The persistence of the placebo response in antidepressant clinical trials

Northwest Clinical Research Center, Bellevue, WA 98004, USA.
Journal of Psychiatric Research (Impact Factor: 3.96). 09/2008; 42(10):791-6. DOI: 10.1016/j.jpsychires.2007.10.004
Source: PubMed


Our objective was to assess the persistence of the placebo response during at least 12 weeks of continued placebo administration in depressed patients who have responded to 6-8 weeks of acute placebo treatment. We identified 8 placebo-controlled antidepressant trials with a total of 3,063 depressed patients in which, after acute phase placebo treatment, placebo was continued for more than 12 weeks. The number of patients entering the continuation phase and percentages relapsing during this phase were determined. Based on the total number of patients entering the continuation phase 79% of placebo responders remained well (did not meet relapse criteria) during this phase compared to 93% of antidepressant responders. Although significantly more patients on placebo than on antidepressants relapsed in the continuation phase, 4 out of 5 placebo responders stayed well. The widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking.

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    • "Here, we found that the placebo responses were stable over time, in spite of trials lasting up to three years. This is in line with the stable placebo effects seen in various long lasting clinical trials[68,69]. We hope that future studies will investigate the long-term effects of placebo treatment in ID patients. "
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    ABSTRACT: Background: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. Objective: To determine if placebo response exists in patients with genetically determined ID. Data sources and study selection: We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. Data extraction and synthesis: Two investigators extracted outcome data independently. Main outcomes and measures: Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression. Results: Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. Conclusions and relevance: Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID.
    Full-text · Article · Aug 2015 · PLoS ONE
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    • "Although the placebo response in MDD has often been attributed to non-specific relief that is not thought to endure, most patients who respond to placebos actually stay well (Khan et al. 2008). Additionally, studies on the long-term course of untreated depression suggest that the outcomes of individuals who do not receive treatment for depression are comparable with the long-term outcomes of individuals who are treated with antidepressants (Hughes & Cohen, 2009), again a somewhat puzzling findings if we assume most cases of MDD to be either severe, chronic, recurrent or treatment-resistant. "
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    ABSTRACT: Two different and seemingly competing views on the diagnosis of major depressive disorder (MDD) exist. The first is that the diagnosis conflates adaptive sadness reactions with pathological states of depressed mood and that MDD is overdiagnosed and overtreated. The second is that MDD is an underdiagnosed and undertreated disorder, and one that is best characterised by a severe, chronic, recurrent or treatment-resistant course. Existing research suggests that both views are valid and merit being integrated. Anywhere from 30 to 50% of individuals will meet criteria for MDD at some point in their life. About half of these episodes are of brief duration and unlikely to recur. However, a remaining half is either chronic or recurrent. Data on the outpatient diagnosis of depression support the view that depression is simultaneously underdiagnosed and undertreated as well as overdiagnosed and overtreated. About one-third of the patients who meet criteria for MDD and receive placebos experience clinically significant and long-lasting improvement. Many other patients, however, are unresponsive to one or multiple active treatments. Thus, the diagnosis of MDD likely applies to individuals who are experiencing either normal periods of sadness or single-episode afflictions that are mild, unlikely to recur, and are placebo responsive, as well as to individuals with more severe clinical profiles. More research is needed that can help ascertain what contextual or biopsychological variables help distinguish between individuals who may be experiencing adaptive states of negative affect and those who experience severe, chronic, recurrent or treatment-resistant depressions.
    Full-text · Article · Jun 2015 · Epidemiology and Psychiatric Sciences
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    • "It is difficult to demonstrate the role of expectations, cognitions, or conditioned responses in the failure to respond to successive antidepressant medication trials in humans. It is known that administration of an antidepressant is less effective after the patient has received no benefit from either a first antidepressant21 or a placebo,43 but multiple crossover trials would be necessary to determine the mechanism for this loss of effectiveness. There is clearer evidence from human pain studies, however, that ineffective medication trials directly contribute to decreases in the effectiveness of subsequent analgesic medications. "
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    ABSTRACT: Current treatment of Major Depressive Disorder utilizes a trial-and-error sequential treatment strategy that results in delays in achieving response and remission for a majority of patients. Protracted ineffective treatment prolongs patient suffering and increases health care costs. In addition, long and unsuccessful antidepressant trials may diminish patient expectations, reinforce negative cognitions, and condition patients not to respond during subsequent antidepressant trials, thus contributing to further treatment resistance. For these reasons, it is critical to identify reliable predictors of antidepressant treatment response that can be used to shorten or eliminate lengthy and ineffective trials. Research on possible endophenotypic as well as genomic predictors has not yet yielded reliable predictors. The most reliable predictors identified thus far are symptomatic and physiologic characteristics of patients that emerge early in the course of treatment. We propose here the term "response endophenotypes" (REs) to describe this class of predictors, defined as latent measurable symptomatic or neurobiologic responses of individual patients that emerge early in the course of treatment, and which carry strong predictive power for individual patient outcomes. Use of REs constitutes a new paradigm in which medication treatment trials that are likely to be ineffective could be stopped within 1 to 2 weeks and other medication more likely to be effective could be started. Data presented here suggest that early changes in symptoms, quantitative electroencephalography, and gene expression could be used to construct effective REs. We posit that this new paradigm could lead to earlier recovery from depressive illness and ultimately produce profound health and economic benefits.
    Full-text · Article · Dec 2009 · Dialogues in clinical neuroscience
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