When an antidepressant stops working: rates of 9% to 57%, and four strategies with limited evidence
A 2019 review of lost antidepressant response during maintenance treatment, called tachyphylaxis. Rates ran from 9% to 57% by population and follow-up. Dose change, class switch, augmentation and psychotherapy: all limited evidence.
Weak or heavily disputed. Treat as a question, not an answer. how we score evidence
Caveat on this rating: A narrative review of heterogeneous studies with strict inclusion criteria; the authors say the findings may not generalise. The 9%-to-57% range is a definition problem as much as a measurement. The abstract does not separate drug tolerance from natural recurrence, and none of the four strategies is established.
The clinical name for "it stopped working" is tachyphylaxis, and this is the most recent review of what is known about it.
Significant findings
Kinrys and colleagues at Massachusetts General Hospital searched the literature to January 2017 for clinical trials and meta-analyses of tachyphylaxis in major depressive disorder. Their definition: "a re-emergence or worsening of symptoms despite ongoing treatment with previously effective antidepressant pharmacotherapy."
The rate: "Rates of tachyphylaxis varied from 9% to 57% depending on the patient population and duration of follow-up."
The options: "Limited evidence suggests potentially beneficial strategies for managing tachyphylaxis, including change in antidepressant dosing, switch of class of antidepressant medication, augmentation or combination pharmacotherapy, and psychotherapy."
The conclusion: "Few established treatment strategies exist to manage antidepressant tachyphylaxis. Further interventional research is needed."
The other direction
The range is wide because the studies are: "largely heterogeneous in nature" with "strict inclusion/exclusion criteria; thus, these findings may not be generalizable to all depressed populations." A rate of 9% and a rate of 57% cannot both describe the same thing, so the honest reading is that the phenomenon is common and has not been counted properly. Nothing in the abstract says how often the return of symptoms is the drug fading rather than the depression coming back on its own, which is the question a person actually has.
What this does not show
It does not rank the four strategies, and it does not say which one fits any given person. Every one of them is a change to a prescription, which means every one of them is a decision for the prescriber, with the person's history in front of them. This row does not tell anyone to raise, lower, switch or stop anything.
Worth asking
Which of the four strategies are you thinking of, and what is the evidence for it in someone like me?
Source
Tachyphylaxis in major depressive disorder: A review of the current state of research — Kinrys G, Gold AK, Pisano VD, Freeman MP, Papakostas GI, Mischoulon D, Nierenberg AA, Fava M (2019)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1016/j.jad.2018.10.357
DOI: 10.1016/j.jad.2018.10.357
How this was scored
- Study design
- Narrative review
- Funding
- Funding not disclosed
- Published in
- Reputable peer-reviewed journal
- Sample size
- not recorded
- 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 "contested". Weak or heavily disputed. Treat as a question, not an answer. It scores 33 out of 100 on our published rubric. One caveat travels with that badge: A narrative review of heterogeneous studies with strict inclusion criteria; the authors say the findings may not generalise. The 9%-to-57% range is a definition problem as much as a measurement. The abstract does not separate drug tolerance from natural recurrence, and none of the four strategies is established. 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 in major depressive disorder: A review of the current state of research — Kinrys G, Gold AK, Pisano VD, Freeman MP, Papakostas GI, Mischoulon D, Nierenberg AA, Fava M (2019). Published in: Reputable peer-reviewed journal. DOI: 10.1016/j.jad.2018.10.357. 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: Narrative review. 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.