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Ketamine relieves depression within a day, but patients feel its psychoactive effects, so its benefit could depend on that experience. We asked whether ketamine and esketamine lower depressive symptoms when every dose is given under general anesthesia. Under a registered plan, we coded randomized trials' dosing from their Methods alone and pooled effects (Hedges' g) one to three days after surgery or childbirth. In 23 masked trials (3202 participants), depressive symptoms were lower with the drug than with an inert control (g -0.61, confidence interval -0.81 to -0.4; Holm-adjusted p < 0.001), though trials varied widely. Across trials in surgery, awake dosing did not show a larger effect (difference 0.12, -0.24 to 0.48), but this compares trials, and the one trial that randomized timing favored awake dosing. Masked doses also lowered pain. Ketamine can lower depressive symptoms after surgery without reaching an awake patient; whether experiencing the drug adds to that, these trials can't say. This version corrects counts, checks, and a reading that the first version's reviews found wrong.

• Published, Reproduced.Published, Reproduced: In 23 randomized trials (3,202 participants) that gave every dose of ketamine or esketamine under general anesthesia, between its induction and the end of surgery or cesarean delivery, depressive symptoms 1 to 3 days after the procedure were lower than with an inert control (Hedges' g −0.61, 95% CI −0.81 to −0.40; Holm-adjusted p < 0.001), though the trials varied widely (95% prediction interval −1.51 to 0.29). The difference remained among the 17 of these trials that passed the pre-registered integrity screen (g −0.48, −0.63 to −0.33), among the 13 whose last dose is known to have ended more than 30 minutes before the end of surgery (g −0.67, −1.04 to −0.30), among the 19 whose doses all began after induction rather than with it (g −0.60, −0.85 to −0.36), and with any single trial left out (largest p < 0.001).
• Published, Reproduced.Published, Reproduced: Among trials in surgery (37 comparisons: 22 masked, 15 with some dosing while patients were awake), trials that dosed patients while they were awake did not show a larger effect on depressive symptoms 1 to 3 days after surgery than masked trials: allowing for trials that enrolled only depressed patients, the coefficient of awake dosing in a meta-regression across trials was +0.12 (95% CI −0.24 to 0.48; p = 0.51), and the pooled effects in surgery were g −0.62 with masked and −0.45 with awake dosing. The comparison is between trials, which also differ in drug, dose, procedure, and patients, not between patients randomized to one timing or the other.
• Published, Reproduced.Published, Reproduced: The masked doses were pharmacologically active: masked ketamine lowered pain scores on day 1 or 2 after the procedure (g −0.55, 95% CI −0.97 to −0.14; 22 trials; g −0.38, −0.54 to −0.22 without the one trial whose printed dispersions can't be standard deviations), as awake ketamine did (g −0.33, −0.54 to −0.11; 32 trials; awake minus masked in surgery +0.32, −0.21 to 0.86). Masked ketamine still raised the odds of each trial's most frequent psychotomimetic adverse event (Mantel–Haenszel odds ratio 2.11, 1.48 to 2.99, in 22 trials), and awake ketamine raised them more (3.63, 2.97 to 4.43, in 40 trials): p = 0.0083 for the difference in the registered comparison, and p = 0.21 when the odds ratio may vary between trials (ratio of odds ratios 1.69, 0.74 to 3.84).

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Whether antidepressants raise suicidal behaviour in adults is disputed: the FDA's pooled trials found no increase past young adulthood, and re-analyses of approval data on newer drugs found more suicide attempts. We tested this in the serious adverse events placebo-controlled trials posted to ClinicalTrials.gov, under a registered plan. This version corrects the first, which counted a participant listed under two of an outcome's terms twice. With the posted tables and the trials' public reports, serious suicidal behaviour affected 43 adults on antidepressants and 17 to 18 on placebo (risk ratio 1.86 to 1.96): nominally significant, but at the least favourable count not after the registered correction for two endpoints. Without the trials the re-analyses also used, the excess is similar but less certain. Pediatric trials showed more serious suicidality on antidepressants, as the FDA found. These data lean toward more suicidal behaviour in adults but cannot establish it.

