Prior antidepressant courses predicted a weaker response to paroxetine, and no weaker response to cognitive therapy
240 people with moderate to severe depression, randomised to paroxetine or cognitive therapy for 16 weeks. More prior antidepressant exposures meant a poorer response to the drug, not to the therapy. The authors ask for replication first.
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: A secondary analysis of a trial designed for a different comparison; one drug, 16 weeks. The authors themselves make the practice implication conditional on replication in rigorous studies, and the abstract does not report that replication. Confounding by illness severity cannot be fully excluded.
The trial that asked whether a history of antidepressants blunts the next treatment, and found it depended on what the next treatment was.
Significant findings
Leykin, Amsterdam, DeRubeis and colleagues used a randomised trial of 240 patients with moderate-to-severe major depressive disorder, comparing paroxetine with cognitive therapy over 16 weeks. Each person's history of prior antidepressant exposure was assessed "with structured interviews, self-report, and medical records." The analysis used hierarchical linear models on the intent-to-treat sample.
"After controlling for various demographic and clinical factors, more prior AD exposures predicted poor response to paroxetine therapy but not to CT, as measured by the Hamilton Rating Scale for Depression." Spelled out: "Whereas CT outcome was not significantly related to the number of prior AD exposures, a higher number of prior AD exposures was significantly associated with a lower response to paroxetine."
The implication the authors draw is conditional: "If these findings are replicated in methodologically rigorous studies of paroxetine and other antidepressants, CT should be recommended, in preference to AD, for patients with multiple prior AD exposures."
The other direction
The word "if" is doing real work. The authors ask for replication in rigorous studies of paroxetine and other drugs before the finding should change what anyone is offered, and the abstract does not say that replication has happened. It is one drug, paroxetine, over 16 weeks. The trial was designed to compare two treatments, not to test the prior-exposure question, so this is a secondary analysis. And a history of many antidepressant courses may mark a depression that is harder to treat by any means; the therapy arm's flat result argues against that, but does not settle it.
What this does not show
It does not say cognitive therapy is better than paroxetine for everyone, or that anyone with a long medication history should stop a drug. It says the two treatments responded differently to one variable, in one trial. Which treatment fits a given person is a decision with a prescriber and, where therapy is on the table, a therapist.
Worth asking
Given how many antidepressants I have tried, is therapy on the table, whether or not we change the medication?
Source
Progressive resistance to a selective serotonin reuptake inhibitor but not to cognitive therapy in the treatment of major depression — Leykin Y, Amsterdam JD, DeRubeis RJ, Gallop R, Shelton RC, Hollon SD (2007)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1037/0022-006X.75.2.267
DOI: 10.1037/0022-006X.75.2.267
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Funding not disclosed
- Published in
- Reputable peer-reviewed journal
- Sample size
- 240
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 29, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 59 out of 100 on our published rubric. One caveat travels with that badge: A secondary analysis of a trial designed for a different comparison; one drug, 16 weeks. The authors themselves make the practice implication conditional on replication in rigorous studies, and the abstract does not report that replication. Confounding by illness severity cannot be fully excluded. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
Progressive resistance to a selective serotonin reuptake inhibitor but not to cognitive therapy in the treatment of major depression — Leykin Y, Amsterdam JD, DeRubeis RJ, Gallop R, Shelton RC, Hollon SD (2007). Published in: Reputable peer-reviewed journal. DOI: 10.1037/0022-006X.75.2.267. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Randomised controlled trial. Funding: Funding not disclosed. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.