Meta-analysis of the placebo response in antidepressant trials

Division of Clinical Psychology and Psychotherapy, University of Marburg, Germany.
Journal of Affective Disorders (Impact Factor: 3.38). 03/2009; 118(1-3):1-8. DOI: 10.1016/j.jad.2009.01.029
Source: PubMed


Improvements in placebo groups of antidepressant trials account for a major part of the expected drug effects. We aimed to determine overall effect sizes of placebo and drug effects in antidepressant trials, and to analyze whether the placebo effect in antidepressant trials also occurs for patient self-perception, general psychopathology, and quality of life.
Search terms covered different variants of pharmacotherapy for patients with depressive disorders from January 1980 to December 2005 in the databases Medline/Pubmed, PsychInfo and CENTRAL, a.o. We included RCTs with a placebo group and an antidepressant group in people with depression.
We computed within group effect sizes for several outcome variables and integrated them using random-effect models. A total of 96 studies were included. Mean effect size in the placebo group for primary outcome variables was d=1.69 (95% CI=1.54-1.84) compared to 2.50 in the drug group (95% CI=2.30-2.69). There was a major difference between placebo effect sizes assessed with observer ratings (d=1.85, 95% CI=1.69-2.01) versus patient self-perception (d=0.67; 95% CI=0.49-0.85). The effect sizes in placebo groups in 2005 were more than twice as great as those in 1980, but only for observer ratings, not for patient self-ratings. The result was partly due to increased homogeneity of samples of recently published trials.
The placebo effect accounted for 68% of the effect in the drug groups. Whereas clinical trials need to control the placebo effect, clinical practice should attempt to use its full power.

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Available from: Yvonne Nestoriuc
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    • "However, these treated versus control effect sizes cannot be used for comparisons of psychological therapies and medications . In psychotherapy trials, the control condition is mostly a waiting list, which usually has a low pre–post effect size, whereas drugs are usually compared with a pill placebo, which has a larger effect (Rief et al., 2009). Moreover, patients are mainly interested in the question 'How much will my anxiety improve with the treatment?' – which is reflected by the pre–post effect size. "
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    ABSTRACT: To our knowledge, no previous meta-analysis has attempted to compare the efficacy of pharmacological, psychological and combined treatments for the three main anxiety disorders (panic disorder, generalized anxiety disorder and social phobia). Pre-post and treated versus control effect sizes (ES) were calculated for all evaluable randomized-controlled studies (n=234), involving 37 333 patients. Medications were associated with a significantly higher average pre-post ES [Cohen's d=2.02 (1.90-2.15); 28 051 patients] than psychotherapies [1.22 (1.14-1.30); 6992 patients; P<0.0001]. ES were 2.25 for serotonin-noradrenaline reuptake inhibitors (n=23 study arms), 2.15 for benzodiazepines (n=42), 2.09 for selective serotonin reuptake inhibitors (n=62) and 1.83 for tricyclic antidepressants (n=15). ES for psychotherapies were mindfulness therapies, 1.56 (n=4); relaxation, 1.36 (n=17); individual cognitive behavioural/exposure therapy (CBT), 1.30 (n=93); group CBT, 1.22 (n=18); psychodynamic therapy 1.17 (n=5); therapies without face-to-face contact (e.g. Internet therapies), 1.11 (n=34); eye movement desensitization reprocessing, 1.03 (n=3); and interpersonal therapy 0.78 (n=4). The ES was 2.12 (n=16) for CBT/drug combinations. Exercise had an ES of 1.23 (n=3). For control groups, ES were 1.29 for placebo pills (n=111), 0.83 for psychological placebos (n=16) and 0.20 for waitlists (n=50). In direct comparisons with control groups, all investigated drugs, except for citalopram, opipramol and moclobemide, were significantly more effective than placebo. Individual CBT was more effective than waiting list, psychological placebo and pill placebo. When looking at the average pre-post ES, medications were more effective than psychotherapies. Pre-post ES for psychotherapies did not differ from pill placebos; this finding cannot be explained by heterogeneity, publication bias or allegiance effects. However, the decision on whether to choose psychotherapy, medications or a combination of the two should be left to the patient as drugs may have side effects, interactions and contraindications.
    Full-text · Article · Apr 2015 · International clinical psychopharmacology
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    • "Expectations, an important constituent of the placebo effect [25,26], may influence how people respond to brain training and account for at least some of the positive findings in the brain training literature and success of the commercial market. A rich literature on such concepts as the Hawthorne effect [27] and the use of expectations to enhance therapeutic effects [15,28] supports the role of psychological or environmental factors in altering behaviour and biology [17,29]. Brain training studies rarely account for participants' expectations , despite extensive evidence for their importance in other areas16171819 . "
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    ABSTRACT: "Brain training" (i.e., enhancing, rehabilitating, or simply maintaining cognitive function through deliberate cognitive exercise) is growing rapidly in popularity, yet remains highly controversial. Among the greatest problems in current research is the lack of a measure of participants' expectations, which can influence the degree to which they improve over training (i.e., the placebo effect). Here we created a questionnaire to measure the perceived effectiveness of brain-training software. Given the growth in advertising of these programs, we sought to determine whether even a brief positive (or negative) message about brain training would increase (or decrease) the reported optimism of participants. We measured participants' expectations at baseline, and then following exposure to separate, brief messages that such programs have either high or low effectiveness. Based on the knowledge they have gleaned from advertising and other real-world sources, people are relatively optimistic about brain training. However, brief messages can influence reported expectations about brain-training results: Reading a brief positive message can increase reported optimism, whereas reading a brief negative message can decrease it. Older adults appear more optimistic about brain training than young adults, especially when they report being knowledgeable about brain training and computers. These data indicate that perceptions of brain training are malleable to at least some extent, and may vary depending on age and other factors. Our questionnaire can serve as a simple, easily-incorporated tool to assess the face validity of brain training interventions and to create a covariate to account for expectations in statistical analyses. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jan 2015 · Behavioural Brain Research
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    • "Antidepressant drugs tend to fail in late-stage clinical trials after a significant investment has been made. The need to improve the quality of clinical trials, the patients they recruit and to control for a placebo effect that in clinical trials accounts for approximately two-thirds of antidepressant drug effect has been dealt with elsewhere (Nutt and Goodwin, 2011; Rief et al., 2009), and will not be discussed in this review. Even if an antidepressant drug is approved, frequent market access and commercial failures due to lack of compelling differentiation in the clinical profile make an unpromising case for further antidepressant drug development. "
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    ABSTRACT: Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated "hypodopaminergic" adverse effects of decreased libido, weight gain and "blunting" of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD.
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