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. 2011 Dec 14;37(4):851–864. doi: 10.1038/npp.2011.306

Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review

Juan Undurraga 1,2, Ross J Baldessarini 1,*
PMCID: PMC3280655  PMID: 22169941

Abstract

Antidepressant–placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug–placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug–placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug–placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.

Keywords: antidepressants, evidence-based medicine, depression, meta-analysis, controlled trials, secular changes

INTRODUCTION

Efficacy of antidepressant drugs for treatment of acute, unipolar, major depressive episodes continues to be a research and clinical topic of considerable interest. There have been major changes in clinical practice involving antidepressants since the early 1990s (Healy, 1997; Baldessarini, 2005; Ghaemi, 2008). Currently favored drugs include the serotonin reuptake inhibitors (SRIs) introduced since the late 1980s, and a series of additional modern, ‘second-generation' antidepressants. These include agents with mixed inhibitory actions on the neuronal-uptake and inactivation of serotonin and norepinephrine (SNRIs, including desvenlafaxine, duloxetine, milnacipran, venlafaxine, and others), and ‘atypical' agents with other actions (such as bupropion, nefazodone, mirtazapine, and vilazodone). These modern or ‘second-generation' antidepressants have largely displaced older antidepressants including tricyclics (TCAs) and monoamine oxidase (MAO) inhibitors (Baldessarini, 2005, 2012).

The superiority of most clinically employed antidepressants over placebos in controlled trials has been modest in adult patients diagnosed with major depression, even lower in juvenile depressed patients, and probably has declined in recent years (Walsh et al, 2002; Baldessarini, 2005; Cipriani et al, 2007; Papakostas et al, 2007; Gartlehner et al, 2008; Kirsch et al, 2008; Tsapakis et al, 2008; Bridge et al, 2009; Wooley et al, 2009; Masi et al, 2010; Pigott et al, 2010; Khin et al, 2011). Evident decline in superiority of drugs over placebos has occurred despite evidence of selective reporting of positive findings of potential commercial interest from therapeutic trials (Ioannidis, 2008; Turner et al, 2008).

Moreover, there is little evidence that one antidepressant or pharmacological class of antidepressants is clearly and convincingly more effective than others (Anderson, 2001; Baldessarini, 2005, 2012; Cipriani et al, 2007; Papakostas et al, 2007; Gartlehner et al, 2008; Kirsch et al, 2008; Khin et al, 2011). In part, this lack of clear differentiation may arise from the modest drug–placebo differences in many controlled trials of antidepressants, which, in turn, may reflect broad clinical heterogeneity arising from the current broad concept of ‘major depression' (Healy, 1997; Ghaemi, 2008). Possible differentiation of efficacy among antidepressants was a lively question soon after introduction of the SRIs and SNRIs (Healy, 1997; Baldessarini, 2005, 2012). However, the popularity of most modern antidepressants owes far more to their perceived safety, relative ease of use, and broad clinical utility rather than to well-demonstrated superior efficacy in major depressive disorder compared with older agents (Baldessarini, 2005, 2012; Cipriani et al, 2007; Papakostas et al, 2007; Wooley et al, 2009; Pigott et al, 2010; Khin et al, 2011).

Given current uncertainties regarding the relative efficacy of specific drugs and pharmacological classes of antidepressants, we carried out a systematic, meta-analytic review of peer-reviewed, placebo-controlled trials, reported since 1980, limiting inclusion to drugs with regulatory approval for major depression that are currently employed clinically in the United States. Specific aims were to: (a) compare the efficacy of older and modern antidepressants compared with placebo; (b) further test the apparently widely held assumption that modern agents are at least equivalent in efficacy to older antidepressants (specifically TCAs); and (c) examine factors associated with anticipated declining differences in drug- vs placebo-associated responses in randomized, placebo-controlled trials of antidepressants.

MATERIALS AND METHODS

Search Strategy

We conducted a computerized literature review using Medline, CINAH Library, Cochrane Library, and PsycINFO literature databases using the following search-terms: ‘antidepressant, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, depression (or major depression), desmethylvenlafaxine, duloxetine, escitalopram, fluoxetine, imipramine, isocarboxazid, mirtazapine, maprotiline, monoamine oxidase (or MAO) inhibitors, nortriptyline, phenelzine, paroxetine, S-citalopram, selegiline, sertraline, tranylcypromine, trazodone, tricyclic antidepressants, trimipramine, and venlafaxine,' alone and in various combinations. Also, reference lists of articles and reviews on antidepressant efficacy were hand-searched for relevant reports. The search was limited to peer-reviewed, published, randomized, placebo-controlled trials (RCTs) in acute episodes of adult major depressive disorder diagnosed by standardized criteria, and reported from 1980 through August 2011.

Eligibility Criteria

Included were reports of randomized, double-blind, placebo-controlled trials in adults in an acute, apparently unipolar, major depressive episode (or with ⩽10% identified cases of bipolar depression or diagnoses other that major depression) based on DSM-III, III-R, or -IV, ICD-9 or -10, or RDC diagnostic criteria, and with at least 20 subjects per arm. We excluded trials of drugs that are not US FDA-approved and indicated in the United States for treatment of acute episodes of major depressive disorder, as well as reports involving special populations, such as juvenile or geriatric patients, treatment-resistant depression or depression associated with major neuromedical or other psychiatric disorders. Only monotherapy trials were included; antidepressant doses could be fixed or flexible, with or without low-doses (below the approximate equivalent (Baldessarini, 2005) of 2 mg/day of lorazepam) of supplemental sedative or hypnotic agents. For 35 trials with three randomized treatment conditions involving two active agents and a placebo arm, we compared each drug–placebo pair separately; in some three-arm trials involving an experimental agent and a standard comparator, we considered only a marketed agent vs placebo. When an active agent was used in different doses in the same trial, we calculated mean doses and outcome measures, all considered as a single drug-arm. Total daily drug doses (mg/day) were converted to approximate imipramine-equivalents (IMI-eq), based on the median of the range of clinical doses recommended by the manufacturers as summarized elsewhere (Baldessarini et al, 2010), so as to permit comparisons of agents of dissimilar potency.

Outcome Measures

The primary outcome measure was categorical ‘response,' usually defined as ⩾50% reduction in initial depression rating-scale scores. Most often, ratings were based on the Hamilton (HDRS) or Montgomery–Åsberg (MADRS) Depression Rating Scales (Hamilton, 1960; Montgomery and Åsberg, 1979), or Clinical Global Impression (CGI) ratings (Guy, 1976) when these measures were not available. Scores employed for analyses were standardized as the percentage of maximum attainable scores on each rating scale (eg, 48 for 17-item HDRS, 60 for the MADRS, and 61 for 21-item HDRS). When the number of items in the HDRS was not specified by the investigators, we considered it to be the most commonly employed 17-item version. When more than one depression rating scale was employed, we gave priority to results obtained with the HDRS for greater comparability. All measures of initial depression severity and its change by end-point were standardized by use of percentages of observed ratings to the maximum attainable score with each rating scale employed. Continuous measures of change in depression ratings with drug vs placebo were considered as secondary measures, because lack of variance measures in most trials precluded formal meta-analysis. We considered factors that might influence outcomes, including numbers of subjects and collaborating sites, percentage women, initial depression ratings, IMI-eq daily drug doses, trial-duration, dropout rates, specific drugs and types, and year of reporting. As manufacturers of the drugs involved sponsored almost all trials, sources of support were not further considered.