• Published, Reproduced.Published, Reproduced: Of the 932 interventional studies naming an antidepressant with results posted on ClinicalTrials.gov on 2026-10-13, 393 randomized trials compare an antidepressant with placebo in 413 comparisons with 99,730 participants at risk in their adverse-event tables. In the 306 adult trials that randomized participants from the start (71,643 participants), nausea is more frequent on antidepressants in the 207 comparisons whose non-serious tables list it (57,580 participants; Mantel-Haenszel risk ratio 2.08, 95% CI 1.98 to 2.18), as these drugs' known side effects predict.
• Published, Reproduced.Published, Reproduced: In those adult trials, the posted tables bound the participants with serious suicidal behaviour (completed suicide, suicide attempt, intentional self-harm or intentional overdose) at 43 to 46 of 40,564 on antidepressants and 16 to 19 of 31,079 on placebo, and those with any serious suicidality at 71 to 81 against 36 to 43, because a participant listed under two of an outcome's terms may be one person or two. Across every count the tables allow, the Mantel-Haenszel risk ratio is 1.76 to 2.20 for serious suicidal behaviour (p 0.0097 to 0.0502) and 1.29 to 1.73 for any serious suicidality (p 0.0078 to 0.20). At the counts least favourable to an increase neither is significant after the registered Holm correction across the two co-primary endpoints (adjusted p 0.10 and 0.20); at the most favourable both are (0.016 and 0.016).
• Published, Reproduced.Published, Reproduced: Public reports of the trials (their publications, regulators' reviews and the sponsors' documents) settle how many participants share terms in 11 of the 17 adverse-event groups the tables leave open and narrow it in 3 more. With them, serious suicidal behaviour affected 43 of 40,564 adults on antidepressants and 17 to 18 of 31,079 on placebo (Mantel-Haenszel risk ratio 1.86 to 1.96; p 0.025 to 0.036), and any serious suicidality 72 to 77 against 40 to 41 (1.38 to 1.51; p 0.041 to 0.12). After the registered Holm correction across the two, the adjusted p-values are 0.071 and 0.12 at the counts least favourable to an increase and 0.0496 for both at the most favourable.

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People with depression report that time drags, yet laboratory timing studies disagree. A temporal account of depression predicts that time is dilated within the experienced present moment (targets up to a few seconds) and accelerated beyond it. In a time production task, dilation means producing intervals that are too long and acceleration producing them too short. In a registered meta-analysis of 11 case-control production studies, re-extracted from the primary papers where possible, the depression effect was 0.4836 standardised units higher above the 3 s boundary than below it (one-sided p = 0.03380082115675086), with overproduction at short targets (g = -0.2851) and underproduction at longer ones (g = 0.1985), neither significant alone. The effect rose by 0.6302 per tenfold increase in duration. Re-extraction also showed that an earlier meta-analysis coded a 30-s production as longer than 10 min.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Across 11 case-control studies of time production in depression, the pooled standardised difference (positive = depressed participants produce shorter intervals than controls) is 0.4836 higher for target intervals above 3 s than for targets of 3 s or less (95% CI -0.0431 to 1.0103; one-sided p = 0.034), with pooled g = -0.2851 at 3 s or less (3 studies; 95% CI -0.6917 to 0.1214) and g = 0.1985 above 3 s (10 studies; 95% CI -0.1378 to 0.5348).
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Across the per-interval effects extracted from 7 primary papers (20 target intervals from 1 to 240 s), the depression effect on time production rises by 0.6302 standardised units per tenfold increase in target duration (cluster-robust SE 0.2128; one-sided p = 0.016), from overproduction at the shortest targets toward underproduction at the longest.
• Published, Reviewed.Published, Reviewed: The time production task of Kitamura and Kumar (1983) asked participants to produce 30 s, but the meta-analysis of Thones and Oberfeld (2015, Table A2) coded it as a long (over 10 min) interval, where it was the only production effect; no case-control production study of depression in that meta-analysis or since has used a target over 10 min.

