Contribution of spontaneous improvement to placebo response in depression: A meta-analytic review

https://doi.org/10.1016/j.jpsychires.2012.02.008Get rights and content

Abstract

Objectives

It is unknown to what degree spontaneous improvement accounts for the large placebo response observed in antidepressant trials for Major Depressive Disorder (MDD). The purpose of this study was to estimate the spontaneous improvement observed in treatment-seeking individuals with acute MDD by determining the symptom change in depressed patients assigned to wait-list controls in psychotherapy studies.

Method

The databases PubMed and PsycINFO were searched to identify randomized, prospective studies randomizing outpatients to psychotherapy or a wait-list control condition for the treatment of acute MDD. Standardized effect sizes calculated from each identified study were aggregated in a meta-analysis to obtain a summary statistic for the change in depression scores during participation in a wait-list control.

Results

Ten trials enrolling 340 participants in wait-list control conditions were identified. The estimated effect size for the change in depression scores during wait-list control was 0.505 (95% CI 0.271–0.739, p < 0.001), representing an average improvement of 4 points on the Hamilton Rating Scale for Depression.

Discussion

Depressed patients acutely experience improvement even without treatment, but spontaneous improvement is unlikely to account for the magnitude of placebo response typically observed in antidepressant trials. These findings must be interpreted in light of the small number wait-list control participants available for analysis as well as certain methodological heterogeneity in the psychotherapy studies analyzed.

Section snippets

Background and objectives

Scientific and popular interest in placebo effects has been rising due to increased recognition of their therapeutic effectiveness in the treatment of some illnesses, such as Major Depressive Disorder (MDD). Placebo response in acute randomized controlled trials (RCTs) of antidepressant medications for MDD averages 30% (Walsh et al., 2002), and meta-analyses suggest that placebo treatment conditions may duplicate 50–75% of the improvement observed with active treatment (Kirsch and Sapirstein,

Search strategy and selection criteria

PubMed and PsycINFO were searched to identify prospective clinical studies contrasting psychotherapy to a wait-list control condition in adults with depression. To capture all available psychotherapy studies, we used the search terms “psychotherapy” OR the specific names of all known psychotherapy modalities (e.g., cognitive behavior therapy, behavior therapy, interpersonal therapy, psychodynamic psychotherapy, etc.), which we compiled by referencing standard textbooks of psychiatry (Sadock and

Characteristics of included studies and participants

Ten trials met the study's inclusion and exclusion criteria (Arean et al., 1993; Bolton et al., 2003; Clarke et al., 1999; Cohen et al., 2010; Diamond et al., 2002; Mufson et al., 1999; Nezu, 1986, Nezu and Perri, 1989; O'Leary and Beach, 1990; Wright et al., 2005). As shown in Table 1, the 10 trials had a mean sample size of 32.3 ± 51.6 patients, duration of 10.0 ± 3.7 weeks, and dropout rate of 18.6% ± 17.1%. The 340 participants assigned to wait-list control conditions across these 10 trials

Discussion

Consistent with the hypothesis of this meta-analysis, patients with MDD randomized to wait-list control conditions experienced symptomatic improvement. The magnitude of this improvement corresponds to a medium effect size of approximately 0.5, which was significantly different from zero (p < 0.001). Left untreated, patients with MDD may expect an improvement on average of approximately 4 HRSD points based upon the passage of time alone.

For the purpose of comparison, prior meta-analyses of

Conflict of interest

Dr. Rutherford, Ms. Mori, Dr. Sneed, and Ms. Pimontel report no disclosures or potential conflicts of interest. Dr. Roose reports serving on a Data and Safety Monitoring Board for Medtronics, Inc.

Role of the funding source

This study was supported by a Hope for Depression Research Grant (BRR) as well as National Institute of Mental Health grants K23 MH085236 (BRR), K23 MH075006 (JRS), and R21 MH087774 (JRS).

Contributors

Dr. Rutherford designed the study and drafted the manuscript. Ms. Mori assisted with the literature review and data extraction. Dr. Sneed, Dr. Roose, and Ms. Pimontel assisted with the statistical analyses and revision of the manuscript. All authors contributed to and have approved the final manuscript.

Acknowledgments

This work was supported by a National Institute of Mental Health grants K23 MH085236 (BRR), K23 MH075006 (JRS), R21 MH087774 (JRS), T32 MH15144 (SPR), and a Hope for Depression Research Foundation (BRR). Dr. Rutherford, Ms. Mori, Dr. Sneed, and Ms. Pimontel have no disclosures to report. Dr. Roose reports serving on a Data and Safety Monitoring Board for Medtronics, Inc. This paper has not been previously presented.

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