Data Analysis

Averaged data are means with SD, unless stated otherwise. Meta-analyses based on Stata metan programs, used random-effects modeling to limit effects of inter-trial variance; responder rates for each drug–placebo pair yielded pooled rate ratios (RRs) and rate differences (RDs) with their computed 95% confidence intervals (CIs) (Tsapakis et al, 2008; Yildiz et al, 2011a, 2011b). Percentage-improvement in depression for drug–placebo pairs was compared by paired-t testing and averaged to provide overall estimates of response differences (RDs). We also carried out bivariate and multiple linear regression modeling from these analyses to evaluate associations of selected covariates with reporting year. Correlations employed nonparametric Spearman rank methods (rs) to avoid effects of non-normally distributed data and potential nonlinear relationships. The primary study-hypothesis was that all marketed antidepressants would be statistically more effective than placebo, on average, with only minor differences among specific drugs or types. Analyses were based on standard commercial software (Stata.8; StataCorp, College Station, TX; Statview.5; SAS Institute, Cary, NC).

RESULTS

Trials Characteristics

Initially, we screened >2000 potentially relevant reports appearing between 1980 and 2011. Based on reviewing abstracts, 179 reports appeared to meet selection criteria and not to include multiple reports of the same trials. Exclusions (71/179) were as follow: (a) 17 studies involved <20 patients per arm; (b) another 17 included >10% of subjects with diagnoses other than major depressive episode; (c) 11 studies involved special populations; (d) 4 trials did not include a placebo control arm; (e) another 22 reports were excluded for various other reasons, including outcomes that were not quantified or did not include responder rates or improvement in depression ratings, represented subpopulations of larger trials already considered, or involved unapproved drugs. Detailed review of entire reports led to inclusion of 107; they involved 142 drug–placebo comparisons (Table 1), owing to 35 trials arising from studies with three randomized arms (for which a total of 3677 placebo-treated subjects were considered twice). There were 27 127 non-duplicated adult subjects (17 059 randomized to an antidepressant, 9925 to placebo), of average age 40 years (62.0±9.9% women). Antidepressants tested (n=19) ranked by trial-count as: imipramine (23 trials), fluoxetine (17), venlafaxine (15), paroxetine (14), amitriptyline (12), duloxetine (10), bupropion (9), desvenlafaxine (8), sertraline (8), R,S-citalopram (7), S-citalopram (5), mirtazapine (4), selegiline (3), desipramine (2), clomipramine (1), nortriptyline (1), phenelzine (1), tranylcypromine (1), and trazodone (1). Types of antidepressants ranked: SRIs (52 trials (36.6%)), TCAs (38 (26.8%)), SNRIs (33 (23.2%)), atypical agents (bupropion, mirtazapine, trazodone; 14 (9.9%)), and MAO-inhibitors (5 (3.5%)). Subjects per trial ranked: SNRIs (288±118) >SRIs (230±146) > atypical agents (224±144) >MAO-inhibitors (181±98) > TCAs (139±101); there were far more sites per trial since the median reporting-year of 1998 (range 1983–2010): 22.7±16.8 vs 7.22±5.98, as well as more subjects per trial: 270±114 vs 181±122, indicating a major secular trend toward increasing trial-size.

Table 1. Characteristics of Placebo-Controlled Trials of Antidepressants in Major Depression.

