The 1998 review that named the problem: symptoms returned on a steady dose in 9% to 57% of patients
Byrne and Rothschild reviewed every study since 1966 and listed seven possible explanations, from the placebo effect wearing off to the depression itself worsening. Twenty years later the range and the list are unchanged.
Weak or heavily disputed. Treat as a question, not an answer. how we score evidence
Caveat on this rating: A narrative review from 1998 pooling trials with different relapse definitions; the range is as wide as the definitions. It lists seven explanations and rules none in or out, and it tests no strategy. Its call for double-blind studies has largely gone unanswered.
The paper that set the terms of the argument. The 2019 review repeats its range almost word for word.
Significant findings
Byrne and Rothschild searched MEDLINE from 1966 for studies of what they call loss of antidepressant efficacy: "Many patients with unipolar depression experience a return of depressive symptoms while taking a constant maintenance dose of an antidepressant."
The rate: "The return of depressive symptoms during maintenance antidepressant treatment has occurred in 9% to 57% of patients in published trials."
The candidate explanations, listed in the abstract: "loss of placebo effect, pharmacologic tolerance, increase in disease severity, change in disease pathogenesis, the accumulation of a detrimental metabolite, unrecognized rapid cycling, and prophylactic inefficacy." Seven possibilities, and the review does not pick one.
The conclusion: "Although several strategies have been proposed to overcome the loss of antidepressant efficacy, double-blind controlled studies are needed to ascertain the optimal strategy for this perplexing clinical problem."
The other direction
Read the list again. Three of the seven are about the illness rather than the drug: the depression getting worse, changing character, or turning out to be a cycling illness that was never recognised. Another two say the drug was never doing what it seemed to: the placebo part of the response faded, or the drug was never protective. Only one of the seven is tolerance in the pharmacological sense. A person whose symptoms return on a steady dose has no way, from this list, to know which one is theirs, and neither does the review.
What this does not show
It is a 1998 literature review, so it pools studies that used different definitions of relapse, which is why the range is so wide. It proposes no strategy and tests none. The double-blind studies it asked for are, per the 2019 review on the same shelf, still mostly missing. Nothing here is a reason to change a prescription.
Worth asking
Is this the drug fading, or the depression coming back through it, and how would we tell the difference?
Source
Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments — Byrne SE, Rothschild AJ (1998)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.4088/jcp.v59n0602
DOI: 10.4088/jcp.v59n0602
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 from 1998 pooling trials with different relapse definitions; the range is as wide as the definitions. It lists seven explanations and rules none in or out, and it tests no strategy. Its call for double-blind studies has largely gone unanswered. 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?
Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments — Byrne SE, Rothschild AJ (1998). Published in: Reputable peer-reviewed journal. DOI: 10.4088/jcp.v59n0602. 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.