Any second-line strategy beats pushing the dose higher
STUDY: Pérez V et al, British Journal of Psychiatry 2025;
STUDY TYPE: Randomized clinical trial
FUNDING: Instituto de Salud Carlos III (Spanish Government), co-financed by the European Regional Development Fund
Background
The DEPRE’5 replicates some of the moves of the STAR*D trial, and adds further skepticism to be benefits of raising SSRI doses in depression.
The Study
257 adults with major depressive disorder who had not responded to at least six weeks of an SSRI at an adequate dose.
Randomized across ten Spanish hospitals to one of five arms
- SSRI higher dose
- Lithium augmentation
- Nortriptyline augmentation
- Switch to venlafaxine
- Add problem-solving therapy
Across all four alternatives combined, response rates were nearly double those of dose-raising (28.2% vs. 14.3%). However, much like STAR*D, the other steps did not differ significantly in their benefits.
Switching to venlafaxine and adding problem-solving therapy showed the most consistent effects, with venlafaxine driving a roughly 2.5-fold higher odds of response (odds ratio 2.53) and the psychotherapy group showing the largest reduction in HDRS-17 scores (-3.1 points). Neither reached conventional statistical significance individually. The trial was underpowered, having recruited about half its target sample. Remission rates were low across all groups, consistent with a population that had already failed an SSRI.
Problem-solving therapy produced the fewest side effects (28.1% adverse event rate vs. 75% with nortriptyline). Lithium users had the lowest medication adherence (38.6%).
Limitations: The trial was not blinded, leaving open the possibility that adding a new treatment brought a bigger placebo effect than raising the dose. However, approximately 20 meta-analyses of fixed-dose trials show no additional benefit beyond the medium ranges in the table below (from Difficult to Treat Depression):
Practice Implications
- With tricyclic antidepressants, higher doses often brought bigger responses, but that hasn’t turned out with SSRIs and other modern day antidepressants.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
