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Drug Class Review on Second Generation Antidepressants Drug Class Review on Second Generation Antidepressants FINAL REPORT November 2004 The Agency for Healthcare Research and Quality has not yet seen or approved this report Gerald Gartlehner, M.D., M.P.H. Richard A. Hansen, Ph.D. Leila Kahwati, M.D., M.P.H. Kathleen N. Lohr, Ph.D. Bradley Gaynes, M.D., M.P.H Tim Carey, M.D., M.P.H. Produced by RTI-UNC Evidence-based Practice Center Cecil G. Sheps Center for Health Services Research University of North Carolina at Chapel Hill 725 Airport Road, CB# 7590 Chapel Hill, NC 27599-7590 Tim Carey, M.D., M.P.H., Director Final Report Drug Effectiveness Review Project Table of Contents Introduction........................................................................................................................ 4 Overview................................................................................................................. 4 Scope and Key Questions ....................................................................................... 7 Methods............................................................................................................................. 10 Literature Search................................................................................................... 10 Study Selection ..................................................................................................... 10 Data Abstraction ................................................................................................... 12 Quality Assessment............................................................................................... 12 Data Synthesis....................................................................................................... 13 Results ................................................................................................................................................. 14 Overview............................................................................................................... 14 Question 1: Major Depressive Disorder in Adults................................................ 16 Question 1: Dysthymia.......................................................................................... 34 Question 1: Major Depressive Disorder in Children .................................... ……36 Question 1: Bipolar Disorder ................................................................................ 40 Question 1: General Anxiety Disorder.................................................................. 41 Question 1: Obsessive Compulsive Disorder........................................................ 43 Question 1: Panic Disorder. .................................................................................. 46 Question 1: Post-Traumatic Stress Disorder......................................................... 49 Question 1: Social Anxiety Disorder. ................................................................... 51 Question 1: Adjustment Disorder. ........................................................................ 56 Question 1: Premenstrual and Late Luteal Phase Dysphoric Disorder................. 56 Question 2: Adverse Events.................................................................................. 59 Question 3: Subgroups.......................................................................................... 67 References......................................................................................................................... 75 In-text Tables Table 1: Approved Second-Generation Antidepressants ....................................... 6 Table 2: Dosing Range and Frequency ................................................................... 7 Table 3: Outcomes and Eligibility Criteria............................................................. 9 Table 4: Abbreviations of Diagnostic Scales........................................................ 15 Table 5: Studies Indicating a Faster Onset of Mirtazapine………………………29 Table 6: Studies Indicating Fewer Sexual Adverse Events with Bupropion ........ 30 Table 7: Studies Indicating a Better Sleep Profile with Nefazodone…………… 31 Table 8: Included Studies for Major Depressive Disorder ................................... 32 Table 9: Included Studies for Dysthymia ............................................................. 35 Table 10: Included Studies for Major Depressive Disorder in Children .............. 39 Table 11: Included Studies for Bipolar Disorder .................................................. 41 Table 12: Included Studies for Generalized Anxiety Disorder............................. 43 Table 13: Included Studies for Obsessive Compulsive Disorder ......................... 46 Table 14: Included Studies for Panic Disorder ..................................................... 49 Second Generation Antidepressants Page 2 of 381 Final Report Drug Effectiveness Review Project Table 15: Included Studies for Post-Traumatic Stress Disorder........................... 51 Table 16: Included Studies for Social Anxiety Disorder ...................................... 55 Table 17: Included Studies for Premenstrual Dysphoric Disorder ....................... 58 Table 18: Included Studies for Adverse Events.................................................... 66 Table 19: Included Studies for Subgroups............................................................ 74 Exhibits Exhibit 1: Meta-analysis Fluoxetine-Paroxetine................................................... 88 Exhibit 2: Meta-analysis Fluoxetine-Sertraline .................................................... 90 Exhibit 3: Meta-analysis Fluoxetine-Venlafaxine ................................................ 92 Exhibit 4: Meta-analysis of Discontinuation Rates………………………………94 Figures Figure 1: Results of Literature Search ................................................................ 100 Evidence Tables Evidence Table 1: Major Depressive Disorder Adults ....................................... 102 Evidence Table 2: Dysthymia............................................................................. 193 Evidence Table 3: Major Depressive Disorder Children.................................... 201 Evidence Table 4: Bipolar Disorder.................................................................... 209 Evidence Table 5: General Anxiety Disorder..................................................... 211 Evidence Table 6: Obsessive Compulsive Disorder........................................... 215 Evidence Table 7: Panic Disorder....................................................................... 227 Evidence Table 8: Post-Traumatic Stress Disorder ............................................ 239 Evidence Table 9: Social Anxiety Disorder........................................................ 249 Evidence Table 10: Premenstrual and Late Luteal Phase Dysphoric Disorder .. 269 Evidence Table 11: Adverse Events ................................................................... 279 Evidence Table 12: Subgroups ........................................................................... 318 Appendices Appendix A: Search Strategy.............................................................................. 354 Appendix B: Quality Criteria.............................................................................. 356 Appendix C: Excluded Studies ........................................................................... 358 Appendix D: Pharmacokinetic Properties and Drug Interactions....................... 361 Appendix E: Placebo-controlled trials (not included)......................................... 366 Appendix F: Abstract-only Studies (not included) ............................................. 380 Appendix G: Acknowledgements ....................................................................... 381 Many thanks to our abstractors Heather Himburg and Melissa Butler and to our supporting staff Leah Randolph, Laura Morgan, Diane Greer, and Susan Goulet. Second Generation Antidepressants Page 3 of 381 Final Report Drug Effectiveness Review Project INTRODUCTION A. Overview Axis I psychiatric disorders such as depressive disorder, bipolar disorder, anxiety disorder, adjustment disorder, and premenstrual disorders, are serious disabling illnesses. Combined, they affect approximately one in five Americans.1 Major depressive disorder is the most prevalent, affecting more than 16 percent (lifetime) of US adults.2 In 2000, the economic burden of depressive disorders was estimated to be $83.1 billion.3 More than 30 percent of these costs were attributable to direct medical expenses. Pharmacotherapy dominates the medical management of Axis I psychiatric disease. Before the late 1980s, pharmacologic treatment was limited to tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) (with the exception of premenstrual disorder, which historically was untreated). The TCAs and MAOIs sometimes are referred to as traditional or first-generation antidepressants. Because these drugs are often accompanied by multiple side effects that many patients find intolerable (e.g., TCAs tend to cause anticholinergic effects including dry mouth and eyes, urinary hesitancy, and sometimes retention and constipation; MAOIs have the potential to produce hypertensive crisis if taken along with certain foods or dietary supplements containing excessive amounts of tyramine), first-generation antidepressants are no longer agents of choice in many circumstances. Newer treatments include selective serotonin reuptake inhibitors
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