Effect Size Deflation With Increasing Sample Size in Adjunctive Trials for Negative Symptoms in Schizophrenia: A
Joshua T Kantrowitz1,2,3, Megan R Mayer1, Tse-Hwei Choo1,2
1New York State Psychiatric Institute, New York.
Objective:
Meta-analytic evidence supports the effectiveness of several mechanisms of action adjunctive to antipsychotics for the treatment of negative symptoms in schizophrenia. Nevertheless, the results have not been replicated consistently in multicenter randomized clinical trials. The authors' primary objective in this study was to assess whether differential scaling of response in the placebo arm by sample size could account for the discrepant results between smaller- and larger-scale trials.
Methods:
The authors conducted a meta-analysis and meta-regression of the potential contribution of differential scaling by sample size, site number, and other potential moderators in randomized clinical trials of adjunctive mechanisms of action in schizophrenia that included negative symptom outcomes.
Results:
Eight mechanisms of action were identified across 159 active-placebo comparisons with 13,020 unique participants (59.2% male [SD=26.8]; 57.2% multicenter studies). Between-group differences in negative symptoms were observed for four mechanisms of action. The size of the between-group treatment effects decreased significantly with increasing sample size (b=-0.60) and site number (b=-0.33). This was attributable primarily to significantly greater improvement in the placebo arm (b=-0.45, SE=0.21), but not the active treatment arm (b=0.14, SE=0.21). Consequently, significant between-group effects were observed preferentially in studies with ≤150 participants and ≤10 sites, along with a mean of >20 participants per site ("recruitment density") (b=-0.52).
Conclusions:
This differential placebo-active scaling with increased sample size is unlikely to be of physiological origin and may indicate that site management issues contribute to negative clinical results in large-scale trials for the negative symptoms of schizophrenia. Current power analytic approaches do not adequately consider the consequences of sample size-dependent effect size deflation, leading to excessive risk of type II error with increasing sample size or site numbers and decreasing recruitment density.
Insights
Larger trials for schizophrenia negative symptoms show smaller effects due to greater placebo improvement, not drug efficacy changes. This suggests site management issues, not physiological effects, impact results in large-scale studies.
Area of Science:
- Psychiatry
- Clinical Psychology
- Psychopharmacology
Background:
- Meta-analyses suggest adjunctive treatments improve negative symptoms in schizophrenia.
- However, multicenter randomized clinical trials (RCTs) show inconsistent results.
- Discrepancies may arise from differences in trial scale and methodology.
Purpose of the Study:
- To investigate if differential scaling of placebo response by sample size explains inconsistent findings in RCTs of adjunctive treatments for schizophrenia negative symptoms.
- To analyze the impact of sample size, site number, and recruitment density on treatment effect sizes.
Main Methods:
- A meta-analysis and meta-regression of 159 active-placebo comparisons from RCTs involving 13,020 participants.
- Examined eight adjunctive mechanisms of action for schizophrenia negative symptoms.
- Assessed moderators including sample size, number of sites, and recruitment density.
Main Results:
- Four mechanisms showed significant between-group differences in negative symptoms.
- Treatment effect sizes decreased significantly with increasing sample size and site number.
- Greater improvement in the placebo arm, not active treatment, drove this deflation.
- Significant effects were more common in smaller trials (≤150 participants, ≤10 sites) with higher recruitment density.
Conclusions:
- Differential placebo-active scaling with increasing sample size is likely due to site management issues, not physiological effects.
- Current power analyses inadequately account for sample size-dependent effect size deflation.
- This can lead to an increased risk of Type II errors in large-scale schizophrenia trials.
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