Dose-response relationships in antidepressant pharmacotherapy of depressive disorders with (S)SNRI: a systematic review and meta-analysis

Lead Investigator: Christopher Baethge, Department of Psychiatry at University of Cologne Medical School
Title of Proposal Research: Dose-response relationships in antidepressant pharmacotherapy of depressive disorders with (S)SNRI: a systematic review and meta-analysis
Vivli Data Request: 5098
Funding Source: None.
Potential Conflicts of Interest: None.

Summary of the Proposed Research:

With a lifetime prevalence of 16-20% internationally, up to every 5th person worldwide is at risk to suffer from depressive disorders at least once in their lifetime. So far, an initial pharmacotherapy lead to a response rate of approximately 60%. For patients not responding to the first step pharmacotherapy national and international guidelines offer, several so called second step strategies including the switch of the antidepressant as well as raising the dose of the initially used antidepressant. In order to justify a dose increase we need to assume a dose response relationship for antidepressants.

Although numerous studies have compared the effectiveness of different doses of antidepressants, a meta-analysis examining a possible dose response relationship in (selective) serotonin-norepinephrine reuptake inhibitors ((S)SNRI) has not been carried out yet.

Our aim is to analyze trial results in pairwise meta-analyses and in sensitivity analyses by means of network meta-analysis. Our findings may contribute to the discussion of adequate second step strategies for patients not responding to initial antidepressant pharmacotherapy and help to find the optimal treatment for patients with depressive disorders.

Statistical Analysis Plan:

Data regarding the intention-to-treat population will be preferred. In a sensitivity analysis per-protocol data will be analyzed as needed.
The first approach to analyzing the dose effect relationship will be a linear model, and we will try to calculate slopes (with corresponding standard errors) for each trial included. Linearity will be examined by plotting slope against mean dose. Only if linear models fail we will consider other models.
The meta-analysis is based on a random-effects model for dose-effect slopes.
If this approach turns out to be unfeasible and depending on the data structure, a qualitative approach (e.g., high versus low dose) or a network meta-analysis may be necessary.
Statistical heterogeneity will be determined and potential sources for the heterogeneity will be examined by means of subgroup analysis and/or meta regression.
For comparison within one class of antidepressants we will calculate standard antidepressant doses in imipramine equivalents.
We will use Excel and SPSS software for statistical calculations and Review Manager program (RevMan), Comprehensive Meta-Analysis, or Open Meta-Analyst for meta-analyses.

Requested Studies:

Duloxetine Versus Venlafaxine Extended Release in the Treatment of Major Depressive Disorder
Sponsor: Eli Lilly and Company
Study ID: NCT00067912
Sponsor ID: 7999

Public Disclosure:
Rink L, Adams A, Braun C, Bschor T, Kuhr K, Baethge C. Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials. Psychother Psychosom 2021. doi: 10.1159/000520554.