Trial (reference) Drug mg/day IMI-eq Weeks Total N Sites % Women Response N Rx % Resp Rx N Pbo % Resp Pbo RR Resp Ratings Initial Dep Rx Change Rx (%) Initial Dep Pbo Change Pbo (%) RD % Change Dropout Rx (%) Dropout Pbo (%) ITT Washout
Claghorn et al (1983) AMI 180 180 4 172 3 56 HDRS≥50% 85 62.4 87 42.5 1.47 HDRS21 42.6 — 45.9 — — 58 58 Yes Yes
Feighner et al (1983) IMI 163 163 6 487 5 71 CGI 244 57.8 243 32.5 1.78 HDRS21 42.6 — 42.6 — — 24 40 Yes Yes
Itil et al (1983) IMI 127 127 4 47 — 44 CGI 25 44 22 22.7 1.94 HDRS16 47.8 53 43.5 18 34.8 48 50 No Yes
Pitts et al (1983) BUP 525 262 4 59 — 34 HDRS≥50% 34 — 25 — — HDRS21 50.8 48 50.8 29 19.3 — — No Yes
White et al (1984) NRT 109 136 4 120 1 45 CGI 61 41 59 32.2 1.27 HDRS 52.1 54 56.2 37 16.6 34 24 Yes Yes
White et al (1984) TCP 44 145 4 122 1 45 CGI 63 39.7 59 32.2 1.23 HDRS 56.3 45 56.2 37 8.1 41 24 Yes Yes
Cohn and Wilcox (1985) FLX 70 350 6 112 — 62 HDRS≥50% 54 74.1 58 20.7 3.58 HDRS21 42.6 55 41 16 39.3 35 72 Yes Yes
Cohn and Wilcox (1985) IMI 152 152 6 112 — 53 HDRS≥50% 54 40.7 58 20.7 1.97 HDRS21 42.6 34 41 16 17.9 63 72 Yes Yes
Rickels et al (1985) AMI 148 148 6 254 — 66 HDRS≥50% 124 53.2 130 26.9 1.98 HDRS21 41 42 42.6 28 13.6 27 45 No Yes
Mendels and Schless (1986) IMI 167 167 6 68 — 46 HDRS≥50% 34 38.2 34 17.6 2.17 HDRS17 50 40 50 23 16.7 52 52 Yes Yes
Rickels et al (1987) IMI 143 143 6 124 — 62 HDRS≥50% 63 69.8 61 37.7 1.85 HDRS21 39.3 42 41 20 21.2 41 39 No Yes
Wernicke et al (1987) FLX 40 200 6 240 10 57 HDRS≥50% 207 54.1 33 — — — — — 0 — — 44 44 No Yes
Hollyman et al (1988) AMI 110 119 6 178 — 83 CGI 90 58.9 88 44.3 1.33 HDRS 31.3 62 31.2 41 21.3 26 16 No No
Wernicke et al (1988) FLX 22 110 — 363 — 61 HDRS≥50% 285 46.3 78 23.1 2 HDRS21 41 43 42.6 27 15.7 37 46 Yes Yes
Feighner et al (1989a) FLX 80 400 6 99 — 75 CGI 51 — 48 — — HDRS21 42.6 31 42.6 22 8.5 51 68 No Yes
Feighner et al (1989a) IMI 150 159 6 55 — 74 CGI 36 — 19 — — HDRS21 42.6 38 42.6 22 2 48 68 No Yes
Feighner et al (1989b) IMI 159 150 6 94 — 89 HDRS≥50% 46 — 48 — — HDRS21 44.3 39 41 37 15.9 — — No Yes
Larsen et al (1989) CMI 150 165 6 38 — 66 HDRS<9 20 55 18 22.2 2.48 HDRS17 37.5 58 37.5 32 26.2 15 28 Yes No
Miller et al (1989) PRX 30 150 4 47 — 71 CGI 22 45.5 25 36 1.26 HDRS21 39.3 25 39.3 26 –0.50 45 20 Yes Yes
Quitkin et al (1989) IMI 150 150 6 54 2 55.9 HDRS≥50% 27 51.9 27 18.5 2.81 HDRS17 30.2 65 30.2 26 39.3 26 30 Yes Yes
Quitkin et al (1989) PNZ 75 150 6 53 2 55.9 HDRS≥50% 26 57.7 27 18.5 3.12 HDRS17 30.2 50 30.2 26 24.8 26 27 Yes Yes
Gelenberg et al (1990) IMI 175 175 4 43 — 32 HDRS≥50% 22 — 21 x x HDRS27 33.3 51 34 35 15.9 36 23 No Yes
Lineberry et al (1990) BUP 287 144 6 219 5 65 HDRS≥50% 110 50.9 109 33.9 1.5 HDRS21 — — 44.3 38 — 23 29 Yes Yes
Reimherr et al (1990) AMI 104 104 8 299 8 54 HDRS≥50% 149 57.7 150 32.7 1.77 HDRS18 44.2 61 44.2 37 23.5 42 — — —
Reimherr et al (1990) SRT 145 181 8 299 8 54 HDRS≥50% 149 51.7 150 32.7 1.58 HDRS18 44.2 53 44.2 37 15.9 41 37 Yes Yes
Roth et al (1990) DMI 224 168 6 53 2 59 CGI 24 62.5 29 37.9 1.65 HDRS17 62.5 38 60.4 29 8.6 — — No Yes
Smith et al (1990) AMI 111 111 6 100 — 57 HDRS≥50% 50 56 50 30 1.87 HDRS17 50 54 47.9 29 24.8 30 — Yes —
Smith et al (1990) MTZ 18 77.4 6 100 — 57 HDRS≥50% 50 54 50 30 1.8 HDRS17 47.9 47 47.9 29 17.8 40 50 Yes Yes
Carman et al (1991) AMI 200 200 6 150 — — HDRS≥50% — — — — — HDRS21 45.9 51 44.3 26 24.5 4 4 No Yes
Khan et al (1991) VNX 74 66.6 6 93 — 60 HDRS≥50% 67 — 26 — — HDRS21 41 56 42.6 31 25.7 21 15 — Yes
Bakish et al (1992) AMI 112 112 7 112 5 43 HDRS≥50% 57 50.9 55 34.5 1.47 HDRS17 47.9 — 47.9 — — 32 49 Yes Yes
Claghorn et al (1992) PRX 38 190 6 337 4 52 HDRS<10 168 38.1 169 24.3 1.57 HDRS21 44.3 48 42.6 33 15.2 35 44 Yes Yes
Cohn and Wilcox (1992) PRX 37 175 6 67 — 58 HDRS≥50% 31 — 36 — — HDRS17 52.1 34 54.2 20 20.9 31 67 Yes Yes
Cohn and Wilcox (1992) IMI 175 185 6 71 — 54 HDRS≥50% 35 — 36 — — HDRS17 52.1 41 54.2 20 14.2 26 67 Yes Yes
Fabre (1992) IMI 135 135 6 80 1 62 HDRS≥50% 40 — 40 — — HDRS21 — — — — — 21 53 No —
Fabre (1992) PRX 29 145 6 80 1 62 HDRS % 40 — 40 — — HDRS21 — — — — — 21 53 No Yes
Feighner (1992) IMI 113 113 6 79 — — HDRS≥50% 40 50 39 12.8 3.9 HDRS21 — — — — — 41 54 Yes Yes
Feighner (1992) PRX 26 130 6 78 — — HDRS≥50% 39 28.2 39 12.8 2.2 HDRS21 — — — — — 60 54 Yes X
Kiev (1992) PRX 31 155 6 78 — 45 HDRS≥50% 34 55.9 44 25 2.24 HDRS17 60.4 45 58.3 24 20.7 38 44 No Yes
Rickels et al (1992) PRX 32 160 6 111 — 64 HDRS≥50% 55 40 56 19.6 2.04 HDRS21 — — 42.6 — — 29 21 No Yes
Feighner et al (1993) IMI 140 140 6 477 6 49 HDRS<10 237 26.6 240 12.9 2.06 HDRS21 42.6 35 44.3 22 13.3 54 53 Yes Yes
Feighner et al (1993) PRX 30 150 6 480 6 51 HDRS<10 240 24.6 240 12.9 1.9 HDRS21 42.6 38 44.3 22 16.1 42 53 Yes Yes
Cunningham et al (1994) TZD 297 346 6 153 6 66 CGI 77 59.7 76 55.3 1.08 HDRS21 41 43 39.3 36 7.3 36 36 Yes Yes
Cunningham et al (1994) VNX 158 142 6 148 6 66 CGI 72 72.2 76 55.3 1.31 HDRS21 41 48 39.3 36 11.1 29 36 Yes Yes
Doogan and Langdon (1994) SRT 75 93.8 6 200 — 68 MADRS≥50% 99 50.5 101 39.6 1.28 MADRS 46.6 55 44.5 45 10.4 19 10 Yes Yes
Fontaine et al (1994) IMI 214 214 6 90 1 58 HDRS≥50% 45 48.9 45 31.1 1.57 HDRS17 54.2 42 54.2 26 15.6 42 47 Yes Yes
Rickels et al (1994) IMI 191 191 8 187 12 63 HDRS≥50% 95 65.3 92 44.6 1.46 HDRS17 50 — 50 — — 49 37 No Yes
Schweizer et al (1994) IMI 176 176 6 151 2 66 HDRS≥50% 73 61.6 78 47.4 1.3 HDRS21 39.3 43 41 38 5.2 45 27 No —
Schweizer et al (1994) VNX 182 164 6 151 2 66 HDRS≥50% 73 76.7 78 47.4 1.62 HDRS21 41 55 41 38 16.5 36 27 No Yes
Silverstone (1994) IMI 150 150 6 135 13 55 HDRS≥50% 66 50 69 50.7 0.99 HDRS17 52.1 48 50 43 4.4 40 35 No No
