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Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials.
J Clin Psychiatry 2015; 76(6):702-11JC

Abstract

BACKGROUND

The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning.

METHOD

This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo.

RESULTS

TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs.

DISCUSSION

In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data.

CONCLUSIONS

The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Authors+Show Affiliations

Swanston Centre-Barwon Health, PO Box 281, Geelong, Victoria 3220, Australia seetald@barwonhealth.org.au.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis

Language

eng

PubMed ID

26132671

Citation

Dodd, Seetal, et al. "Nocebo Effects in the Treatment of Major Depression: Results From an Individual Study Participant-level Meta-analysis of the Placebo Arm of Duloxetine Clinical Trials." The Journal of Clinical Psychiatry, vol. 76, no. 6, 2015, pp. 702-11.
Dodd S, Schacht A, Kelin K, et al. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015;76(6):702-11.
Dodd, S., Schacht, A., Kelin, K., Dueñas, H., Reed, V. A., Williams, L. J., ... Berk, M. (2015). Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. The Journal of Clinical Psychiatry, 76(6), pp. 702-11. doi:10.4088/JCP.13r08858.
Dodd S, et al. Nocebo Effects in the Treatment of Major Depression: Results From an Individual Study Participant-level Meta-analysis of the Placebo Arm of Duloxetine Clinical Trials. J Clin Psychiatry. 2015;76(6):702-11. PubMed PMID: 26132671.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. AU - Dodd,Seetal, AU - Schacht,Alexander, AU - Kelin,Katarina, AU - Dueñas,Héctor, AU - Reed,Victoria A, AU - Williams,Lana J, AU - Quirk,Frances H, AU - Malhi,Gin S, AU - Berk,Michael, PY - 2013/10/28/received PY - 2014/06/05/accepted PY - 2015/7/2/entrez PY - 2015/7/2/pubmed PY - 2015/9/25/medline SP - 702 EP - 11 JF - The Journal of clinical psychiatry JO - J Clin Psychiatry VL - 76 IS - 6 N2 - BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation. SN - 1555-2101 UR - https://www.unboundmedicine.com/medline/citation/26132671/Nocebo_effects_in_the_treatment_of_major_depression:_results_from_an_individual_study_participant_level_meta_analysis_of_the_placebo_arm_of_duloxetine_clinical_trials_ L2 - http://www.psychiatrist.com/jcp/article/pages/2015/v76n06/v76n0604.aspx DB - PRIME DP - Unbound Medicine ER -