Most people who start an antidepressant stay on it for months, and many for years. A quarter of Americans who have taken one did so for a decade or more, according to the CDC. Yet most antidepressant trials last about eight weeks. A study published Tuesday tries to fill that gap, and it gives a useful yardstick for the question hanging over every psychedelic drug now at the FDA: how long does the relief last?
What the New Study Found
The analysis, in The Lancet Psychiatry, pooled 115 randomized trials with more than 30,000 people who stayed on an antidepressant for more than 12 weeks. First author Paul van Haaren and Professor Henricus (Eric) Ruhé of Radboud University Medical Center in the Netherlands compared 20 drugs against fluoxetine (Prozac).
- Escitalopram (Lexapro), duloxetine (Cymbalta) and agomelatine were more likely than Prozac to get people better and keep them better. Agomelatine isn't sold in the U.S. and carries a risk of liver failure.
- Bupropion (Wellbutrin) and reboxetine did worse than several other drugs.
- Among people whose depression had already improved, about 62% who kept taking their drug stayed well for six months or more, compared with about 45% switched to a placebo, The New York Times' Christina Caron reported.
The authors flag real limits: about half the trials were at high risk of bias, and there's little data beyond a year, because regulators don't require it. "Why change a winning team?" Ruhé told the Times, advising people already doing well on a drug not to switch.
The Durability Data, Side by Side
| Treatment | How it's taken | What "lasting" meant | Result | People | Status |
|---|---|---|---|---|---|
| Antidepressants overall (Lancet Psychiatry) | Daily pill | Staying well 6+ months on the drug, after improving | ~62% vs. ~45% on placebo | 115 trials, 30,000+ | Approved; mostly generic |
| Esketamine (Spravato), SUSTAIN-1 | Nasal spray in a clinic, weekly or every other week, plus a daily antidepressant | Avoiding relapse after reaching stable remission | 26.7% relapsed vs. 45.3% on placebo | 176 in remission | FDA-approved, 2019 |
| COMP360 psilocybin (Compass), COMP006 | Two doses, three weeks apart | At least a 25% symptom drop at week 6, held through week 26 | 39% of the high-dose group | 581 | NDA filed Nov. 9 |
| DT120 LSD (Definium), Emerge | One dose | Symptom gap vs. placebo at week 12 | 7.3 points better than placebo (8.1 at week 6) | 149 | Breakthrough Therapy; filing planned for H1 2027 |
| Psilocybin, Johns Hopkins | Two doses | Response and remission at 12 months | 75% response, 58% remission | 24 | Academic study; no placebo group at 12 months |
| Psilocybin (Usona), uAspire | One dose | Not yet public | Not yet public | ~240 | NDA filed, reported Nov. 2 |
Why This Isn't a Straight Comparison
The bar is different. For antidepressants and esketamine, "lasting" means staying well while still taking the drug. For psilocybin and LSD, it means staying well months after the last dose. That difference is the whole promise: one or two supervised sessions instead of a pill every day.
The evidence is uneven. The antidepressant numbers pool 115 trials. Each psychedelic has a handful, mostly with fewer than 600 people. The most striking psychedelic number, 58% remission at a year from Johns Hopkins, comes from 24 people with no placebo group at that point, and a third of them had gone back on daily antidepressants by then.
The measures aren't the same. Compass counted a 25% symptom drop as meaningful. The usual definition of "response" is 50%. On that stricter measure, LSD did better: 35% of Definium's patients responded at week 6, against 7% on placebo.
People can tell what they got. In psychedelic trials that checked, more than 90% of participants could tell whether they got the drug, which can inflate results. We covered how the FDA wants that handled in Everyone Knows Which Pill They Got.
Why It Could Still Be Revolutionary
Even with those caveats, the shape of the data is different. A daily antidepressant keeps about 62 of every 100 improved patients well, but only as long as they keep taking it, with side effects that can last years, as we laid out in The Side-Effect Math. Definium's LSD tablet was still well ahead of placebo 12 weeks after a single dose. Compass's psilocybin held for six months in 39% of its high-dose group after two.
If those results hold in larger trials, and over longer follow-up than eight-week trials or even this new analysis provide, the measure of success changes from "how long can you stay on it" to "how long do you need it." That is what the FDA is now weighing on three psychedelic applications. We track each on our trials page and laid out what happens the day after an approval in The Day After Approval.
This is journalism, not medical advice. Don't stop or switch an antidepressant without talking to your prescriber; stopping suddenly can cause withdrawal. Psilocybin and LSD are not FDA-approved for any use.
Sources
- Paul van Haaren et al., "Comparative efficacy and acceptability of antidepressants in the long-term treatment of major depressive disorder: a systematic review and network meta-analysis,"00326-3/abstract) The Lancet Psychiatry, Nov. 10, 2026
- Christina Caron, "New Research Compares Long-Term Relief From 21 Antidepressants," The New York Times, Nov. 10, 2026
- Radboud University Medical Center, "Study identifies antidepressants that get patients well and keep them well," EurekAlert!, Nov. 2026
- Ella Daly et al., "Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention" (SUSTAIN-1), JAMA Psychiatry, 2019
- Compass Pathways, "Six-Month Data from Second Phase 3 Trial," July 7, 2026
- Definium Therapeutics, "Positive Topline Results from Phase 3 Emerge Study," June 22, 2026
- Natalie Gukasyan et al., "Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up," Journal of Psychopharmacology, 2022