Vartiainen and Leinonen (1994) MTZ 32.5 140 6 114 8 54 HDRS≥50% 59 — 55 — — HDRS21 42.6 59 42.6 48 10.7 37 44 Yes Yes
Wilcox et al (1994) AMI 122 122 6 99 2 47 HDRS≥50% 50 56 49 24.5 2.29 HDRS21 42.6 59 42.6 45 14.2 44 55 Yes Yes
Bremner (1995) AMI 186 186 6 100 — 68 HDRS≥50% 50 58 50 34 1.71 HDRS17 56.3 — 56.2 — — 20 24 Yes Yes
Bremner (1995) CTP 30 129 6 100 — 68 HDRS≥50% 50 70 50 34 2.06 HDRS17 58.3 — 56.2 — — 18 24 Yes Yes
Claghorn and Lesem (1995) MTZ 16 68.8 6 90 — 44 HDRS≥50% 42 50 48 27.1 1.85 HDRS17 45.8 — 47.9 — — 40 58 No Yes
Fabre et al (1995) SRT 171 214 6 369 8 53 CGI 278 60.1 91 41.8 1.44 HDRS17 52.1 47 52.1 34 12.3 23 49 Yes Yes
Guelfi et al (1995) VNX 350 315 4 93 6 85 HDRS≥50% 46 52.2 47 31.9 1.63 HDRS17 — — 60.4 17 — 24 57 Yes Yes
Khan (1995) MTZ 36 155 6 54 1 67 HDRS≥50% 27 55.6 27 37 1.5 HDRS17 47.9 53 45.8 29 24.7 33 41 Yes Yes
Laakman et al (1995) AMI 102 102 6 146 — 71 HDRS≥50% 72 73.6 74 21.6 3.4 HDRS17 41.7 60 39.6 25 34.9 5 12 No Yes
Mynors-Wallis et al (1995) AMI 139 139 12 61 15 74 HDRS≤7 31 51.6 30 26.7 1.94 HDRS17 — — 37.5 36 — 19 60 No No
Cassano et al (1996) IMI 150 150 6 123 18 52.8 MADRS≥50% 64 — 59 — — MADRS 51.8 41 51.7 28 13.1 27 39 Yes Yes
Claghorn et al (1996) IMI 136 136 6 89 — 64 CGI 44 45.5 45 26.7 1.7 HDRS21 42.6 40 42.6 25 15.2 58 60 Yes Yes
Cohn et al (1996) IMI 126 126 8 80 — 70 HDRS≥50% 38 60.5 42 35.7 1.69 HDRS17 — — 47.9 39 — 39 26 Yes Yes
Feiger (1996) IMI 224 224 8 81 8 68 CGI 41 61 40 30 2.03 HDRS17 50 46 50 29 16.6 33 55 Yes Yes
Cunningham (1997) VNX 128 115 12 278 — 63 HDRS≥50% 179 57.5 99 30.3 1.9 HDRS21 39.3 55 40.8 36 18.8 34 41 Yes Yes
Lecrubier et al (1997) IMI 114 114 10 151 24 66 MADRS≥50% 75 62.7 76 59.2 1.06 MADRS 40 57 40 54 3.7 31 25 Yes Yes
Lecrubier et al (1997) VNX 125 112 10 154 24 69 MADRS≥50% 78 82.1 76 59.2 1.39 MADRS 41.7 64 40 54 10.6 29 25 Yes Yes
Lydiard et al (1997) AMI 91 91 8 260 15 67 HDRS≥50% 131 55.7 129 37.2 1.5 HDRS17 45.8 58 45.8 40 18.1 38 29 Yes Yes
Lydiard et al (1997) SRT 91 114 8 261 15 67 HDRS≥50% 132 54.6 129 37.2 1.47 HDRS17 45.8 52 45.8 40 11.8 27 29 Yes Yes
Thase (1997) VNX 150 135 8 197 12 61 HDRS≥50% 95 57.9 102 29.4 1.98 HDRS21 39.3 48 39.3 30 18.2 27 40 Yes Yes
Ban et al (1998) DMI 150 112 4 174 6 62 HDRS≥50% 89 48.3 85 35.3 1.37 HDRS17 — — — — — 10 10 Yes Yes
Fava et al (1998) FLX 50 250 12 73 5 51 HDRS≥50% 54 57.4 19 52.6 1.09 HDRS21 39.3 45 39.3 48 –3.30 31 21 Yes Yes
Fava et al (1998) PRX 35 175 12 74 5 51 HDRS≥50% 55 58.2 19 52.6 1.11 HDRS21 37.7 48 39.3 48 –0.50 29 21 Yes Yes
Khan et al (1998) VNX 142 128 12 382 12 64 HDRS≥50% 286 — 96 — — HDRS21 41 45 41 30 15 — — Yes Yes
Massana (1998) FLX 30 150 8 255 — — HDRS≥50% 127 55.9 128 34.4 1.63 HDRS21 — — — — — 24 41 — —
Reimherr et al (1998) BUP 218 109 8 362 — 68 HDRS % 241 — 121 — — HDRS17 — — — — — 44 50 Yes Yes
Rudolph et al (1998) VNX 204 184 6 323 — 33 HDRS≥50% 231 48.9 92 29.3 1.67 HDRS21 — — — — — 53 41 Yes Yes
Coleman et al (1999) BUP 290 145 8 235 9 57 HDRS≥50% 118 66.1 117 56.4 1.17 HDRS31 — 59 — 50 9.4 22 32 Yes Yes
Coleman et al (1999) SRT 106 132 8 226 9 57 HDRS≥50% 109 60.5 117 56.4 1.07 HDRS31 — 57 — 50 6.9 36 32 Yes Yes
Croft et al (1999) BUP 293 146 8 232 8 51 HDRS≥50% 116 66.4 116 47.4 1.4 HDRS31 — — — — — 30 34 Yes Yes
Croft et al (1999) SRT 121 151 8 232 8 50 HDRS≥50% 116 68.1 116 47.4 1.44 HDRS31 — — — — — 33 34 Yes Yes
Feighner and Overo (1999) CTP 33 142 6 650 — 60 MADRS≥50% 521 — 129 — — HDRS21 41 46 40.8 38 7.7 — — Yes Yes
Mendels et al (1999) CTP 52 224 4 180 3 62 HDRS≥50% 89 80.9 91 47.3 1.71 HDRS17 50 39 50 29 10.7 48 44 Yes Yes
Philipp et al (1999) IMI 100 100 8 151 18 78 HDRS≥50% 105 62.9 46 47.8 1.31 HDRS17 45.8 64 47.9 53 10.7 — — Yes Yes
Rudolph and Feiger (1999) FLX 47 235 8 200 12 70 HDRS≥50% 103 50.5 97 42.3 1.19 HDRS21 42.6 45 41 41 4.6 27 21 — —
Rudolph and Feiger (1999) VNX 175 158 8 192 12 70 HDRS≥50% 95 56.8 97 42.3 1.34 HDRS21 41 50 41 41 9.2 19 21 Yes Yes
Silverstone and Ravindran (1999) FLX 40 200 12 237 — 60 HDRS≥50% 119 63 118 43.2 1.46 HDRS17 56.3 56 56.2 41 15.1 26 40 Yes —
Silverstone and Ravindran (1999) VNX 141 127 12 240 — 60 HDRS≥50% 122 64.8 118 43.2 1.5 HDRS17 56.3 58 56.2 41 17.7 29 40 Yes Yes
Corrigan et al (2000) FLX 20 100 8 70 8 — HDRS≥50% 35 48.6 35 25.7 1.89 HDRS17 45.8 — 43.8 — — 14 34 Yes Yes
Stahl (2000) CTP 57 245 8 215 8 60 HDRS≥50% 107 55.1 108 39.8 1.38 HDRS17 54.2 58 54.2 46 11.5 20 22 Yes Yes
Stahl (2000) SRT 143 179 8 216 8 60 HDRS≥50% 108 54.6 108 39.8 1.37 HDRS17 56.3 55 54.2 46 9.1 26 — Yes Yes
Coleman et al (2001) BUP 335 168 8 302 15 62 HDRS≥50% 150 56 152 50 1.12 HDRS21 41 65 39.3 55 10.5 37 33 Yes Yes
Coleman et al (2001) FLX 29 145 8 306 15 63 HDRS≥50% 154 57.1 152 50 1.14 HDRS21 41 63 39.3 55 8.4 37 33 Yes Yes
Andreoli et al (2002) FLX 40 200 8 255 33 60 HDRS≥50% 127 55.9 128 33.6 1.66 HDRS21 44.3 — 44.3 — — 8 12 Yes Yes
Bodkin and Amsterdam (2002) SLG 6 100 6 176 6 60 HDRS≥50% 88 37.5 88 22.7 1.65 HDRS17 47.7 38 48.5 26 11.8 11 17 Yes Yes
Burke et al (2002) CTP 40 172 8 244 35 61 MADRS≥50% 125 45.6 119 27.7 1.65 HDRS21 42.6 38 42.6 29 8.8 — — Yes Yes
Burke et al (2002) S-CTP 15 128 8 360 35 66 MADRS≥50% 241 50.6 119 27.7 1.83 HDRS21 41 44 42.6 29 14.3 — — Yes Yes
Davidson (2002) SRT 75 93.8 8 225 12 66 HDRS≥50% 109 48.6 116 43.1 1.13 HDRS17 47.9 46 47.9 40 5.8 28 28 Yes Yes
Detke et al (2002a) DLX 60 108 9 267 18 54 HDRS≥50% 139 44.7 128 23 1.95 HDRS17 43.8 52 43.8 29 –11.2 — — Yes Yes
Detke et al (2002b) DLX 60 108 9 245 21 99 HDRS≥50% 123 50.4 122 35.2 1.43 HDRS17 41.7 40 41.7 52 23.1 39 35 Yes Yes
