“Building evidence for sequenced depression treatment”

In 2009 we published one of the earlier network meta-analyses (NMA) of 12 new generation antidepressants in the acute phase treatment of depression 1. In 2018 we expanded and updated this NMA by including five more new generation antidepressants and four old antidepressants (522 trials, 116 477 participants) 2. The major difficulty in these endeavors was to identify unpublished trials, as publication bias has unfortunately been the pervasive practice not only in psychopharmacology but in biology and science at large 3. Through extensive collaboration with some industry and regulatory agencies, we were able to identify 86 unpublished trials and find unpublished information for 188 additional trials. The results challenged the old clinical wisdom that there are no major differences in efficacy among antidepressants.

Examination of the response rates on placebo among the included studies in the past four decades cast serious doubts on the decade-long superstition that the placebo response rate was increasing over the years in antidepressant trials. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% 4.

The comprehensive dataset has also enabled us to conduct the dose-response meta-analysis of SSRIs, venlafaxine and mirtazapine based on a sizable number of fixed-dose trials. The results suggested a dose-response up to doses between 20 mg and 40 mg of fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses. Dropouts due to adverse effects increased steeply through the examined range. Taken together, for these commonly used second-generation antidepressants, the lower range of the licensed dose achieved the optimal balance between efficacy, tolerability, and acceptability 5. Using the flexible adjustment in accordance with the patient’s response did not confer any benefit over prescribing at the minimum licensed dose 6.

A large pragmatic trial comparing the minimum vs maximum dose of sertraline as the first step treatment for hitherto untreated episodes of major depression and comparing second-line strategies of continuation vs switching to mirtazapine vs augmentation with mirtazapine if the patients do not remit by week 3 confirmed the above findings 7.

The exiting psychopharmacology guidelines should be rewritten: (1) Start with one of the more efficacious and acceptable antidepressants, (2) Aim at the minimum licensed dose; do not titrate to the maximum, (3) Switch or augment if the patients do not show early response.

1.         Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.

2.         Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.

3.         Ioannidis JP. Acknowledging and Overcoming Nonreproducibility in Basic and Preclinical Research. JAMA. 2017.

4.         Furukawa TA, Cipriani A, Atkinson LZ, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016;3(11):1059-1066.

5.         Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry. 2019;6(7):601-609.

6.         Furukawa TA, Salanti G, Cowen PJ, Leucht S, Cipriani A. No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review. Acta Psychiatr Scand. 2020;141(5):401-409.

7.         Kato T, Furukawa TA, Mantani A, et al. Optimising first- and second-line treatment strategies for untreated major depressive disorder – the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial. BMC Med. 2018;16(1):103.

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