The paper

Methods

Everything below was fixed in a registered plan before any comparison between arms was computed. The plan, its codebooks, both codings and the registered code are under plan/; the one addition since is listed in deviations.json.

The question. The FDA pooled 372 placebo-controlled trials of antidepressants in adults. For suicidal behaviour (completed suicide, attempts or preparatory acts) it reported odds ratios of 2.30 under age 25, 0.87 at 25 to 64, and 0.06 at 65 or over, declining by 4.6% per year of age (Stone et al. (2009)). In 24 pediatric trials, suicidality had a risk ratio of 1.95 (Hammad et al. (2006)).

Re-analyses of FDA summary data on newer antidepressants disagree about adults:

• Hengartner and Plöderl (2019) found an odds ratio of 2.38 for suicide attempts.
• Kaminski and Bschor (2020), analysing the same data by Mantel–Haenszel, found 1.63.
• Hayes et al. (2019) found no statistical evidence of increased suicide.
• Khan et al. (2018), counting patient-years of exposure, found no difference.

All of these rest on data sponsors submitted to the FDA, mostly before 2008. ClinicalTrials.gov has since received the results of trials of drugs regulated in the United States. Those results include every serious adverse event (one that results in death, is life-threatening, or requires or prolongs hospitalization), by arm and by MedDRA term, whether or not the trial was published; publications often report these events incompletely (Tang et al. (2015)).

Data. We searched ClinicalTrials.gov's API (version 2.0.5, data as of 2026-10-09) on 2026-10-13. The 39 antidepressant names in data/search.json found 932 interventional studies with posted results, whose records are in data/ctgov/ as returned.

Eligibility. The code kept randomized parallel or factorial trials with at least two adverse-event groups (639 of 932). Two coders then read each trial's titles, conditions, eligible ages, arms and adverse-event groups, without counts. Under a codebook they decided:

• which groups compare an antidepressant with placebo with nothing else different (pooling doses and antidepressants, and marking combination products);
• the design: randomized from the start ("acute"), randomized withdrawal, or other;
• and the indication: depressive, other psychiatric, or non-psychiatric.

The coders agreed on eligibility for 635 of 639 trials (Cohen's kappa 0.987) and on identical comparisons for 395 of the 398 both accepted. A third reader decided the 11 trials on which they differed. The code took each trial's age group from its eligible ages and its mean age from the posted baseline age. It took the completion date from the record.

Outcomes. Two coders assigned each of 4,029 distinct adverse-event terms, under a second codebook, to:

• suicidal behaviour (completed suicide, suicide attempt, intentional self-harm, intentional overdose);
• suicidal ideation;
• completed suicide;
• overdose of unstated intent;
• or nausea.

They gave identical outcome sets to 4,028 terms (kappa 0.995), and a third reader decided 10 terms. All coders and readers were separate instances of Claude Opus 5.5, each working alone.

Suicidal outcomes are counted from the serious-event tables, which list every serious event. Nausea is counted from the non-serious tables, only in comparisons that list it, since those tables omit terms below a frequency threshold. An outcome's count in an arm is the sum over its terms of participants affected, capped at those at risk.

Analyses. The co-primary analyses cover adult trials randomized from the start (minimum eligible age 18) and exclude combination products:

• P1, serious suicidal behaviour;
• P2, any serious suicidality (behaviour or ideation).

The estimate for each is the Mantel–Haenszel risk ratio across comparisons, with the variance of Greenland and Robins (1985), a 95% confidence interval and a two-sided Wald test. The two co-primary p-values are adjusted by Holm's method.

The 19 registered secondary analyses are adjusted by the method of Benjamini and Hochberg (1995). They cover:

• ideation alone, completed suicide, and behaviour counting overdoses of unstated intent;
• indication;
• trials enrolling only people aged 60 or over;
• trials completed after 2017;
• drug class (SSRIs; SNRIs; bupropion; esketamine, zuranolone, brexanolone and dextromethorphan–bupropion; tricyclics, MAOIs and other monoaminergic drugs);
• combination products included;
• randomized-withdrawal trials;
• pediatric trials (behaviour; any suicidality);
• and trials spanning adolescents and adults.

An analysis with fewer than 10 participants affected is reported but not tested.

Every tested analysis is also estimated:

• by Peto's odds ratio (Yusuf et al. (1985));
• by random effects (DerSimonian and Laird (1986), with 0.5 added to every cell of a comparison with a zero cell);
• with a conservative variance allowing for participants counted twice;
• by its most frequent preferred term alone;
• with each trial left out;
• and in two halves of the trials, paired by size and drawn by a seeded generator.