Golden et al (2002) PRX 43.2 216 12 622 40 65 HDRS≥50% 417 58 205 47.8 1.21 HDRS17 50 53 50 46 7.1 — — Yes Yes
Goldstein et al (2002) DLX 107 193 8 140 8 64 HDRS≥50% 70 64.3 70 48.6 1.32 HDRS17 37.5 53 39.6 34 18.9 34 34 Yes —
Goldstein et al (2002) FLX 20 100 8 103 8 64 HDRS≥50% 33 51.5 70 48.6 1.06 HDRS17 37.5 44 39.6 34 9.2 36 34 Yes —
Wade et al (2002) S-CTP 10 85 8 380 40 76 MADRS≥50% 191 55 189 41.8 1.32 MADRS 48.3 51 48.3 42 9.2 16 15 Yes Yes
Amsterdam (2003) SLG 6 100 8 289 16 64 HDRS≥50% 145 32.4 144 27.8 1.17 HDRS17 47.5 36 47.9 29 6.7 28 28 Yes Yes
Lepola et al (2003) CTP 28 120 8 313 69 72 MADRS≥50% 159 52.8 154 48.1 1.1 MADRS — — 48.3 42 — 5 10 Yes Yes
Lepola et al (2003) S-CTP 14 119 8 309 69 72 MADRS≥50% 155 63.9 154 48.1 1.33 MADRS — — 48.3 42 — 6 — — —
Detke et al (2004) DLX 100 180 8 281 — 70 HDRS≥50% 188 68.1 93 44.1 1.54 HDRS17 41.7 58 41.7 44 13.8 11 19 Yes Yes
Detke et al (2004) PRX 20 100 8 179 — 71 HDRS≥50% 86 74.4 93 44.1 1.69 HDRS17 41.7 58 41.7 44 14.5 12 19 Yes Yes
Goldstein et al (2004) DLX 60 108 8 266 19 60 HDRS≥50% 177 47.5 89 31.5 1.51 HDRS17 37.5 44 35.4 29 15 39 42 Yes Yes
Goldstein et al (2004) PRX 20 100 8 176 19 64 HDRS≥50% 87 40.2 89 31.5 1.28 HDRS17 37.5 36 35.4 29 6.7 44 42 Yes Yes
Trivedi et al (2004) PRX 19 95 8 447 40 58 HDRS≥50% 301 — 146 — — HDRS17 47.9 52 50 42 9.5 21 23 Yes Yes
Bjerkenstedt et al (2005) FLX 20 100 4 109 15 79 HDRS≥50% 54 37 55 — — HDRS21 39.3 37 41 38 –1.10 11 5 Yes Yes
Brannan et al (2005) DLX 60 108 7 280 25 65 HDRS≥50% 141 42 141 39.7 1.06 HDRS17 47.9 46 45.8 46 — — — Yes Yes
Fava et al (2005) FLX 20 100 12 90 2 59 HDRS<8 47 29.8 43 20.9 1.42 HDRS17 41.7 32 41.7 37 –4.60 49 51 Yes Yes
Clayton et al (2006) S-CTP 13 158 8 549 — 59 HDRS≥50% 276 61.2 273 48.7 1.26 HDRS17 47.9 58 47.9 52 4.4 25 24 Yes Yes
Clayton et al (2006) BUP 316 110 8 554 — 59 HDRS≥50% 281 59.1 273 48.7 1.21 HDRS17 50 56 47.9 52 6.9 25 24 Yes Yes
Feiger et al (2006) SLG 9 150 8 265 3 57 HDRS≥50% 132 40.2 133 30.1 1.34 HDRS17 48.8 37 49.4 32 5.6 24 20 Yes Yes
Gastpar et al (2006) CTP 20 86 6 257 21 69 HDRS≥50% 127 55.9 130 39.2 1.43 HDRS17 45.8 53 45.8 41 11.9 18 19 Yes —
Jefferson et al (2006) BUP 352 176 8 274 24 68 CGI 135 53.3 139 38.1 1.4 IDSIVR30 54.8 46 54.8 38 8.1 24 21 Yes No
Moreno et al (2006) FLX 20 100 8 46 1 83 HDRS≥50% 20 55 26 42.3 1.3 HDRS21 24.6 53 26.2 31 22.1 20 27 Yes Yes
Perahia et al (2006) DLX 100 180 8 295 22 70 HDRS≥50% 196 66.3 99 51.5 1.29 HDRS17 43.8 59 43.8 52 6.2 12 10 Yes No
Perahia et al (2006) PRX 20 100 8 196 22 70 HDRS≥50% 97 60.8 99 51.5 1.18 HDRS17 43.8 57 43.8 52 4.3 9 10 Yes —
DeMartinis et al (2007) dVNX 233 291 8 470 25 60 HDRS≥50% 350 — 120 — — HDRS17 47.9 45 47.9 33 11.7 25 18 Yes Yes
Liebowitz et al (2007) dVNX 187 234 8 238 — 60 HDRS≥50% 121 43 117 34.2 1.26 HDRS17 50 40 50 36 4.2 18 25 Yes Yes
Nemeroff and Thase (2007) FLX 41 205 6 206 13 62 HDRS≥50% 104 45.2 102 37.3 1.21 HDRS21 39.3 — — — — 17 24 Yes —
Nemeroff and Thase (2007) VNX 142 128 6 204 13 62 HDRS≥50% 102 52.9 102 37.3 1.42 HDRS21 39.3 — — — — 24 24 Yes —
Nierenberg et al (2007) S-CTP 10 108 8 410 36 66 HDRS≥50% 273 45.3 137 37.2 1.22 HDRS17 37.5 41 37.5 34 9.5 24 29 Yes Yes
Nierenberg et al (2007) DLX 60 85 8 411 36 63 HDRS≥50% 274 48.7 137 37.2 1.31 HDRS17 37.5 43 37.5 34 6.9 31 29 Yes Yes
Septien-Velez et al (2007) dVNX 300 375 8 369 35 66 HDRS≥50% 245 58 124 37.9 1.53 HDRS17 52.1 49 52.1 37 12.6 27 22 Yes No
Boyer et al (2008) dVNX 75 93.8 8 485 44 70 HDRS≥50% 324 63.9 161 50.3 1.27 HDRS17 50 56 50 45 11.4 15 9 Yes Yes
Lieberman et al (2008) VNX 162 399 8 471 — 68 HDRS≥50% 226 60.3 245 46.9 1.29 HDRS17 54.2 57 54.2 47 9.2 18 14 Yes Yes
Lieberman et al (2008) dVNX 319 146 8 487 — 66 HDRS≥50% 242 54.9 245 46.9 1.17 HDRS17 52.1 56 54.2 47 10 26 14 Yes Yes
Liebowitz et al (2008) dVNX 75 93.8 8 447 25 60 HDRS≥50% 297 32.7 150 24 1.36 HDRS17 47.9 49 47.9 41 7.6 21 16 Yes Yes
Cutler et al (2009) DLX 60 108 6 308 38 60 MADRS≥50% 151 49.7 157 36.3 1.37 HDRS17 52.1 49 52.1 40 8.3 30 21 Yes Yes
Feiger et al (2009) dVNX 349 436 8 230 12 65 HDRS≥50% 117 41.9 118 29.7 1.41 HDRS17 47.9 46 47.9 32 14.1 25 13 Yes Yes
Sheehan et al (2009) FLX 58 290 6 194 22 66 HDRS≥50% 99 35.3 95 36.7 0.96 HDRS21 49.2 39 47.5 37 1.2 23 29 Yes No
Sheehan et al (2009) VNX 235 212 6 186 22 56 HDRS≥50% 91 51.6 95 36.7 1.41 HDRS21 49.2 48 47.5 37 10.4 29 29 Yes No
Tourian et al (2009) dVNX 75 108 8 317 21 64 HDRS≥50% 157 44 160 38.1 1.15 HDRS17 47.9 44 50 36 8.5 25 27 Yes Yes
Tourian et al (2009) DLX 60 93.8 8 458 21 62 HDRS≥50% 298 47.1 160 38.1 1.24 HDRS17 47.9 45 50 36 7.8 26 27 Yes Yes
Hewett et al (2010) BUP 180 90 8 390 65 66 MADRS 203 57.1 187 49.2 1.16 MADRS 51.7 48 51.7 43 4.9 22 22 No No
Hewett et al (2010) VNX 85 76.5 8 385 65 66 MADRS 198 66.2 187 49.2 1.34 MADRS 50 56 51.7 43 13.4 23 22 No —
Means/sums 142 Trials — 156±67 7.2±1.8 27 127a 16±15 62±9.9 — 17 059 53.8±10.9 9925a 36.6±10.9 1.57±0.49 — 45.3±6.4 48.6±8.4 45.1±36.0 36±9.5 12.6±8.2 29.8±12.3 33.3±15.7 78.90% 81.7%
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Abbreviations: AMI, amitriptyline; BUP, bupropion; CMI, clomipramine; CTP, citalopram; S-CTP, escitalopram; Dep, depression rating; DLX, duloxetine; DMI, desipramine; FLX, fluoxetine; IMI, impramine; ITT, findings based on intent-to-treat: at least one dose and one assessment; MTZ, mirtazapine; N, responders or cases treated; NRT, (nortriptyline:); Pbo, placebo; PNZ, phenelzine; PRX, paroxetine; RD, response difference, %-Improvement, drug—placebo; RR, response rate ratio, drug–placebo; Rx, drug; SLG, selegiline; SRT, sertraline; TCP, tranylcypromine; TZD, trazodone; VNX, venlafaxine; dVNX, desvenlafaxine.

