[
 {
  "local_id": "C1",
  "type": "empirical",
  "core": true,
  "statement": "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).",
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    "result": "R1.k",
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    "result": "R1.n",
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   {
    "result": "R1.loo_max_p_text",
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   {
    "result": "R5.P1.trustworthy.k",
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   {
    "result": "R5.P1.trustworthy.g",
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   {
    "result": "R5.P1.trustworthy.lower",
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   {
    "result": "R5.P1.trustworthy.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
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   {
    "result": "R5.P1.strict_masking.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R5.P1.strict_masking.g",
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   {
    "result": "R5.P1.strict_masking.lower",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
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   {
    "result": "R5.P1.strict_masking.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
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   {
    "result": "R5.P1.after_induction.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R5.P1.after_induction.g",
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   {
    "result": "R5.P1.after_induction.lower",
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   {
    "result": "R5.P1.after_induction.upper",
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  ],
  "depends_on": [],
  "falsified_if": "A re-run of the analysis on the bundle's data gives a 95% CI for the masked effect that includes 0, overall, among trustworthy trials, with strict masking, or among trials whose doses all began after induction; or a re-extraction from the trials' sources moves these estimates by more than their stated precision.",
  "confidence": 0.8
 },
 {
  "local_id": "C2",
  "type": "negative_result",
  "core": true,
  "statement": "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.",
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   {
    "result": "R2.k",
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   {
    "result": "R2.masked.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R2.awake.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R2.g",
    "produced_by": "code/analyze.R",
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   },
   {
    "result": "R2.lower",
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   },
   {
    "result": "R2.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
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   {
    "result": "R2.p_text",
    "produced_by": "code/analyze.R"
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   {
    "result": "R2.masked.g",
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   {
    "result": "R2.awake.g",
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  ],
  "depends_on": [],
  "falsified_if": "A re-run gives a 95% CI for the coefficient of awake dosing that lies wholly below 0, or a re-extraction from the trials' sources moves it by more than its stated precision.",
  "confidence": 0.7
 },
 {
  "local_id": "C3",
  "type": "empirical",
  "core": false,
  "statement": "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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   {
    "result": "R3.masked.g",
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    "tolerance": 0.01
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   {
    "result": "R3.masked.lower",
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   {
    "result": "R3.masked.upper",
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   {
    "result": "R3.masked.k",
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   {
    "result": "R3.dispersions_trusted.masked.g",
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   {
    "result": "R3.dispersions_trusted.masked.lower",
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   {
    "result": "R3.dispersions_trusted.masked.upper",
    "produced_by": "code/analyze.R",
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   {
    "result": "R3.awake.g",
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   {
    "result": "R3.awake.lower",
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   {
    "result": "R3.awake.upper",
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   {
    "result": "R3.awake.k",
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   {
    "result": "R3.difference.g",
    "produced_by": "code/analyze.R",
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   {
    "result": "R3.difference.lower",
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   },
   {
    "result": "R3.difference.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.masked.or",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.masked.lower",
    "produced_by": "code/analyze.R",
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   },
   {
    "result": "R4.masked.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.masked.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R4.awake.or",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.awake.lower",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.awake.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.awake.k",
    "produced_by": "code/analyze.R"
   },
   {
    "result": "R4.p_difference_text",
    "produced_by": "code/analyze.R"
   },
   {
    "result": "R4.random_effects.p_text",
    "produced_by": "code/analyze.R"
   },
   {
    "result": "R4.random_effects.ratio_awake_to_masked",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R4.random_effects.lower",
    "produced_by": "code/analyze.R",
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   {
    "result": "R4.random_effects.upper",
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  ],
  "depends_on": [],