The anterior insula is often proposed as a hub where time perception, interoception and graviception meet, and as the system through which depressed experience is felt as heaviness, low mood, low energy and slowing. Because the insula appears in a large share of all neuroimaging studies, co-localisation needs a base-rate control. In a registered analysis of 13459 full-text articles from NeuroQuery, we asked whether studies discussing each function, or depressive-symptom terms, report anterior-insula coordinates more often than studies on random topics. Interoception studies did (association z 10.259), but equally in the posterior insula; time perception (z {{R1.terms.time perception.anterior_insula.z}}) and vestibular studies (z -0.945) did not, so the three-way conjunction was no more selective than random term triples (percentile 0.5456). Symptom terms were not selective either (percentile 0.7064). At the resolution of literature meta-analysis, the anterior insula is not a selective meeting point for these functions.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Across 13459 NeuroQuery full-text articles with coordinates, studies that discuss time perception or vestibular processing report anterior-insula coordinates no more often than studies on random topics (anterior-insula association z 0.424 and -0.945; percentiles 0.4959 and 0.2351 among 2773 comparison terms), so the conjunction of time perception, interoception and vestibular processing in the anterior insula is not selective (minimum z -0.945, percentile 0.5456 among random term triples), even though interoception alone is strongly associated (z 10.259).
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Studies discussing fatigue, psychomotor change, sadness or mood are not selectively associated with the anterior insula: their mean association z (1.057) lies at percentile 0.7064 of random four-term sets, with fatigue negative and only sadness near the upper tail.
• Published, Reproduced.Published, Reproduced: In the same articles, interoception studies are as strongly associated with the posterior as with the anterior insula (z 10.389 vs 10.259), and vestibular studies lean posterior (anterior minus posterior z -2.366, percentile 0.0999 among random terms), so none of the three functions shows an anterior-insula preference.

An account of depression as accumulated physical load distributed across body systems predicts that each system's state tracks the symptoms it produces, that bodily measures relate to somatic symptoms beyond mood, and that socially distributed load appears somatically. We tested these predictions in a registered analysis of 14722 adults in the US National Health and Nutrition Examination Survey (NHANES), relating limitation in load-bearing tasks, slow bowel transit, body mass index (BMI), an allostatic load index and income to PHQ-9 depressive symptom items. Load-bearing limitation, BMI and allostatic load related to somatic symptoms beyond cognitive-affective ones, and more than to cognitive-affective symptoms beyond somatic ones. But the predicted system-specific pattern did not appear: load-bearing limitation tracked sleep, energy and appetite (0.2946) far more than slow transit did (0.0404). Low income related more to cognitive-affective than to somatic symptoms (difference -0.0996). Bodily load is linked to somatic depression generally, not system by system.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In 14722 NHANES 2005-2010 adults, limitation in load-bearing tasks is associated with the PHQ-9 psychomotor item more than slow bowel transit is (age-, sex- and cycle-adjusted partial Spearman 0.2038 vs 0.0296), but also with the sleep, energy and appetite items more than slow transit is (0.2946 vs 0.0404; difference -0.2542, 95% CI -0.2762 to -0.2312), so the predicted double dissociation between a structural and a transport system does not appear.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In the same adults, load-bearing limitation, body mass index and a nine-marker allostatic load index are each associated with somatic depressive symptoms after adjusting for cognitive-affective symptoms (partial Spearman 0.1916, 0.0558, 0.08) and more strongly than with cognitive-affective symptoms after adjusting for somatic ones (differences 0.0711, 0.0399, 0.0646; Holm-adjusted p 0.002, 0.016, 0.002), whereas slow bowel transit shows no such specificity (difference 0.0074, 95% CI -0.0209 to 0.0347).
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Lower family income relates more to cognitive-affective than to somatic depressive symptoms in these adults (partial Spearman 0.1275 vs 0.0279; difference -0.0996, 95% CI -0.1299 to -0.0695), opposite to the prediction that socially distributed load expresses itself somatically.