a

Corrected for 3677 repeated placebo cases in 35 trials.

There are a total of 142 drug–placebo comparisons from 107 studies, involving a total of 26 948 patients.

Initial depression scores (as percentage of scale maxima were similar in drug- (45.6±6.5%) and placebo-arms (48.6±8.4%)). There were 120±90 subjects (range: 11–521) per antidepressant arm and 96±57 per placebo arm (range: 18–273) or 216±136 participants per trial, and 16.1±15.3 collaborating sites per trial. Treatment lasted approximately 7.2±1.8 weeks, uncorrected for early dropouts at unspecified times, at rates of approximately 29.8±12.3% or 4.54±2.58% per week with drugs, and 33.3±15.7% or 5.06±3.02% per week with placebos (paired-t=2.71, p=0.007). Supplemental use of moderate doses of sedative-anxiolytics was permitted in 59.1% of all trials. Most trials (81.7%) included at least brief periods to allow previously administered drugs to ‘wash-out,' and most (78.9%) employed intention-to-treat methods; 97.4% of trials were sponsored by pharmaceutical manufacturers. The overall estimated IMI-eq standardized dose was 158±68 mg/day, and did not differ by drug-type or between older (TCAs, MAO-inhibitors: 155±49 mg/day) and modern antidepressants (SRIs, SNRIs, and atypical agents: 159±77 mg/day).

Meta-Analysis

Meta-analyses with the 122 trials reporting on responder rates yielded pooled drug–placebo RRs (RR with CIs) for each agent, and an overall pooled RR value of 1.42. (95% CI: 1.38–1.48; z=16.3, p<0.0001). Among agents with more than one trial, amitriptyline ranked highest in apparent efficacy, and bupropion lowest; however, CIs for most agents overlapped, indicating the need for caution in attempting to rank drugs by efficacy (Figure 1). Single-trial data available for phenelzine, clomipramine, nortriptyline, trazodone, and tranylcypromine are likely to be unstable and unreliable (Figure 1). Construction of a ‘funnel plot' (1/standard-error-of-RR vs 1/RR) for all reports with data on responder rates yielded a V-shaped distribution of values that was symmetrically distributed around the pooled value of 1/RR (not shown); this finding may provide evidence against selective reporting of positive trials results.

Figure 1.

Figure 1

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Summary of meta-analytically computed relative rates (RR) of response after randomization to drug vs placebo) with 95% confidence intervals (CI, horizontal bars when n⩾2 trials per drug) for controlled trials of each of 19 antidepressants (with numbers of trials on the left axis, and numerical values on the right). Drugs are listed by descending apparent efficacy, with symbol-size approximately proportional to weighting by trials per drug. The vertical solid line=null (1.0); vertical dotted line and solid diamond (width=CI)=pooled RR for all agents tested (*p<0.05; **p⩽0.01; ***p⩽0.001). Overall pooled RR=1.42 (CI: 1.38–1.48), indicating an average of 42% superiority of antidepressants over placebos. Note that phenelzine, clomipramine, tranylcypromine and trazodone (n=1 trial each) appear to be outliers.

