Each previous antidepressant course cut the odds of responding to sertraline by about a fifth
276 people with depression took sertraline for eight weeks. The more prior antidepressant trials they had had, the less likely they were to respond: odds ratio 0.81 per trial, a 19.9% drop each time. A post hoc analysis.
Suggestive but preliminary. Not settled. how we score evidence
Caveat on this rating: Post hoc, by the authors' own description. An odds ratio per prior course, with no absolute response rates in the abstract. The continuation phase showed no association. Confounding by harder-to-treat illness cannot be excluded from the abstract. It does not test restarting the same drug.
The closest measurement to "does it work the second time," from a trial that counted how many drugs each person had already tried.
Significant findings
Amsterdam and colleagues treated 276 patients with major depressive disorder with sertraline at 150 to 200 mg a day for eight weeks. People who were still depressed were then randomised to eight more weeks of sertraline plus atomoxetine (72 people) or sertraline plus placebo (74). The question added afterwards was whether a longer history of antidepressant trials predicted a weaker response.
It did. "The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial."
In the second phase the pattern disappeared: "the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy."
The conclusion: "This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials."
The other direction
The abstract calls this a post hoc analysis, meaning the trial was designed to test atomoxetine, not this question, and the finding was extracted afterwards. An odds ratio of 0.81 per prior course is a slope, not a cliff: it does not say what fraction of people with two or three prior courses responded, and the abstract gives no absolute rates. The second phase found no association at all. And people with more prior courses may simply have had harder-to-treat depression, which would produce the same numbers without the drug being to blame; the abstract cannot separate those.
What this does not show
It does not measure the case people ask about most: restarting the same drug that worked before. It does not say a drug will not work after several courses, only that the odds shift. It is not a reason to avoid, restart or stop anything; how a treatment history should shape the next step is a prescriber's judgment.
Worth asking
How many antidepressant courses have I had, and does that number change what you would try?
Source
Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder — Amsterdam JD, Williams D, Michelson D, Adler LA, Dunner DL, Nierenberg AA, Reimherr FW, Schatzberg AF (2009)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1159/000226611
DOI: 10.1159/000226611
How this was scored
- Study design
- Cohort study
- Funding
- Funding not disclosed
- Published in
- Reputable peer-reviewed journal
- Sample size
- 276
- 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 "early signal". Suggestive but preliminary. Not settled. It scores 49 out of 100 on our published rubric. One caveat travels with that badge: Post hoc, by the authors' own description. An odds ratio per prior course, with no absolute response rates in the abstract. The continuation phase showed no association. Confounding by harder-to-treat illness cannot be excluded from the abstract. It does not test restarting the same drug. 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?
Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder — Amsterdam JD, Williams D, Michelson D, Adler LA, Dunner DL, Nierenberg AA, Reimherr FW, Schatzberg AF (2009). Published in: Reputable peer-reviewed journal. DOI: 10.1159/000226611. 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: Cohort study. 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.