A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors
Artikel i vetenskaplig tidskrift, 2016

The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n = 2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10-20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose-response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs.

efficacy

standard

metaanalysis

Psychiatry

clinical-trials

guidelines

major depressive disorder

double-blind

severity

placebo

escalation

Författare

F Hieronymus

Göteborgs universitet

Staffan Nilsson

Chalmers, Matematiska vetenskaper, matematisk statistik

Göteborgs universitet

Elias Eriksson

Göteborgs universitet

Translational Psychiatry

2158-3188 (ISSN)

Vol. 6 6 artikel nr e834- e834

Ämneskategorier

Psykiatri

DOI

10.1038/tp.2016.104

PubMed

27271860