Determining maximal achievable effect sizes of antidepressant therapies in placebo‐controlled trials

Objective Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that sizes as high 0.875 are necessary for a minimal clinically important difference. Whether such achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what theoretically antidepressants. Methods Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes simulated antidepressant therapies placebo-treated participants (n = 2201) from clinical selective serotonin reuptake inhibitors. Results An optimally effective antidepressant, where all treated achieve HDRS-17 scores comparable those displayed by healthy volunteers (remission-type model), had maximum 1.75, mean difference 11.6 points on the HDRS-17. In simulations patients received additional 50% symptom reduction over obtained (improvement-type was 1.08 7.2. When adjusting normal rates treatment discontinuation, were 1.10 model) and 0.76 differences 8.8 5.6, respectively. Conclusions Three methodological issues (i) large variable response, (ii) rate dropout (iii) HDRS-17-ratings significantly larger than zero volunteers, reduce degree treatment-placebo separation depression trials. Assuming who discontinue have only partial even highly would difficulties surpassing cut-offs signify