The registered rule calls an estimate robust when p < 0.05 holds in the main analysis, with the conservative variance, under random effects, and with every trial left out.

Two analyses relate effect to age. They regress each comparison's Peto log odds ratio on the trial's mean age, weighted by Peto's variance, across all acute comparisons with events. Each estimate is set against the earlier estimates the plan named for it.

Software. The analysis runs in Python 3.12 with NumPy 2.5.3 and SciPy 1.18.1 in seconds. A second script rounds its outputs. results/analyses.csv lists every registered analysis, and results/comparisons.csv every comparison's counts.

Results

Trials. Of 932 studies found, 639 passed the structural filter and 393 compared an antidepressant with placebo, in 413 comparisons with 99730 participants: 56808 on antidepressants and 42922 on placebo, since many trials randomized several doses or drugs against one placebo group. The co-primary analyses cover 306 adult trials randomized from the start, with 322 comparisons and 71643 participants (40564 on antidepressants, 31079 on placebo; median trial mean age 44.4 years). 34345 of them were in trials of depressive disorders.

Check of the data. Nausea, listed in 207 adult comparisons, affected 6100 of 33497 participants on antidepressants and 2057 of 24083 on placebo (risk ratio 2.08, 1.98 to 2.18), as expected.

Serious suicidal behaviour (P1). Serious suicidal behaviour affected 46 of 40564 participants on antidepressants and 19 of 31079 on placebo, in 43 comparisons with events. The risk ratio was 1.86 (1.06 to 3.27; p 0.030; Holm-adjusted p 0.060). The sensitivity analyses gave:

• Peto's odds ratio: 1.76 (1.06 to 2.91);
• the conservative variance: p 0.044;
• with each trial left out: estimates from 1.76 to 2.08, the largest p being 0.051;
• random effects: 1.22 (0.78 to 1.9; p 0.38).

The halves of the trials gave 1.09 (0.48 to 2.52) and 2.79 (1.26 to 6.19). The most frequent term, Suicide attempt, gave 1.59 alone (0.79 to 3.2). By the registered rule the estimate is not robust.

Any serious suicidality (P2). Any serious suicidality affected 82 participants on antidepressants and 43 on placebo (risk ratio 1.48, 1.01 to 2.18; p 0.045; Holm-adjusted p 0.060). Peto's odds ratio was 1.45, random effects gave 1.1 (0.78 to 1.55), and the conservative variance p 0.075. The halves gave 1.01 and 1.94.

Against earlier estimates. The interval for serious suicidal behaviour lies above the FDA's estimate for middle-aged adults (0.87). It contains the re-analyses' estimates for suicide attempts, 2.38 and 1.63. The interval for any serious suicidality lies above the FDA's suicidality estimate for that age range (0.79). Computed before registration, blind to arm, the co-primary behaviour analysis had power 0.93 to detect the larger re-analysis estimate and 0.5 to detect the smaller.

Secondary analyses. Table 1 shows the tested secondary analyses. None reached the registered false discovery threshold. Too few events remained to test:

• bupropion (2 against 4);
• tricyclic, MAOI and other monoaminergic drugs (4 against 4);
• other psychiatric indications (4 against 5);
• non-psychiatric indications (5 against 2);
• completed suicide;
• randomized-withdrawal trials;
• trials of older adults;
• and trials spanning adolescents and adults.

Table 1. Tested secondary analyses: participants affected on antidepressants and placebo, risk ratio (confidence interval), p, and Benjamini–Hochberg q.

Pediatric trials. The 30 pediatric trials had 7094 participants, with a median trial mean age of 13.5 years. Their interval for any serious suicidality contains the FDA's pediatric estimate (1.95).

Age. Across 51 comparisons with suicidal behaviour and a known mean age, the odds ratio changed by 1.5% per year of mean age (-1.9% to 5.1%; p 0.38). Across 73 comparisons with any suicidality, it changed by -1.3% (-3.5% to 1.1%; p 0.28).

All serious events and death. Any serious adverse event affected 913 participants on antidepressants and 743 on placebo (1.09, 1 to 1.19). Death from any cause, in 121 comparisons that reported it for every group, affected 159 against 136 (1.17, 0.98 to 1.39).

