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The Percentage of Placebo-Treated Patients Falling into Respective Categories of Change From Baseline on Total Positive and Negative Syndrome Scale (PANSS) Scores Shows Fairly Large Differences at Many Specific Levels and a Significant Overall Shift Toward Greater Placebo Improvement and Less Placebo Worsening at 6 wk in Later Trials Compared With Earlier Trials.
Source publication
On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, cl...
Context in source publication
Context 1
... comparison showed that, by and large, participants in the later RCTs had a signifi- cantly larger response to placebo on both PANSS total scores and Clinical Global Impression-Severity ratings at 6 weeks, relative to baseline. As shown in figure 2, the percentage of placebo-treated patients falling into re- spective categories of change from baseline on total PANSS scores shows a significant overall shift toward greater improvement/less worsening at 6 weeks in later trials compared with earlier trials. Paralleling this in- crease in placebo response, L.A. also reported a reduction in active drug response, further contributing to an overall diminishing of drug-placebo differences. ...Citations
... Several strategies have been proposed to reduce the placebo effects. Limiting the time of recent exacerbation of symptoms to within 1 month to induce a great drug response [59] ; educating clinical trial participants to respond as the way it is because not everyone who participates in the clinical trial will improve and even if they do not improve, the researcher is not disappointed [60] ; reducing the expected bias of researchers caused by the same rater by alternately evaluating different raters with high reliability between raters and well-trained ones [54] ; excluding cases that improve after the stress factor is removed or naturally improve over time [60] ; and preventing exaggeration of the initial score by applying different scales used for screening tests and primary endpoints. [51] Second, it may have been difficult to confirm the efficacy of YWT because of the insufficient number of participants. ...
Background
Major depressive disorder (MDD) occurs more often in women than that in men due to various complex causes. This study aimed to evaluate the effectiveness and safety of Yukwool-tang (YWT) for MDD in women.
Methods
A total of 72 patients diagnosed with MDD and Korean version of the Hamilton Depression Rating Scale (K-HDRS) ≥ 14 points were randomly assigned to the YWT or placebo group, and 1 bottle (30 mg) of No-S solution and placebo was administered to the YWT and placebo groups, respectively, orally thrice a day for 8 weeks. The evaluation was conducted through K-HDRS, Korean version of the Beck Depression Inventory (BDI-K), Korean version of the Beck Hopelessness Scale (K-BHS), Korean version of the Insomnia Severity Index (ISI-K), State-Trait Anxiety Inventory (STAI-K), EuroQol-5 dimension (EQ-5D), and Pattern Identifications Tool for Depression (PITD). Fifty patients completed the trial.
Results
In the YWT group, the K-HDRS, BDI-K, K-BHS, ISI-K, STAI-K, and EQ-5D scores changed significantly at the 8th week, but there were no significant differences with the placebo. In subgroup analysis, the K-BHS score with an initial K-HDRS score < 18 points was significantly decreased compared to placebo at the 12th week ( P < .05). In the YWT group, the ratio of Stagnation of Liver Gi (肝氣鬱結) was the highest, but Dual Deficiency of the Heart and Spleen (心脾兩虛) became the highest after administration, which was also the highest in the placebo group both before and after administration.
Conclusion
YWT improved depression and accompanying symptoms in women with MDD, although it was not significant compared to placebo, and it might be effective in improving the degree of hopelessness. The effect of YWT will become relatively clear through further research that can overcome certain limitations.
... Many recent attempts at developing drugs with novel MOAs have failed (Downing et al., 2014;Bugarski-Kirola et al., 2017), with results from animal models not translating to benefits in humans. Potential reasons for failure include increasingly high placebo response rates, (Kemp et al., 2010) limitations in trial design or execution (Javitt and Kantrowitz, 2022) and, importantly, the lack of biomarkers to identify subpopulations whose neuropathology is likely to respond to the MOA of a drug (J. T. Kantrowitz, 2019;Stuke, 2023). ...
Background:
Schizophrenia is a disabling disorder that profoundly affects functioning and quality of life. While available antipsychotics have improved outcomes for patients with schizophrenia, they are relatively ineffective for negative and cognitive symptoms and are associated with a range of troublesome side effects. A significant unmet medical need for more effective and better tolerated therapies remains.
Methods:
A roundtable consisting of 4 experts in the treatment of patients with schizophrenia convened to discuss the current treatment landscape, unmet needs from patient and societal perspectives, and the potential of emerging therapies with novel mechanisms of action (MOAs).
Results:
Key areas of unmet need include optimal implementation of available treatments, effective treatment of negative and cognitive symptoms, improvements in medication adherence, novel MOAs, avoidance of post-synaptic dopamine blockade-related adverse effects, and individualized approaches to treatment. With the possible exception of clozapine, all currently available antipsychotics act primarily by blocking dopamine D2 receptors. Agents with novel MOAs are urgently needed to effectively target the full range of symptoms in schizophrenia and facilitate an individualized treatment approach. Discussion focused on promising novel MOAs that have demonstrated potential in Phase 2 and 3 trials include muscarinic receptor agonism, trace amine-associated receptor 1 (TAAR1) agonism, serotonin receptor antagonism/inverse agonism, and glutamatergic modulation.
