Placebo Response in Studies of Major Depression

Walsh, B. Timothy; Seidman, Stuart N.; Sysko, Robyn; Gould, Madelyn S.

doi:10.1001/jama.287.14.1840

Cited by 1,047 publications

(757 citation statements)

References 80 publications

Supporting

Mentioning

672

Contrasting

Unclassified

Order By: Relevance

“…Therefore, increasing placebo effects may contribute in decreasing drug‐placebo differences in galantamine and rivastigmine patch studies. Increasing placebo effects over time were found in antipsychotic and antidepressant trials (Walsh et al , 2002; Rutherford et al , 2014). We assume that similar phenomena could occur in trials of ChEIs.…”

Section: Resultsmentioning

confidence: 99%

The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

Kobayashi¹,

Ohnishi²,

Nakagawa³

et al. 2015

Int J Geriat Psychiatry

View full text Add to dashboard Cite

BackgroundComparative evidence for efficacy and safety of second‐generation cholinesterase inhibitors (ChEIs) is still sparse.ObjectivesThe purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild‐to‐moderate Alzheimer's disease (AD).MethodsWe conducted a systematic review for published articles and included randomised, double‐blind, placebo‐controlled trials and head‐to‐head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS‐Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview‐Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta‐analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions.ResultsAmong the 21 trials included, network meta‐analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS‐Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety.ConclusionsOur analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild‐to‐moderate AD.

show abstract

Section: Resultsmentioning

confidence: 99%

The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

Kobayashi¹,

Ohnishi²,

Nakagawa³

et al. 2015

Int J Geriat Psychiatry

View full text Add to dashboard Cite

show abstract

“…It is also important to consider that many of the TCA trials were conducted in the 1980s, while the SSRI studies ran in the 1990s. This may impact the placebo response rate, which has been observed to increase over time (Walsh et al, 2002), and so may impact NNT.…”

Section: Discussionmentioning

confidence: 99%

“…For elderly populations, a 12-week trial would allow a sufficient time for clinical response in most of this patient population (Cohn et al, 1990), including very old subjects (Gildengers et al, 2002) and elderly patients with comorbid illness who may require longer to respond (Alexopoulos et al, 1996). However, extending trial duration may increase the risk of placebo response (Walsh et al, 2002).…”

Section: Methodological Considerations For Antidepressant Trials In Tmentioning

confidence: 99%

“…Although many have questioned the continued need for placebo controls (Rothman and Michels, 1994), representatives from the scientific community (Charney, 2000;Schatzberg and Kraemer, 2000;Kupfer and Frank, 2002;Walsh et al, 2002), the National Institute of Mental Health (Hyman and Shore, 2000), and mental health consumers (Charney et al, 2002) have acknowledged that placebo-controlled trials continue to be necessary for the appropriate evaluation of new agents for the treatment of mood disorders. They also concur that such need should be balanced with appropriate safeguards to provide protection and benefit to study participants.…”

Section: Placebo Response Rate In Clinical Trialsmentioning

confidence: 99%

“…Placebo response rates are variable across antidepressant trials (Quitkin, 1999;Walsh et al, 2002), and may occur for a variety of reasons. As discussed by Schatzberg and Kraemer (2000), these may include trial design flaws, rater bias at assessment of baseline symptom favoring enrollment over exclusion, spontaneous remission, or other pretreatment characteristics of individual subjects.…”

Section: Placebo Response Rate In Clinical Trialsmentioning

confidence: 99%

See 2 more Smart Citations

A Systematic Review of Antidepressant Placebo-Controlled Trials for Geriatric Depression: Limitations of Current Data and Directions for the Future

Taylor

Doraiswamy

2004

Neuropsychopharmacol

View full text Add to dashboard Cite

Depression in the elderly is a major public health problem as untreated depression adversely impacts comorbid illnesses. It is important to develop safe and effective antidepressant therapies for older individuals. We performed a systematic review of all published randomized, placebo-controlled antidepressant medication trials in populations over age 55 years. Papers were obtained via MEDLINE (1966( -August 2003 and PSYCINFO (1872-August 2003. Unpublished trials, trials examining nonpharmacologic interventions, and papers reporting post hoc analyses were not included in this review unless they provided new insights. A total of 18 placebo-controlled trials examining acute efficacy met our criteria. The combined sample size in these studies was 2252. The mean sample size was 51 (range 20-728) and mean trial duration was 7 weeks. A total of 12 trials examined tricyclic antidepressants (TCAs), five trials examined selective serotonin reuptake inhibitors (SSRIs), two trials examined bupropion, and one trial examined mirtazapine. There were no published trials of venlafaxine or nefazodone. In all, 71.5% of trials reported significantly greater efficacy with drug than placebo. In conclusions, there is a paucity of published controlled antidepressant trials in the elderly. Most published studies examine small sample sizes and do not include common comorbid conditions. Efficacy studies examining relapse prevention are lacking. Large placebo response rates, lack of controlled head to head comparisons, and other methodological design differences make crosstrial comparisons difficult. Large simple studies are urgently needed to address the unmet needs for data on safety and efficacy of antidepressants in this population.

show abstract

Trajectories of Depression Severity in Clinical Trials of Duloxetine

Gueorguieva¹

2011

Arch Gen Psychiatry

109

View full text Add to dashboard Cite

Context The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response. Objective To assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression. Design We reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression (HAM-D) scores during treatment. We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms. Effects of duloxetine hydrochloride, selective serotonin reuptake inhibitor (SSRI), and covariates on the probability of following a particular trajectory were assessed. Outcomes in different trajectories were compared using mixed-effects models. Setting Seven randomized double-blind clinical trials of duloxetine vs placebo and comparator SSRI. Patients A total of 2515 patients with major depression. Interventions Duloxetine and comparator SSRI. Main Outcome Measure Total score on the HAM-D. Results In the entire sample and in the antidepressant-treated subsample, we identified trajectories of responders (76.3% of the sample) and nonresponders (23.7% of the sample). However, placebo-treated patients were characterized by a single response trajectory. Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients. Conclusions Most patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients. However, some patients receiving these medications did more poorly than patients receiving placebo. These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment. They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment. Trial Registration clinicaltrials.gov Identifier: NCT00073411

show abstract

Placebo Response in Studies of Major Depression

Cited by 1,047 publications

References 80 publications

The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

A Systematic Review of Antidepressant Placebo-Controlled Trials for Geriatric Depression: Limitations of Current Data and Directions for the Future

Trajectories of Depression Severity in Clinical Trials of Duloxetine

Contact Info

Product

Resources

About