  "falsified_if": "A re-run gives a 95% CI for the masked pain effect that includes 0, with or without that trial, or a registered Mantel–Haenszel comparison of the psychotomimetic odds ratios whose p is 0.05 or more.",
  "confidence": 0.75
 },
 {
  "local_id": "C4",
  "type": "empirical",
  "core": false,
  "statement": "The masked effect was also present in the 7 masked trials that enrolled only patients with depression or depressive symptoms (g −0.78, 95% CI −1.24 to −0.31), and later after the procedure: on days 4 to 14 (g −0.51, −0.90 to −0.13; 18 trials) and days 15 to 90 (g −0.54, −0.75 to −0.33; 11 trials). Among the masked trials whose doses all began after induction, the days 4 to 14 interval included zero (g −0.61, −1.33 to 0.12; 10 trials).",
  "evidence": [
   {
    "result": "R5.P1.selected_only.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R5.P1.selected_only.g",
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   {
    "result": "R5.P1.selected_only.lower",
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   {
    "result": "R5.P1.selected_only.upper",
    "produced_by": "code/analyze.R",
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   {
    "result": "R6.P1.middle.g",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R6.P1.middle.lower",
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   {
    "result": "R6.P1.middle.upper",
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   {
    "result": "R6.P1.middle.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R6.P1.late.g",
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   },
   {
    "result": "R6.P1.late.lower",
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    "tolerance": 0.01
   },
   {
    "result": "R6.P1.late.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
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   {
    "result": "R6.P1.late.k",
    "produced_by": "code/analyze.R"
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   {
    "result": "R6.P1.middle_after_induction.g",
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    "tolerance": 0.01
   },
   {
    "result": "R6.P1.middle_after_induction.lower",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R6.P1.middle_after_induction.upper",
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    "tolerance": 0.01
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   {
    "result": "R6.P1.middle_after_induction.k",
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  ],
  "depends_on": [],
  "falsified_if": "A re-run gives a 95% CI that includes 0 for the depressed-only masked trials or for either later window.",
  "confidence": 0.7
 },
 {
  "local_id": "C5",
  "type": "empirical",
  "core": false,
  "statement": "In the only trial the search found that randomized when esketamine was given (77 participants analysed in its two esketamine arms), those given it two hours before induction of anesthesia, while awake, had fewer depressive symptoms (PHQ-9) on the first day after surgery than those given it after induction (g −0.72, 95% CI −1.18 to −0.26).",
  "evidence": [
   {
    "result": "R8.within_trial.T097.n",
    "produced_by": "code/analyze.R"
   },
   {
    "result": "R8.within_trial.T097.g",
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    "tolerance": 0.01
   },
   {
    "result": "R8.within_trial.T097.lower",
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    "tolerance": 0.01
   },
   {
    "result": "R8.within_trial.T097.upper",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   }
  ],
  "depends_on": [],
  "falsified_if": "A re-run from the bundle's data gives a within-trial 95% CI that includes 0.",
  "confidence": 0.7
 },
 {
  "local_id": "C6",
  "type": "empirical",
  "core": false,
  "statement": "Of the 39 eligible ClinicalTrials.gov registrations whose primary completion was at least 12 months before the search, 18 (46%) had neither posted results nor a report naming them that the search found; among the masked trials Egger's test did not detect funnel-plot asymmetry (p = 0.7), and the PET estimate of the masked effect, allowing for small-study effects, was g −0.47 (95% CI −1.23 to 0.29).",
  "evidence": [
   {
    "result": "D.registry.due",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.registry.unreported",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.registry.unreported_pct",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "R7.egger_p_text",
    "produced_by": "code/analyze.R"
   },
   {
    "result": "R7.pet_peese.g",
    "produced_by": "code/analyze.R",
    "tolerance": 0.01
   },
   {
    "result": "R7.pet_peese.lower",
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    "tolerance": 0.01
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   {
    "result": "R7.pet_peese.upper",
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    "tolerance": 0.01
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  ],
  "depends_on": [],
  "falsified_if": "A search of the listed registrations finds reports or posted results that change the count, or a re-run gives an Egger p below 0.05.",
  "confidence": 0.8
 },
 {
  "local_id": "C7",
  "type": "empirical",
  "core": false,
  "statement": "Of the 51 trials with a depression effect on days 1 to 3, 19 failed the pre-registered integrity screen, which flags concerns rather than establishing errors: 11 had no trial registration that their reports gave or ClinicalTrials.gov linked to them, 5 were registered after enrollment began, 2 printed two or more depression means that whole-number scores couldn't produce at their stated sample sizes (GRIM), and 1 reported an effect beyond |g| = 2.",
  "evidence": [
   {
    "result": "D.early.trials",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.early.untrustworthy",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.early.unregistered",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.early.retrospective",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.early.grim",
    "produced_by": "code/summarize.R"
   },
   {
    "result": "D.early.implausible",
    "produced_by": "code/summarize.R"
   }
  ],
  "depends_on": [],
  "falsified_if": "A re-check of the trials' registrations, dates, or printed means against their sources finds these counts wrong.",
  "confidence": 0.85
 }
]