We also compared antidepressants by types with pooled data, and compared apparent efficacy by three outcome measures. These included meta-analytically computed response RRs and responder rate-differences (RD), as well as relative differences (RD) in changes in depression ratings with drug–placebo pairs. Although these outcome measures yielded slightly different rankings, TCAs consistently ranked as the most effective antidepressants considered, and atypical agents, seemingly least effective (Table 2). Trials carried out before the median reporting year (1998) yielded higher values of all efficacy measures (Table 2). Median years of trial-reporting ranked: TCAs (1991) < MAO-inhibitors (1997) < atypical agents (1998) = SRIs (1998) < SNRIs (2003). Efficacy based on responder-rate RR values was much greater for TCAs than other types of antidepressants (1.83±0.62 vs 1.48±0.41; F=11.8, p=0.0008). Moreover, when the numbers of placebo-responders and nonresponders in the TCA trials were substituted for corresponding placebo data for trials of modern antidepressants, the meta-analytically pooled RR value was identical to that found in the TCA trials, supporting the impression that apparent differences response rates with the two classes of antidepressants was accounted for by secular changes in placebo responses.

Table 2. Comparisons Among Antidepressant Types and Reporting Years.

Measures All drugs TCAs MAO inhibitors SRIs SNRIs Atypicals Early (1983–1997) Late (1998–2010)
Trials (n): 124 31 5 47 30 11 57 67
                 
Responder RR
 Pooled RR 1.42 1.62 1.39 1.37 1.40 1.25 1.63 1.32
 95% CI 1.38–1.48 1.47–1.78 1.11–1.48 1.27–1.48 1.30–1.51 1.15–1.35 1.49–1.78 1.26–1.38
 z-Score 15.7 9.86 2.88 8.28 8.60 5.50 10.9 12.6
 p-Value <0.0001 0.0001 0.004 0.0001 0.0001 0.0001 0.0001 0.0001
                 
Responder RD
 Pooled RD 16.3% 21.4% 12.1% 14.6% 16.4% 11.9% 20.7% 13.4%
 95% CI 14.4–18.2 17.7–25.1 3.58–20.5 11.5–17.7 12.3–20.5 8.15–15.7 17.5–23.8 11.1–15.6
 z-Score 16.6 11.3 2.79 9.21 7.81 6.19 12.9 11.7
 p-Value <0.0001 0.0001 0.005 0.0001 0.0001 0.0001 0.0001 0.0001
                 
Improvement RD
 Pooled RD 12.5% 16.2% 16.0% 11.5% 9.80% 12.8% 16.8% 9.80%
 95% CI 11.0–14.1 13.3–19.1 0.98–33.0 8.70–14.2 7.14–12.5 8.19–17.4 14.5–19.2 7.17–10.2
 Paired-t 16.1 11.4 2.62 8.40 7.54 6.18 14.5 11.3
 p-Value <0.0001 <0.0001 0.05 <0.0001 <0.0001 0.0001 <0.0001 <0.0001
 NNT 8.0 6.2 6.2 8.7 10.2 7.8 6.0 10.2
 95%CI 7.1–9.1 5.2–7.5 3.0–102 7.0–11.5 8.0–14.0 5.7–12.2 5.2–6.9 9.8–13.9
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Abbreviations: MAO, monoamine oxidase; NNT, number-needed-to-treat (reciprocal of RD); SNRI, serotonin-norepinephrine reuptake inhibitors; SRI, serotonin-reuptake inhibitor; TCA, tricyclic antidepressants.

Based on meta-analytic computation of ratios of responder rates with antidepressants/placebos (RR) or their differences (RD), and on differences in percentage-improvement in initial depression ratings with drug—placebo for 19 antidepressants tested for efficacy in 124 trials summarized in Table 1. Note that most CIs overlap between agents, and that ranking by apparent potency varies among the three outcome measures, but that TCAs appear to be consistently more effective than other types of antidepressants, including SNRIs, SRIs, MAO inhibitors, or atypical agents (bupropion, mirtazapine, and trazodone). Also, early trials (reported in 1983–1997 vs 1998–2010) yield consistently greater drug–placebo differences.

Factors Associated with Trials Results

Given the preceding findings suggesting that older agents, specifically TCAs, might appear to be somewhat more effective than modern antidepressants in general, and that older trials yielded consistently greater drug–placebo differences, we carried out several correlational analyses to further examine effects of reporting-year on numbers of sites and subjects per trial, on responses to drugs and placebos and their ratio (Figure 2). Both sites and subjects per trial increased between 1983 and 2010 (Figures 2a and b). Responses in placebo-arms of trials increased across the same era, but responses to antidepressant drugs decreased slightly (Figures 2c and d) to yield highly significant decreases in the drug–placebo responder rate-ratio (RR) across the same years (Figure 2e); drug–placebo differences in rates of response or of percentage improvement also declined (not shown). Responder RR values also declined significantly as the number of subjects per trial (Figure 2f) as well as sites per trial (not shown) increased. Trial-duration also increased significantly across the years sampled (rs=0.603, p<0.0001), and longer-trials led selectively to larger responses with placebos (slope, 1.90 (CI: 0.85–2.95), p=0.0005) than with drugs (0.92 (–0.15 to 1.99)).

Figure 2.

Figure 2

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Correlations with Spearman nonparametric correlation coefficients (rs): (a) Subjects per trial vs year of trial reporting (p<0.0001); (b) Collaborating sites per trial vs year (p<0.0001); (c) Meta-analytic responder rate (% of subjects) for antidepressants vs year (p=0.58); (d) Responder rate (%) for placebo vs year (p<0.0001); (e) Responder rate ratio (RR: drug–placebo) vs year (p<0.0001); (f) RR vs subjects per trial (p=0.002). In addition RR decreased significantly with more sites per trial (rs=−0.302, p=0.004). Note that response after randomization to placebo but not antidepressant drugs selectively increased over years, as subject and site counts per trial increased, with corresponding decreases in drug–placebo relative response rate-ratio (RR).

Multivariate linear regression modeling indicated that the following factors were associated significantly and independently with more recent reporting-years, as follows: (a) more drugs other than TCAs, (b) larger numbers of subjects per trial (or sites per trial), (c) lower response to drugs, (d) greater responses to placebo, (e) higher proportions of depressed women, and (f) longer trials. However, there was no evidence of secular changes in ratings of depression-severity at intake, IMI-eq drug-dose, or dropout rates (Table 3).

Table 3. Multivariate Linear Regression Model: Factors Associated with Year of Publication of Trial Reports.

Factors Slope function (β) (95% CI) t-Score p-Value
More subjects per trial +0.013 (+0.006 to +0.021) 3.40 0.001
More placebo response +0.183 (+0.067 to +0.300) 3.13 0.002
Less drug response –0.179 (–0.288 to –0.071) 3.27 0.001
Less use of TCAs –5.73 (–7.97 to –3.50) 3.13 0.002
More women subjects +0.155 (+0.053 to +0.258) 3.00 0.003
Longer trials +0.807 (+0.268 to +1.345) 2.97 0.004
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Factors listed are independently and significantly associated with more recent reports among reporting-years (1983–2010) as the continuous outcome measure. Factors not associated with more recent trials included: initial depression severity rating, IMI-eq drug dose, and dropout-rate.

Finally, we carried out a preliminary, hypothesis-generating post hoc analysis of deciles of meta-analytically determined drug–placebo responder RR values as well as depression-improvement RD values vs trial-sizes (not shown). By both outcome measures, the apparently optimal number was 2–10 sites per trial, and 30–75 subjects per trial, with lower efficacy found at both lower and higher counts.