Conclusions:
Results from early clinical trials of agents with novel MOAs are encouraging, particularly for muscarinic and TAAR1 agonists. These agents offer renewed hope for meaningful improvement in the management of patients with schizophrenia.
... Such non-specific effects can magnify the placebo effect; it can then become impossible to detect the superiority of an active comparator. In addition, it can be difficult to distinguish negative trials from failed trials when unexpectedly high placebo response rates eclipse the potential intrinsic efficacy of a pharmacologic compound, essentially increasing the risk of a Type II error ( Kemp et al., 2010 ;Pocock & Stone, 2016 ). Finally, patient groups must have assay sensitivity; the experimental design must have potential to show a differential effect of treatment by appropriate choice of treatment groups ( Howick, 2009 ). ...
The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.
... Besides determining the overall effect size for placebo, we conducted meta-regression analyses to delineate potential predictors of placebo response. First, we investigated whether the placebo effect increased with time in NS trials of schizophrenia (similarly to previous trials of broad-spectrum AP agents which indicated increasing placebo response over the years in the overall symptom severity 11,16 ). For this analysis, we used publication date as a moderator variable in the meta-regression. ...
... We found no change in the placebo response with calendar time, which is noteworthy in the context of several reports on an increasing placebo response over the years. 9,11,16 It should be noted, however, that in some of the studies the time effect was not present 35 and that the meta-analyses that reported increasing placebo response over time typically span longer than the two decades 11 period, which we focused on in the current meta-analysis. One also needs to consider that the calendar time effect on placebo response is closely related to changes in trial design factors, eg, increase in the number of subjects and sites, and change in treatment settings over time. ...
Background
Summarizing evidence from clinical trials of patients with schizophrenia with predominant or prominent negative symptoms (NS), a prior meta-analysis reported a large placebo effect in negative symptoms (Cohen’s d = 2.909). Assuming that such an effect was clinically not plausible, we performed a critical re-assessment and an update of the previous results with newly available data from add-on and monotherapy studies.
Study Design
Random-effect meta/regression analysis of trials that focused on predominant or prominent NS; and adopted a double-blind, randomized, placebo-controlled design. The final pooled meta-analytic database, based on the available add-on and monotherapy studies combined, included 24 publications containing data on a total of 25 studies (21 add-on, 4 monotherapy).
Study Results
The pooled overall estimate for the placebo effect from the primary analysis for all included studies had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091). The estimates were similar in the add-on and monotherapy studies. Meta-regression indicated that the high placebo response was significantly associated with clinical trial characteristics, including the high ratio of patients assigned to active vs. placebo treatment and short trial duration.
Conclusions
These results represent a major downward correction for a current effect size estimate of the placebo response in the negative symptoms of schizophrenia. Our findings also pinpoint certain clinical trial characteristics, which may serve as important predictors of the placebo response. The knowledge of these factors can have important implications for drug development and trial design for new drugs for negative symptoms of schizophrenia.
... Tonic activation of dopaminergic neurons in the dorsal striatum, ventral striatum and prefrontal cortex via positive expectations has been explained by efficacy of excitatory glutamate and inhibitory GABA impulses caused by placebo-derived reward expectation on dopaminergic neurons (5). Kemp et al. (2010) have explained the factors affecting the placebo response as delayed duration of studies, effects of rescue drugs such as sedation, insufficient optimization of drug doses, difficulties in compliance to the therapy or the study protocol, and different study designs (6). Other than that, financial support to participants and regression to the mean have been defined as causes that affect the placebo-drug difference. ...
... Tonic activation of dopaminergic neurons in the dorsal striatum, ventral striatum and prefrontal cortex via positive expectations has been explained by efficacy of excitatory glutamate and inhibitory GABA impulses caused by placebo-derived reward expectation on dopaminergic neurons (5). Kemp et al. (2010) have explained the factors affecting the placebo response as delayed duration of studies, effects of rescue drugs such as sedation, insufficient optimization of drug doses, difficulties in compliance to the therapy or the study protocol, and different study designs (6). Other than that, financial support to participants and regression to the mean have been defined as causes that affect the placebo-drug difference. ...
Objective: Randomized placebo controlled trials (RCT) are very important for testing efficacy and safety of a medical treatment. There is no too much RCT`s in childhood bipolar disorder manic episode. In these trials, high placebo response poses a problem for the definition of real drug responses in practice. Therefore, analysis of predictors of drug and placebo response are important for conducting more reliable RCT`s in the future.
Method: Comprehensive search conducted in PubMed, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and some other electronic databases. Studies including participants with Bipolar Disorder manic episode and associated symptoms (e.g ADHD, irritability) included. There was no restriction in terms of sex, ethnicity or initial severity. Participants over age 18 were excluded. Random effect size model was used for calculate effect sizes for placebo and drugs.
Results: A total of 1974 participants and 11 studies were included in the meta-analysis. Risperidone was highest effect size among drug arms. Number of the sites and number of the participants were associated with higher placebo response in meta-regression. We did not find any variable had an impact on drug response. There was no any publication bias in this meta-analysis.
