotics. No difference in one small trial of clonidine versus risperidone. More patients on haloperidol than risperidone reported sleep problems in one trial. Olanzapine patients had higher odds than mood stabilizer patients in two trials. More common in olanzapine and quetiapine patients than SSRIs patients in three and two trials respectively. Olanzapine patients had lower odds than patients taking conventional antipsychotics in our pooled analysis of three trials. More common in patients taking risperidone, according to our metaanalysis. Quetiapine and aripiprazole were not associated with an increase. More common in olanzapine in one PCT. More common in patients taking aripiprazole, quetiapine, and ziprasidone than placebo according to our meta-analysis. More common in patients taking aripiprazole, olanzapine, quetiapine, and risperidone than placebo according to our meta-analysis. Less common in aripiprazole patients than placebo patients in one PCT. No difference from placebo in one small PCT of ziprasidone. More common in patients taking aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone than placebo in our meta-analysis. BMI = body mass index; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer s Disease; CVA = cerebrovascular accident; EPS = extrapyramidal symptoms; PCT = placebo-controlled trial; SSRI = serotonin selective reuptake inhibitor ES-13