Objective Recent meta‐analyses on dose–response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses. Method Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers’ product monographs, were analyzed in pairwise random‐effects meta‐analyses and in a sensitivity network meta‐analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031). Results Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non‐significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: −0.15 [95%‐CI: −0.28; −0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose—particularly due to side effects. Network meta‐analyses supported our findings. Conclusions There is no conclusive level I or level II evidence of a clinically meaningful dose–response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.

With clinically and statistically nonsignificant effect estimates, there is evidence from RCTs against increasing the dose of SSRIs (with the possible exception of citalopram) in adult patients with major depression and ATF. Dose increase with other antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors) and in other patient groups (minor depression, children and adolescents) or after long periods of first-line antidepressant therapy (ie, 8 weeks) have not been or not been sufficiently studied and, at this time, cannot be recommended in clinical practice.

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<b><i>Introduction:</i></b> Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. <b><i>Objective:</i></b> This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. <b><i>Methods:</i></b> A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers’ product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). <b><i>Results:</i></b> From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of –0.06 (–0.16 to 0.04) and –0.06 (–0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. <b><i>Conclusion:</i></b> Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

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