Review
Meta-analysis of the placebo response in antidepressant trials

https://doi.org/10.1016/j.jad.2009.01.029Get rights and content

Abstract

Improvements in placebo groups of antidepressant trials account for a major part of the expected drug effects. We aimed to determine overall effect sizes of placebo and drug effects in antidepressant trials, and to analyze whether the placebo effect in antidepressant trials also occurs for patient self-perception, general psychopathology, and quality of life.

Methods:

Search terms covered different variants of pharmacotherapy for patients with depressive disorders from January 1980 to December 2005 in the databases Medline/Pubmed, PsychInfo and CENTRAL, a.o. We included RCTs with a placebo group and an antidepressant group in people with depression.

Results:

We computed within group effect sizes for several outcome variables and integrated them using random-effect models. A total of 96 studies were included. Mean effect size in the placebo group for primary outcome variables was d = 1.69 (95% CI = 1.54–1.84) compared to 2.50 in the drug group (95% CI = 2.30–2.69). There was a major difference between placebo effect sizes assessed with observer ratings (d = 1.85, 95% CI = 1.69–2.01) versus patient self-perception (d = 0.67; 95% CI = 0.49–0.85). The effect sizes in placebo groups in 2005 were more than twice as great as those in 1980, but only for observer ratings, not for patient self-ratings. The result was partly due to increased homogeneity of samples of recently published trials.

Conclusions:

The placebo effect accounted for 68% of the effect in the drug groups. Whereas clinical trials need to control the placebo effect, clinical practice should attempt to use its full power.

Introduction

Placebo responses are general phenomena in medicine, and they seem to be particularly powerful in depression. However, the exact size of improvement in placebo groups compared to drug groups remains unclear because of serious shortcomings of existing reports (e.g., strong selection of included studies, poor methodology based on percentage scores, and inclusion of many studies with missing data). Moreover, it is unclear whether the improvements in placebo groups can only be found for primary outcome variables (e.g., depression), or whether they can also be found for other psychopathological variables and quality of life.

For the purpose of this paper, we will use the term “placebo response” to refer to improvements that occur in the placebo groups of clinical trials. Despite some critical evaluations (Hróbjartsson and Gøtzsche, 2001), the placebo response is still impressive in medicine and psychiatry. The most provoking examples of placebo effects in medicine come from sham surgery (Moseley et al., 2002, McRae et al., 2004), but the placebo effect is also impressive in relieving pain (Petrovic et al., 2002) and reducing hypertension (Preston et al., 2000).

The placebo response was also examined in antidepressant trials. Half of the drug group and 30% of the placebo group met the responder criterion of a 50%-reduction in depression scores from baseline (Rush, 1993, Walsh et al., 2002). The positive effects attained with selective serotonin reuptake inhibitors (SSRIs) that are explained by placebo are estimated to be as high as 82% depending on the study inclusion strategy and analysis methods used (Joffe et al., 1996, Kirsch and Sapirstein, 1998, Kahn et al., 2000, Kirsch et al., 2002). A recently published study shows an inverse relationship of placebo response and depression severity, with less placebo response in very seriously depressed patients (Kirsch et al., 2008). When antidepressants were compared not only to inert placebos, but also to active placebo conditions imitating the side effects of antidepressants, the differences in the efficacy of antidepressants and active placebos were much less pronounced (Moncrieff et al., 2004). However, this analysis was based on only a few, older studies.

When comparing different antidepressant trials, it became evident that there was tremendous variation in the size of the placebo response. An intriguing change of the placebo response with time was reported by Walsh and colleagues (Walsh et al., 2002) who analyzed 57 trials and found a correlation of r = 0.45 between the effect size in the placebo group and publication year. The reasons for this “publication year effect” are still poorly understood. In contrast, other studies show a decrease in effectiveness of the drugs with publication year (e.g., statins, Gehr et al., 2006).

Treatment efficacy in psychiatry can be determined using 2 different methods, namely observer ratings and patient's self-ratings. A special characteristic of antidepressant trials is the use of observer ratings to assess depression. Most drug trials focus on results of the Hamilton Depression Scale (HAMD) or the Montgomery Asberg Depression Rating Scale (MADRS). Some studies, however, use additional self-rating scales that allow investigators to examine improvement from the patient's perspective. More information is needed to determine whether placebo effects in antidepressant trials are limited to observer ratings, or whether they also occur in patient self-ratings. Moreover, it is unclear whether the publication year effect can also be found for patient self-ratings.

The aim of this meta-analysis was to analyze the placebo effect when rated by patient self-report as compared to observer ratings. Moreover, the placebo response was not only computed for depression, but also for general psychopathology and quality of life. Special emphasis was given to possible moderating effects, such as publication year, diagnosis, drug groups, and others.

Section snippets

Method

The reporting of methods follows the QUORUM Checklist.

Study characteristics

As shown in Fig. 1, Fig. 3322 different studies fulfilled the first level of inclusion criteria. After excluding studies based on information presented in study abstracts, 406 complete study reports were considered in more detail. The final sample consisted of 96 trials1 that reported sufficient data to compute effect sizes. The placebo groups of these studies comprised 9566 people. Approximately half of the studies

Discussion

We conducted a meta-analysis of improvements in placebo groups in 96 trials containing a total of 9,566 depressed patients. We found that the improvements in the placebo groups corresponded to 67% of the improvements in the active drug groups. We further confirmed that the reported placebo effect sizes increased tremendously from 1980 to 2005. However, this strong publication year effect was only found when the primary outcome variable was an observer rating of depression. Self-ratings of

Role of funding source

Nothing declared.

Conflict of interest

No conflict declared.

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