Review Article Review of Maintenance Trials for Major Depressive Disorder: A 25-Year Perspective From the US Food and Drug Administration Silvana Borges, MD; Yeh-Fong Chen, PhD; Thomas P. Laughren, MD; Robert Temple, MD; Hiren D. Patel, PharmD; Paul A. David, RPh; Mitchell Mathis, MD; Ellis Unger, MD; Peiling Yang, PhD; and Ni A. Khin, MD ABSTRACT Objective: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. Data Sources: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. Study Selection: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. Data Extraction: Trial characteristics, relapse rates, and time to relapse in each study were examined. Results: Relapse rates were significantly lower (P  10; and no single CGI-S ≥ 4 between days 56–180 H 8 HDRS-21 ≤ 10, and CGI-S ≤ 3 at day 56 26 Meeting DSM-IV criteria for MDD and CGI-S ≥ 4, CGI-S ≥ 4 at 2 consecutive visits, or final CGI-S ≥ 4 if withdrawn from study I 8–12 HDRS-17 ≤ 8, and CGI-I ≤ 2 at 2 consecutive 40 Investigator’s judgment, HDRS-17 ≥ 18 at a single visit, visits after week 6 HDRS-17 of 15–17 at 2 consecutive visits, suicide or suicide attempt J 8 CGI-I ≤ 2 on weeks 6, 7, and 8 44 Investigator’s judgment K 10 Two consecutive HDRS-17 ≤ 10 at week 8 or 9 52 HDRS-17 ≥ 14, CGI-S ≥ 3 (with ≥ 2-point increase), and and at week 10 meeting DSM-IV criteria for MDD at 2 consecutive visits L 8 MADRS ≤ 12 36 MADRS ≥ 22 or discontinuation due to insufficient response M 12 Not meeting DSM-IV criteria for MDD, HDRS26 CGI-S of ≥ 2-point increase and meeting DSM-IV criteria 17 ≤ 9, and CGI-S ≤ 2 at weeks 10 and 12 for MDD at 2 consecutive visits N 12 HDRS-17 ≤ 11 at week 12 24 HDRS-17 ≥ 16, CGI-I ≥ 6, or discontinuation for insufficient response O 20 Response: HDRS-17 ≤ 11 and CGI-I ≤ 2 at week 8 26 HDRS-17 ≥ 16, discontinuation for insufficient response, (8 wk response, Stable response: HDRS-17 ≤ 11, CGI-I ≤ 2, and hospitalization for depression, suicide attempt, or suicide 12 wk stability) no HDRS-17 ≥ 16 nor CGI-I ≥ 4 at any visit in stability phase Abbreviations: CGI-I = Clinical Global Impression–Improvement scale, CGI-S = Clinical Global Impression–Severity scale, HDRS = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale, MDD = major depressive disorder.

Table 3. Response and Relapse Rates in Antidepressant Maintenance Studies Double-Blind Randomized Phase Open-Label Relapse Rate (%) Phase Response Rate (%) Percent Study Drug Placebo Drug Differencea Reduction A 63 39 8 31 79 B 78 32 12 20 63 C 58 24 14 10 42 D (2 doses) 66 31 8 23 74 12 19 61 E 47 59 39 20 34 F 27 14 2 12 86 G 49 48 25 23 48 H 65 46 27 19 41 I 38 44 20 24 55 J 51 48 34 14 29 K 48 31 16 15 48 L 54 33 23 10 30 M 52 29 17 12 41 N 64 42 24 18 43 O 63 28 14 14 50 Mean (SD) 52 (15) 37 (11) 18 (10) 18 (6) 52 (17) a

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