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Randomized Controlled Trial
. 2021 Sep;144(3):300-309.
doi: 10.1111/acps.13340. Epub 2021 Jul 8.

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

Fredrik Hieronymus  1   2   3 , Alexander Lisinski  3 , Magnus Hieronymus  4 , Jakob Näslund  3 , Elias Eriksson  3 , Søren Dinesen Østergaard  1   2
Affiliations
Randomized Controlled Trial

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

Fredrik Hieronymus et al. Acta Psychiatr Scand. 2021 Sep.

Abstract

Objective: Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that effect sizes as high as 0.875 are necessary for a minimal clinically important difference. Whether such effect sizes are achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what effect sizes are theoretically achievable in placebo-controlled trials of antidepressants.

Methods: Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes for simulated antidepressant therapies to placebo-treated participants (n = 2201) from clinical trials of selective serotonin reuptake inhibitors.

Results: An optimally effective antidepressant, where all treated participants achieve HDRS-17 scores comparable to those displayed by healthy volunteers (remission-type model), had a maximum effect size of 1.75, with a mean difference of 11.6 points on the HDRS-17. In simulations where patients received an additional 50% symptom reduction over that obtained with placebo (improvement-type model), the maximum effect size was 1.08 with a mean HDRS-17 difference of 7.2. When adjusting for normal rates of treatment discontinuation, maximum effect sizes were 1.10 (remission-type model) and 0.76 (improvement-type model) with HDRS-17 mean differences of 8.8 and 5.6, respectively.

Conclusions: Three methodological issues (i) a large and variable placebo response, (ii) a high rate of dropout and (iii) HDRS-17-ratings significantly larger than zero in healthy volunteers, reduce the degree of treatment-placebo separation achievable in depression trials. Assuming that those who discontinue treatment have only partial response, even a highly effective antidepressant would have difficulties surpassing such effect size cut-offs as have been suggested to signify a minimal clinically important difference.

Keywords: antidepressive agents; depression; minimal clinically important difference; placebo effect; serotonin uptake inhibitors.

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References

REFERENCES

    1. Hieronymus F, Jauhar S, Ostergaard SD, Young AH. One (effect) size does not fit at all: Interpreting clinical significance and effect sizes in depression treatment trials. J Psychopharmacol. 2020;34:1074-1078.
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