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Randomized Controlled Trial
. 2017 Feb;234(3):329-338.
doi: 10.1007/s00213-016-4466-8. Epub 2016 Nov 2.

Learning to experience side effects after antidepressant intake - Results from a randomized, controlled, double-blind study

Julia Rheker  1 , Alexander Winkler  2 , Bettina K Doering  2 , Winfried Rief  2
Affiliations
Randomized Controlled Trial

Learning to experience side effects after antidepressant intake - Results from a randomized, controlled, double-blind study

Julia Rheker et al. Psychopharmacology (Berl). 2017 Feb.

Abstract

Background: Side effects play a key role in patients' failure to take antidepressants. There is evidence that verbal suggestions and informed consent elicit expectations that can in turn trigger the occurrence of side effects. Prior experience or learning mechanisms are also assumed to contribute to the development of side effects, although their role has not been thoroughly investigated. In this study, we examined whether an antidepressant's side effects can be learned via Pavlovian conditioning.

Methods: Participants (n = 39) were randomly allocated to one of two groups and were exposed to a classical conditioning procedure. During acquisition, 19 participants received amitriptyline and 20 participants received a placebo pill. Pills were taken for four nights together with a novel-tasting drink. After a washout phase, both groups received a placebo pill together with the novel-tasting drink (evocation). Side effects were assessed via the Generic Assessment of Side Effects Scale prior to acquisition (baseline), after acquisition, and after evocation. A score of antidepressant-specific side effects was calculated.

Results: Participants taking amitriptyline reported significantly more antidepressant-specific side effects after acquisition compared to both baseline and the placebo group. After evocation, participants who underwent the conditioning procedure with amitriptyline reported significantly more antidepressant-specific side effects than those who never received amitriptyline, even though both groups received a placebo.

Conclusions: Our results indicate that antidepressant side effects can be learned using a conditioning paradigm and evoked via a placebo pill when applied with the same contextual factors as the verum.

Keywords: Antidepressants; Learning; Nocebo; Side effects.

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Conflict of interest statement

Compliance with ethical standards Funding The study was prepared in the context of the FOR1328 research unit on placebo and nocebo mechanisms and was partially supported by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG), RI 574/22–1). Conflict of interest The authors Julia Rheker, Alexander Winkler, Bettina K. Doering, and Winfried Rief have no conflicts of interest including any financial, personal, or other relationships with other people or organizations to declare that could inappropriately influence, or be perceived to influence, the present work. However, Bettina K. Doering has received honoraria from Biologische Heilmittel Heel for presentations on stress reactions. Winfried Rief has received honoraria from Biologische Heilmittel Heel, Berlin Chemie, and Bayer for presentations on placebo effects.

Figures

Fig. 1
Fig. 1
Experimental design
Fig. 2
Fig. 2
Flowchart
Fig. 3
Fig. 3
Antidepressant-specific side effects for both groups and all time points. GASE-AD Antidepressant Composite Score of the Generic Assessment of Side Effects Scale, GASE-AD-MA medication-attributed symptoms of the Antidepressant Composite Score of the Generic Assessment of Side Effects Scale
See this image and copyright information in PMC

References

    1. Abbing-Karahagopian V, Huerta C, Souverein PC, et al. Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications. Eur J Clin Pharmacol. 2014;70:849–857. doi: 10.1007/s00228-014-1676-z. - DOI - PubMed
    1. Ader R, Mercurio MG, Walton J, et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med. 2010;72:192–197. doi: 10.1097/PSY.0b013e3181cbd38b. - DOI - PMC - PubMed
    1. Åkerblad A-C, Bengtsson F, von Knorring L, Ekselius L. Response, remission and relapse in relation to adherence in primary care treatment of depression: a 2-year outcome study. Int Clin Psychopharmacol. 2006;21:117–124. doi: 10.1097/01.yic.0000199452.16682.b8. - DOI - PubMed
    1. Albring A, Wendt L, Benson S, et al. Placebo effects on the immune response in humans: the role of learning and expectation. PLoS One. 2012;7 doi: 10.1371/journal.pone.0049477. - DOI - PMC - PubMed
    1. Amanzio M. Nocebo effects and psychotropic drug action. Expert Rev Clin Pharmacol. 2015;8:159–161. doi: 10.1586/17512433.2015.992877. - DOI - PubMed

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