DISCUSSION

The present findings are congruent with reviews discussed above indicating that antidepressant drug-vs-placebo differences in published reports of controlled trials are generally moderate (Baldessarini, 2005; Gartlehner et al, 2008; Kirsch et al, 2008; Tsapakis et al, 2008; Bridge et al, 2009; Wooley et al, 2009; Masi et al, 2010; Pigott et al, 2010; Khin et al, 2011). This conclusion was reached in the previous literature despite typical reliance on initial improvement on scale ratings rather than less readily achieved clinical remission, and despite growing evidence of publication bias toward underreporting of studies without significant drug–placebo differences (Ioannidis, 2008; Turner et al, 2008). Following nearly identical mid-range, initial depression ratings across drug and placebo arms and reporting-years, the crude response rates in the reports reviewed here averaged 54% with FDA-approved antidepressants that are employed clinically to treat major depression in the United States, compared with 37% with placebo. These differences consistently favor active drugs, but by only 17%.

The present findings also support the broad consensus that drug–placebo differences have been declining for a variety of psychotropic drugs in recent decades, making it increasingly difficult to demonstrate efficacy (Khin et al, 2011; Yildiz et al, 2011a, 2011b). This trend probably has encouraged increased reliance on larger trials (more subjects and collaborating sites) in order to maintain statistical power. Moreover, increasing reliance on complex trials carried out in varied geographic locations and cultures may tend to limit the reliability of research findings (Vázquez et al, 2011).

It is evidently widely held that differences in efficacy among specific drugs or types of antidepressants in the treatment of acute episodes of major depressive disorder are generally minor (Healy, 1997; Baldessarini, 2005, 2012; Cipriani et al, 2007; Gartlehner et al, 2008; Ghaemi, 2008; Pigott et al, 2010; Khin et al, 2011). The present findings support the conclusion that pooling of data from placebo-controlled trials does not yield clear rankings of specific drugs or drug-types by apparent efficacy (Figure 1). Unexpectedly, however, there were significant differences in reported apparent efficacy between TCAs and newer antidepressants (Table 2). We propose that this outcome may reflect important changes in characteristics of clinical trials for depression over the past three decades. These include increasing size and complexity, with selective increases in response rates with placebos and somewhat decreasing responses with antidepressants (Figure 2). It is particularly noteworthy that when placebo-response data from the generally older TCA trials were substituted for those in more recent trials of modern drugs, both types of agents yielded identical meta-analytically pooled RR values. In contrast, we did not find evidence of significant changes over the years in initial ratings of depression-severity (adjusted for variance among rating scales), in approximate IMI-eq antidepressant doses, or in several other measured characteristics of trials (Table 3).

It is increasingly clear that drug–placebo differences in trials of antidepressants and other psychotropic agents have been declining (Gartlehner et al, 2008; Ioannidis, 2008; Kirsch et al, 2008; Tsapakis et al, 2008; Turner et al, 2008; Bridge et al, 2009; Masi et al, 2010; Khin et al, 2011; Vázquez et al, 2011; Yildiz et al, 2011a, 2011b). In accord with recent findings in controlled treatment trials for mania (Yildiz et al, 2011a, 2011b), a secular increase in sites and participants per trial was associated, selectively, with rising placebo-associated response rates, resulting in declining drug–placebo contrasts or effect-size (Figure 2; Table 3). We propose that this tendency may, at least in part, reflect declining quality-control and greater heterogeneity of diagnostic and clinical assessments in large, complex, multi-site trials, particularly when dissimilar cultures are involved and local standardization of assessment methods is limited (Yildiz et al, 2011a, 2011b; Vázquez et al, 2011). We propose that selective increases in response rates associated with randomized placebo-treatment might reflect ‘regression-to-mean' effects (Anderson, 1990; Bland and Altman, 1994) or random outcomes. Placebo-associated responses have increased from former levels of 20 to 30% to current levels of 30 to 50%, and to as high as 59.2% in a 1997 trial involving paroxetine (Lecrubier et al, 1997).

Alternative factors that may contribute to the observed secular trends include changes in the types of patients recruited into antidepressant trials, including less severely ill patients willing to accept potential randomization to a placebo, and even partially treated subjects. Levels of training and expertise of personnel providing diagnostic and symptom-rating assessments may also have declined. In addition, trials have become longer over the years sampled (Table 2), requiring more clinical assessments with greater risk of measurement-variance, and providing more clinical contact and more time for spontaneous improvement—all of which may favor responses associated with placebo treatment. Additional technical factors may include less reliance on expert raters, with greater risk of less stable assessments in a very heterogeneous disorder (Healy, 1997).

If the preceding interpretation of the present findings is correct, it suggests several practical considerations for the design and conduct of therapeutic trials for major depression and perhaps other disorders. These include seeking an optimal range of trial-sizes, with redoubled efforts to maximize quality-control, limit placebo-associated responses, and maximize drug–placebo differences. Preliminary analyses of the present data suggest that an optimal range of collaborating sites per trial may be 2–10, and of subjects per trial, about 30–75. Such conservative considerations for the design of future trials may improve outcomes. Additional potential benefits may include reduced time, complexity, and costs, as well as limiting exposure of as many acutely depressed patient-subjects to placebo-treatment as possible.

Limitations of this study include a lack of relevant details in many reports of controlled trials, sometimes including inconsistent reporting of definitions and outcomes for responder rate and percentage improvement, of the number of rating-scale items and of their maximum attainable scores in a few trials. Also, in most trials, exposure times are estimated from nominal protocol requirements since precise, subject-based actual weeks of treatment usually are not stated. Also, numbers of patients with defined outcomes are usually, but not always, based on prevalent intention-to-treat methods, which can limit responses owing to early dropout. Routine reporting of such details would greatly benefit future meta-analyses. Additional limitations to generalization arise from our requirements of peer-review and publication of findings in placebo-controlled trials concerning antidepressants approved and marketed in the United States for acute adult, major depression.

In conclusion, the present meta-analytic review of outcomes of placebo-controlled trials of antidepressants for acute episodes of major depressive disorder found evidence that older antidepressants, particularly TCAs, yielded somewhat superior apparent efficacy to some modern, second-generation agents. However, such nominal differences appear to have been influenced by secular changes in the nature of such trials over the past three decades. These include rising subject- and site-numbers and increasing placebo-associated responses, leading to falling drug–placebo differences or effect-size. We hypothesize that more conservative numbers of subjects and sites, with improved quality-control of trial methods, may paradoxically yield superior results in controlled trials of some psychotropic drugs, and do so more economically. Finally, the lack of major and compelling differences in apparent efficacy among specific antidepressants, and moderate differences among drug-types, suggest that meta-analyses of controlled trials may have limited value in efforts to develop an evidence-basis (Sackett et al, 1996) for identifying superior treatments.

Acknowledgments

This work was supported by a grant from the Bruce J Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RJB), and by a Traveling Research Fellowship from the University of Barcelona and the Fundación Española de Psiquiatría y Salud Mental (to JU). Leonardo Tondo, MD provided helpful technical advice.

The authors declare no conflict of interest.

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