Discussion

These trials are independent of the data behind the FDA's analyses and their re-analyses: they posted results after 2008, and the posting covers every serious adverse event. In them, serious suicidal behaviour in adults was more frequent on antidepressants by a ratio close to the re-analyses' estimates for suicide attempts (2.38 by Hengartner and Plöderl (2019), 1.63 by Kaminski and Bschor (2020)). That ratio sits above the FDA's estimate for adults aged 25 to 64 (Stone et al. (2009)). The evidence is not strong enough to settle the dispute, for three reasons:

• the increase does not survive the registered correction for testing two endpoints;
• random effects shrink it toward one;
• and the two halves of the trials disagree.

What the data add is an independent estimate that leans the same way as the re-analyses, and an interval that sits above the FDA's estimate for middle-aged adults.

Three readings remain open:

1. A real but modest increase. The crude rates were 11.3 and 6.1 serious suicidal events per 10,000 adults on antidepressants and placebo, over the weeks these trials last. That would be consistent with the activation or akathisia some patients experience early in treatment.
2. Unequal observation. Placebo groups in antidepressant trials often lose more participants to lack of efficacy. If a trial records adverse events only while participants take study medication, the antidepressant groups are watched longer and accumulate more events of every kind. The small excess of all serious adverse events (1.09) is consistent with some such imbalance. It is far smaller than the excess for suicidal behaviour, but posted results give no person-time to correct it, unlike the patient-year analysis of FDA data by Khan et al. (2018).
3. Chance. The estimate rests on few events, and the halves differ.

Posted person-time, or individual participant data from the larger programmes, would tell the first two apart.

In pediatric trials, any serious suicidality was higher on antidepressants, close to the FDA's 2006 estimate (Hammad et al. (2006)), in trials that largely postdate that analysis. The warning for young people rested on that estimate, and these data agree with it, though not after correction across the secondary analyses. Serious suicidal behaviour alone did not differ in these trials, so the pediatric difference lies mostly in serious ideation.

Several things are not supported by these data:

• An age gradient. The FDA found the risk falling with each participant's age. These trials show no such trend in their mean ages. A trial's mean age poorly stands in for its participants' ages, and adult trials cluster in middle age, so this is not evidence against the FDA's participant-level gradient.
• Differences between drug classes. The class estimates rest on few events each, so none can be ranked.
• A conclusion about completed suicide, of which there were 7.
• Advice to individual patients. Effects on suicidal behaviour in short trials are not a measure of antidepressants' net effect on suicide, which also depends on their benefit for depression. Nothing here shows that people taking an antidepressant should stop it; stopping abruptly carries its own risks.

A larger registry analysis, with person-time, would narrow this interval. It should combine ClinicalTrials.gov with the European and other registries that post results, and add trials completed after 2026.

Limitations

• Serious events only. Only serious adverse events are counted. Suicidal ideation that never needed hospital care is not captured, so the outcome is serious suicidality, not all suicidality.
• Few events. Serious suicidal events are rare in trials lasting weeks: tens of events in each analysis, so the intervals are wide.
• No person-time. Posted results give participants at risk but not the time each was observed. Differential dropout and on-treatment reporting could bias the comparison, as the Discussion says.
• Event classification. Adverse-event terms are recorded by investigators and not adjudicated, and trials differ in what they call serious and in how they ask about suicidality.
• Trials included. Trials excluded people at high risk of suicide, except the esketamine trials that enrolled them. Only trials with posted results on ClinicalTrials.gov are included, and many older and non-US trials are missing.
• Age. Age enters only at the level of the trial (its eligible ages and its mean age), never the participant's.
• Pooling. Comparisons pool doses and, in some trials, more than one antidepressant. A combination product enters only one sensitivity analysis.
• Coders. The coders, the third readers and the author are models of one family. They worked blind to the counts, but share whatever priors that family holds.
• Earlier estimates. Risk ratios here are compared with odds ratios from earlier analyses, which is reasonable for events this rare.

Provenance

A person asked for a new study outside mathematics that could matter. The agent, a Claude-family model (claude-opus-5-5), proposed this one with two alternatives; the person chose it and approved registering the plan. The agent designed the study, searched ClinicalTrials.gov, wrote both codebooks, the plan and the code, and registered the plan. Separate instances of the same model screened the trials and coded the terms, two working independently and a third deciding where they differed. The agent then ran the analysis, wrote the claims and this paper, and applied the hazard screen. The data are the ClinicalTrials.gov records retrieved on 2026-10-13, carried unchanged in data/ctgov/. No person wrote, coded, analysed or reviewed any part of the work.