Nocebo in clinical trials for depression: A meta-analysis
Introduction
Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal (Mitsikostas et al., 2011). It includes expected AEs or, less frequently, non-specific effects that cannot be substantiated referring to pharmacological action of the treatment (Mitsikostas et al., 2011). The term nocebo (“I shall harm”) was introduced in contraposition to the term placebo (“I shall please”) by Kennedy in the early 1960s to distinguish the noxious from the pleasing effects of placebo (Kennedy, 1961, Antonaci et al., 2007). Nocebo is related to lower adherence in therapy as well as with high rates of dropouts and significant difficulty in assessing the efficacy and the safety profile of a drug in clinical trials (Barsky et al., 2002, Enck et al., 2008). There is evidence that nocebo is related to negative pretrial suggestions and previous negative experiences during treatment (Benedetti et al., 2007) along with several psychological factors including stress and anxiety (Tracey, 2010, Manchikanti et al., 2011, Elsenbruch et al., 2012). Experimental human studies showed that nocebo is mediated by limbic system after affective and cognitive evaluation (Kong et al., 2008). It would be interesting therefore to investigate nocebo in conditions characterized by limbic system dysfunction in a non-experimental setting. In this context, nocebo can be assessed in randomized controlled trials (RCTs) by estimating the prevalence of adverse effects (AEs) in placebo treated patients (Papadopoulos and Mitsikostas, 2010, Papadopoulos and Mitsikostas, 2012, Mitsikostas et al., 2012, Stathis et al., 2013). In the present study we performed a systematic meta-analysis of RCTs for depression that tested pharmaceutical treatments to estimate the magnitude of nocebo and speculate its possible consequences in clinical practice and trial design.
Section snippets
Methods
A computer-based literature search was conducted on PubMed on January 2, 2012 using key words such as depression, placebo, pharmaceutical treatment, with the limitations humans, randomized controlled trial, English language, adults (≥19 years) and date-range (2000.01.01–2012.01.01), according to the PRISMA recommendations (Moher et al., 2009). We further filtered the search for pharmacotherapy and randomized, placebo controlled trials. All selected studies that were relevant were selected for
Literature search
Twenty-two randomized placebo-controlled studies on the treatment of depression published between 2001 and 2011 were collected for analysis (Fig. 1, PRISMA CHART). To evaluate the proportion of nocebo AE we pooled data from 10 studies that contained data on the number of patients with at least one AE. Similarly, to assess the proportion of nocebo dropout rate we considered 21 papers that included these data (Appendix e-1). The descriptive of studies included in the analysis are presented in
Discussion
This meta-analysis of RCTs for treatment of depression showed that almost half of placebo treated patients experienced at least one drug related AE (44.7%) and almost one out of 20 placebo treated patients discontinued treatment because of AE (4.5%). The more AEs recorded in the active drug arm the more AEs were observed in the placebo arm. Adverse events were correlated between treatment arms (active drug and placebo) not only quantitatively but qualitatively as well: both patient groups
Authors׳ roles
Dr. Dimos D. Mitsikostas conceptualized and designed the study; he interpreted and analyzed the data and wrote the manuscript.
Dr. Nicolaos Chalarakis performed the PubMed search and the data extraction.
Dr. Leonidas Mantonakis performed the PubMed search and the data extraction. He also contributed to the data interpretation.
Acknowledgments
The authors thank Evie-Maria Delicha MSc for her contribution to the statistical analysis.
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