The 2003 hypothesis that long-term antidepressants could worsen the course, stated by its author as untested
Fava reviewed reports of tolerance, resistance on rechallenge and withdrawal, and proposed the oppositional model: the body pushes back against the drug, the effect fades, and stopping leaves the pushback running. He calls it untested.
Weak or heavily disputed. Treat as a question, not an answer. how we score evidence
Caveat on this rating: A single-author literature review proposing a hypothesis its author says is untested and hard to test. The rechallenge and paradoxical effects are reported 'in a few patients' and 'in susceptible individuals', not measured as rates. The same abstract calls antidepressants crucial for major depressive episodes.
The most-cited argument that the drug itself can be part of the problem, carried here with its author's own caveats intact.
Significant findings
Fava's 2003 review opens by saying the possibility "that antidepressant drugs, while effectively treating depression, may worsen its course has received inadequate attention." He searched MEDLINE under tolerance, sensitization, antidepressive agents and switching, and pulled together reports of paradoxical effects.
The findings he lists: "very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation."
His explanation is the oppositional model of tolerance: "Continued drug treatment may recruit processes that oppose the initial acute effects of a drug and may result in loss of clinical effect. When drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse."
The other direction
The author is the first to say what this is. "The possibility that antidepressant drugs may worsen the course of depression needs to be tested, even though its scientific exploration is likely to encounter considerable methodological and ideological difficulties." He also writes, in the same abstract: "Antidepressant drugs are crucial in the treatment of major depressive episodes." The effects he describes occur "in susceptible individuals," and the rechallenge resistance is "in a few patients." It is a hypothesis built from reported findings, not a measured rate.
What this does not show
It does not measure how many people the model applies to, and it cannot tell any one person whether it applies to them. It is not evidence that anyone should stop a drug, and reading it that way inverts the author's own conclusion, which is that understanding paradoxical effects "may lead to more effective use of the drugs."
Worth asking
If we ever change or stop this drug, what does the plan for the weeks afterward look like?
Source
Can long-term treatment with antidepressant drugs worsen the course of depression? — Fava GA (2003)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.4088/jcp.v64n0204
DOI: 10.4088/jcp.v64n0204
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 single-author literature review proposing a hypothesis its author says is untested and hard to test. The rechallenge and paradoxical effects are reported 'in a few patients' and 'in susceptible individuals', not measured as rates. The same abstract calls antidepressants crucial for major depressive episodes. 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?
Can long-term treatment with antidepressant drugs worsen the course of depression? — Fava GA (2003). Published in: Reputable peer-reviewed journal. DOI: 10.4088/jcp.v64n0204. 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.