Drug Class Review on Atypical Antipsychotic Drugs Final Report April 2006 The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within pharmaceutical classes. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Marian S. McDonagh, PharmD Kim Peterson, MS Susan Carson, MPH Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2006 by Oregon Health & Science University Portland, Oregon 97201. All rights reserved. Final Report Update 1 Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION............................................................................................................. 5 Scope and Key Questions ......................................................................................................13 METHODS .................................................................................................................... 15 Literature Search ....................................................................................................................15 Study Selection .......................................................................................................................15 Data Abstraction .....................................................................................................................15 Quality Assessment ................................................................................................................15 Data Synthesis........................................................................................................................16 Peer Review............................................................................................................................18 RESULTS ..................................................................................................................... 18 Overview .................................................................................................................................18 Schizophrenia and Related Psychoses...................................................................................20 Summary of Evidence .........................................................................................................20 Detailed Assessment ..........................................................................................................23 Key Question 1 and 2. Efficacy and Safety.....................................................................23 Key Question 3. Subgroups ............................................................................................84 Bipolar I Disorder ....................................................................................................................86 Summary of Evidence .........................................................................................................86 Detailed Assessment ..........................................................................................................87 Key Question 1. Efficacy .................................................................................................87 Key Question 2. Safety ...................................................................................................94 Key Question 3. Subgroups ............................................................................................96 Behavioral and Psychological Symptoms of Dementia (BPSD)..............................................97 Summary of Evidence .........................................................................................................97 Detailed Assessment ..........................................................................................................98 Key Question 1. Efficacy .................................................................................................98 Key Question 2. Safety .................................................................................................104 Key Question 3. Subgroups ..........................................................................................108 Youths with Autism, Disruptive Behavior Disorder or Attention Deficit Hyperactivity Disorder ..............................................................................................................................................109 Summary of Evidence .......................................................................................................109 Detailed Assessment ........................................................................................................111 Key Question 1. Efficacy ...............................................................................................111 Key Question 2. Safety .................................................................................................113 Key Question 3. Subgroups ..........................................................................................115 Serious Harms ......................................................................................................................116 Summary of Evidence .......................................................................................................116 Detailed Assessment ........................................................................................................117 Mortality.........................................................................................................................118 Cerbrovascular Disease Events....................................................................................119 Diabetes Mellitus...........................................................................................................120 Diabetic Ketoacidosis (DKA) .........................................................................................124 Weight gain ...................................................................................................................124 Neuroleptic Malignant Syndrome ..................................................................................128 Seizures ........................................................................................................................128 Tardive Dyskinesia........................................................................................................129 Atypical Antipsychotic Drugs Page 2 of 233 Final Report Update 1 Drug Effectiveness Review Project Cardiomyopathy and cardiac arrhythmias.....................................................................130 Agranulocytosis.............................................................................................................131 LIMITATIONS OF THIS REVIEW ............................................................................... 132 OVERALL SUMMARY................................................................................................ 132 REFERENCES............................................................................................................ 138 TABLES Table 1. AAP Drug Indications, Doses, and Mechanisms of Action* .......................................6 Table 2. Eligible Effectiveness or Efficacy Outcomes ............................................................14 Table 3. Total Numbers of Head-to-Head Trials of Atypical Antipsychotics...........................25 Table 4. Olanzapine versus Risperidone in the Inpatient Setting...........................................29 Table 5. Mean Change in Quality of Life Scale Scores: Olanzapine Versus Risperidone .....31 Table 6. Change from baseline SF-36 Mental Health Summary Score at 12 months............31 Table 7. Olanzapine versus Risperidone: Mean Change in PANSS* ....................................35 Table 8. Response Rates: Mean change in PANSS >20% from Baseline.............................36 Table 9. Patients Leaving Study Early ...................................................................................37 Table 10. Olanzapine vs Risperidone EPS Assessments......................................................41 Table 11. Olanzapine Versus Risperidone Adverse Events...................................................42 Table 12. Mean Change in Quality of Life Scale Scores........................................................45 Table 13. Clozapine Versus Risperidone: Mean Change (Baseline to Endpoint) ..................49 Table 14. Clozapine Versus Risperidone: PANSS Endpoint Scores .....................................50 Table 15. Response Rates: PANSS >20% ............................................................................50 Table 16. Clozapine vs Risperidone: Dropout Rates .............................................................51 Table 17. Clozapine versus Risperidone: EPS Assessments................................................54 Table 18. Clozapine Versus Risperidone: Adverse Events....................................................55 Table 19. Clozapine vs Olanzapine: Mean Change in Quality of Life Scale Scores ..............58 Table 20. Clozapine Versus Olanzapine: Mean Change in PANSS ......................................61 Table 21. Clozapine Versus Olanzapine: Response Rates ...................................................62