Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database

Khan, Arif; Khan, Shirin; Leventhal, Robyn M.; Brown, Walter A.

doi:10.1017/s1461145701002322

Cited by 188 publications

(195 citation statements)

References 0 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…However, there were also substantial placebo responses for secondary outcomes such as anxiety, general psychopathology and quality of life [13]. The results are in line with the findings from other meta-analyses and confirm the strong placebo response to antidepressant medication [2,4,7,[14][15][16].…”

Section: The Placebo Response In Antidepressant Trialssupporting

confidence: 86%

Lessons learned from placebo groups in antidepressant trials

Shedden-Mora

Nestoriuc

Rief

2011

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

This comprehensive review provides an overview about placebo and nocebo phenomena in antidepressant trials. Improvements in the placebo groups may partly be explained through methodological issues such as natural course of depression and regression to the mean, but also fundamentally reflect investigators' and participants' expectations. A meta-analysis by our group of 96 randomized placebo-controlled trials showed large placebo responses to antidepressant medication. Moderator analyses revealed substantially larger placebo responses in observer ratings compared with self-report. Effect sizes in observer ratings showed strong increase with publication year while this effect was not found for patients' self-ratings. This reflects the strong influence of investigators' expectations. The analysis of 'nocebo effects', e.g. adverse effects in placebo groups of antidepressant trials also confirms the impact of expectations: nocebo symptoms reflected the typical side-effect patterns expected in the drug group, with higher symptoms rates in the placebo groups of tricyclic antidepressant trials compared with placebo groups of trials testing selective serotonin reuptake inhibitors. While the placebo response seems to be similar for women and men, gender differences were found for nocebo rates. In the conclusion, we discuss potential implications for clinical trial designs and argue for interventions aimed at optimizing positive expectations of treatment benefit while minimizing the impact of adverse effects.

show abstract

Section: The Placebo Response In Antidepressant Trialssupporting

confidence: 86%

Lessons learned from placebo groups in antidepressant trials

Shedden-Mora

Nestoriuc

Rief

2011

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

show abstract

“…Effect sizes are clinically significant in all the three behavioral dimensions. They are comparable to those typically demonstrated in antidepressant clinical trials (Khan et al, 2000), and the percentage of trials showing efficacy (480%) is superior to results reported in standard antidepressant and anxiolytic clinical trials (B50%) (Khan et al, 2002). As these agents are thought to exert their therapeutic effects in other patient populations mainly by D2 (Kapur and Seeman, 2001), or by D2 and 5-HT2 (Meltzer, 1989) receptor blockade, it is reasonable to consider similar mechanisms of action in BPD, thereby implicating DA dysfunction in these three dimensions of the disorder.…”

Section: Pharmacological Evidencesupporting

confidence: 83%

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

Friedel

2004

Neuropsychopharmacol

121

View full text Add to dashboard Cite

Research on the biological basis of borderline personality disorder (BPD) has focused primarily on the serotonin model of impulsive aggression. However, there is evidence that dopamine (DA) dysfunction may also be associated with BPD. Pertinent research and review articles, identified by Medline searches of relevant topics, books, references from bibliographies, and conference proceedings from 1975 to 2003, were reviewed. Evidence of DA dysfunction in BPD derives from the efficacy of traditional and atypical antipsychotic agents in BPD, and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder. In addition, human and animal studies indicate that DA activity plays an important role in emotion information processing, impulse control, and cognition. The results of this review suggest that DA dysfunction is associated with three dimensions of BPD, that is, emotional dysregulation, impulsivity, and cognitive-perceptual impairment. The main limitation of this hypothesis is that the evidence reviewed is circumstantial. There is no study that directly demonstrates DA dysfunction in BPD. In addition, the therapeutic effects of antipsychotic agents observed in BPD may be mediated by non-DA mechanisms of action. If the stated hypothesis is correct, DA dysfunction in BPD may result from genetic, developmental, or environmental factors directly affecting specific DA pathways. Alternatively, DA dysfunction in BPD may be a compensatory response to alterations in the primary neural systems that control emotion, impulse control, and cognition, and that are mediated by the brain's main neurotransmitters, glutamate, and GABA, or in one or more other neuromodulatory pathways such as serotonin, acetylcholine, and norepinephrine.

show abstract

“…Unexpectedly, the number of depressed patients completing the trial when assigned to placebo was numerically higher in fixed dose trials (64.7%) compared to flexible dose trials (57.8%) (Khan et al, 2000(Khan et al, , 2001). This pattern is in contrast with some of the assumptions about outcome with fixed vs flexible dose trials.…”

Section: Discussionmentioning

confidence: 94%

“…In the 51 clinical trials (for more specific study information see Khan et al, 2000Khan et al, , 2001, 9313 patients were included in the Intent-to-Treat analysis; 3335 assigned to placebo, 4676 assigned to a new antidepressant, and 1502 assigned to an active comparator.…”

Section: Methodsmentioning

confidence: 99%

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Khan

Walens

et al. 2002

Neuropsychopharmacol

Self Cite

149

View full text Add to dashboard Cite

The assumption that the design of an antidepressant clinical trial affects the outcome of that trial is based on sparse data. We sought to examine if the dosing schedule, either a fixed dose or a flexible dose type, in an antidepressant clinical trial affects the frequency with which antidepressants show statistical superiority over placebo. Randomized, placebo-controlled clinical trials of nine antidepressants approved by the Food and Drug Administration between 1985 and 2000 were reviewed. These trials comprised 9313 depressed patients who participated in 51 antidepressant clinical trials consisting of 92 treatment arms with eventual approved doses. In the flexible dose trials, 59.6% (34/57) of the antidepressant treatment arms were statistically significant compared to placebo, whereas in the fixed dose trials only 31.4% (11/35) of the antidepressant treatment arms were statistically significant compared to placebo (w 2 ¼ 6.9, df ¼ 1, po0.01). These data suggest that the antidepressant dose schedule may influence trial outcome due in part to a significantly lower magnitude of symptom reduction with placebo in flexible dose trials (F ¼ 4.08, df ¼ 1, 48, po0.05) compared to fixed dose trials. Symptom reduction was similar with antidepressants in the flexible and fixed dose trials. Further, the primary function of finding a doseresponse relationship was not found among the fixed dose studies.

show abstract

Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database

Cited by 188 publications

References 0 publications

Lessons learned from placebo groups in antidepressant trials

Lessons learned from placebo groups in antidepressant trials

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

Frequency of Positive Studies Among Fixed and Flexible Dose Antidepressant Clinical Trials: An Analysis of the Food and Drug Administraton Summary Basis of Approval Reports

Contact Info

Product

Resources

About