Conclusion: We found similar results as adult studies. Modifying number of the sites or ramdomized sample size may limit placebo response and could improve the efficacy of RCT`s and enhance drug-placebo contrasts.
... The placebo (or Sham) group had a significant improvement in this study. Indeed, placebo effect was comparable to ECT effect at the endpoint, with no statistical differences (last PANSS and CGI assessments were carried out until seven days after the last procedure) [32][33][34] . One possible explanation could be the cumulative factors that can increase placebo effect, also described and found in other clinical trials, such as: small sample sizes, smaller placebo groups, higher severity of psychopathology at baseline, lower mean age of participants, as well as the briefness of intervention [32][33][34] . ...
... Indeed, placebo effect was comparable to ECT effect at the endpoint, with no statistical differences (last PANSS and CGI assessments were carried out until seven days after the last procedure) [32][33][34] . One possible explanation could be the cumulative factors that can increase placebo effect, also described and found in other clinical trials, such as: small sample sizes, smaller placebo groups, higher severity of psychopathology at baseline, lower mean age of participants, as well as the briefness of intervention [32][33][34] . ...
Abstract
Background: Thirty percent of schizophrenia patients are treatment-resistant. Objective: This is a single-blinded sham-controlled trial to assess the efficacy of electroconvulsive therapy (ECT) as augmentation strategy in patients with clozapine-resistant schizophrenia. Methods: Twenty three subjects were randomly
assigned to 12 sessions of ECT (N = 13) or placebo (Sham ECT) (N = 10). The primary outcome was improvement on psychotic symptoms as measured by the mean reduction of the PANSS positive subscale. The assessments were performed by blind raters. Results: At baseline both groups were similar, except for negative and total symptoms of the PANSS, which were higher in the Sham group. At the endpoint both groups had a significant decrease from basal score.
In the ECT group the PANSS total score decreased 8.78%, from 81.23 to 74.75 (p = 0.042), while the positive subscale had a mean reduction of 19% (19.31 to 16.17, p = 0.006). In the Sham group, the mean reduction of PANSS total score was 15.27% (96.80 to 87.43; p = 0.036), and the PANSS positive subscale decreased 27.81% (22.90 to 19.14, p = 0.008). The CGI score in ECT group decreased 23.0% (5.23 to 4.17; p = 0.001) and decreased 24.31% in the Sham ECT
group (5.80 to 4.86; p = 0.004). Discussion: In this pilot study, we found no difference between the groups.
Melzer-Ribeiro DL et al. / Arch Clin Psychiatry. 2017;44(2):45-50
Keywords: Schizophrenia, electroconvulsive therapy, ECT, single-blinded sham-controlled trial, partial response to clozapine.
... 7 Demonstrating therapeutic benefit in clinical trials has been hindered by factors such as high placebo response rates, high participant dropout rates over time, and variable sensitivity and specificity of clinical trial end points to isolate the pharmacological effect for schizophrenia symptoms. 8 As a result of these challenges, several large pharmaceutical companies have announced plans to abandon drug development programs in psychiatric diseases, including schizophrenia, despite unmet medical needs. 9 There is a public health imperative to facilitate the development of new treatments for schizophrenia, and the FDA has recognized the need to improve the quality of clinical trials of these medications. ...
Importance
Facilitating the development of safe and effective medications for schizophrenia is a public health imperative.
Objectives
To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment.
Data Sources
A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs).
Study Selection
All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected.
Data Extraction and Synthesis
Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016.
Main Outcomes and Measures
The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment–emergent AEs.
Results
The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial.
Conclusions and Relevance
Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.
... There is historical evidence that the treatment effects reported in clinical trials have declined over time (Ioannidis, 2008). At the same time, and across numerous spheres of medicine, the placebo responses have increased in magnitude (Dunlop et al., 2012;Kemp et al., 2010;Rheims, Perucca, Cucherat, & Ryvlin, 2011;Tuttle et al., 2015;Undurraga & Baldessarini, 2012;Vieta & Cruz, 2008;Walsh, Seidman, Sysko, & Gould, 2002). In order to attain the desired statistical power-customarily set to 80% in clinical research and defined as the "probability of rejecting the null hypothesis when the alternative hypothesis is true," there seems to be a trend to devise clinical trials with larger sample sizes and more site numbers. ...
Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.
... In the search for the causes of the apparent declining potency of antipsychotic medication, it has been suggested that the explanation may be found in inadequate rating procedures. 1 For several decades now, Helena Kraemer stressed the fundamental importance of inter-rater reliability (IRR) for randomized clinical trials, 2 in particular for the rating of psychotic symptoms since measurements are largely dependent on observational instruments that require acceptable reliability. In fact, reliability scores in the absence of training procedures are generally low (<0.6) for the observational instruments that are commonly applied in psychosis research. ...
... Other groups have also reported on this problem of increasing placebo response and decreasing effect size in schizophrenia trials, 3-7 but, except for Kemp et al, 3 these were limited to published data. The FDA has access to all of the studies done in drug development programs and is, therefore, uniquely positioned to report on this problem. ...
