The Role of Patient Expectancy in Placebo and Nocebo Effects in Antidepressant Trials

Abstract

Objective To determine whether patient expectancy plays a role in observed placebo and nocebo effects in two clinical trials. Method Data were re-analyzed from two fluoxetine-discontinuation studies conducted from March 1990–September 1992 and May 1997–December 2002. Outpatients aged 18–65 years with DSM-III-R Major Depressive Disorder (MDD) responding to 12-week duration open treatment were randomized to continued fluoxetine or placebo for an additional year. Participants in one of the included studies received a fixed dose of fluoxetine 20mg daily, while the second study utilized flexible fluoxetine doses up to 60mg daily. Mixed effects longitudinal models determined whether the possible randomization to placebo at 12 weeks resulted in significant depressive symptom worsening across treatments. Correlations were computed between early symptom change (weeks 1–3 of open treatment) and post-randomization symptom change (weeks 13–16 following randomization). Results Participants continuing to receive fluoxetine and those switched to placebo had significantly higher mean HAM-D scores immediately post-randomization compared to the final weeks of open treatment (p < 0.001 for both fluoxetine and placebo-treated patients). In both studies, early HAM-D change was significantly correlated with post-randomization HAM-D change for patients receiving fluoxetine (r = −0.46, p < 0.001) as well as placebo (r = −0.48, p < 0.001). Conclusions The possibility of receiving placebo following 12 weeks of open fluoxetine was associated with significant symptom worsening in two large fluoxetine-discontinuation studies. Worsening depression scores following randomization were significantly associated with the degree of improvement participants experienced during weeks 1–3 of open treatment. These results suggest that treatment changes influence patients’ expectations of improvement, which in turn affect their depressive symptoms.

Nocebo in Alzheimer's disease; meta-analysis of placebo-controlled clinical trials

“…Nocebo has been studied in RCTs for several neurological conditions, including multiple sclerosis [9], headache [10,11], neuropathic pain [12], fibromyalgia [1], diabetic peripheral neuropathy [13], Parkinson's disease [14] and depression [2,15]. In these studies dropouts because of AEs in placebo treated patients varied from 2% (in multiple sclerosis) to almost 10% (in Parksinson's disease and fibromyalgia).…”

Predicting placebo response in adolescents with major depressive disorder: The Adolescent Placebo Impact Composite Score (APICS)

“…Developing methods of predicting placebo response in youth with MDD could aid efforts to minimize such placebo response in clinical trials as well as aid in targeting such youth in clinical practice with treatment strategy designed to bolster treatment outcome (Rutherford et al, 2014;Trivedi and Rush, 1994). The high placebo response rate (about 59%) in the recent adolescent selegiline transdermal patch randomized controlled trial (RCT) (DelBello et al, 2014), provides some of the necessary foundation for the current study to develop such a method of prediction.…”

Factors that Affect Adolescent Adherence to Mental Health and Psychiatric Treatment: a Systematic Integrative Review of the Literature

“…It has been found that increases and decreases in depressed symptoms immediately after treatment changes are related to patient expectations. Among adults, patients who continued to take antidepressant medications as well as those who were switched to placebos had higher mean depression rating scale scores (47). However, more highly motivated patients showed greater responses to placebos as compared with less motivated patients, which highlights the importance of the patient's own level of motivation (48).…”