Esketamine nasal spray vs placebo for MADRS change in treatment-resistant depression

Overview

Esketamine nasal spray vs placebo for MADRS change in treatment-resistant depression

In adults with treatment-resistant depression, does intranasal esketamine added to an oral antidepressant reduce the MADRS depression score versus placebo added to an oral antidepressant? (Randomized double-blind trials; mean difference in MADRS points at the ~4-week induction endpoint.)

Primary outcome

Transparency (independently checkable)

30 of 30 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Esketamine nasal spray vs placebo for depressive symptoms in treatment-resistant depression

## PICO
- **Population:** adults with treatment-resistant depression (major depressive disorder, inadequate response to ≥2 antidepressants).
- **Intervention:** intranasal esketamine, added to a newly-initiated oral antidepressant.
- **Comparator:** intranasal placebo, added to a newly-initiated oral antidepressant.
- **Primary outcome:** change from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score at ~4 weeks (mean difference in points; a lower/more-negative MADRS change = greater improvement, so a negative mean difference favours esketamine).

## Eligibility - P/I/C/design only
Include randomized controlled trials when all of the following are true:
- The population is adults with treatment-resistant depression, judged from the title or registry conditions.
- The randomized intervention is intranasal esketamine plus an oral antidepressant.
- The randomized comparator is intranasal placebo plus an oral antidepressant.
- The trial is double-blind or placebo-controlled.

Exclude records for wrong population (bipolar depression, acute suicidality/psychiatric-emergency indication where the design/estimand differs, non-TRD major depression), wrong intervention (racemic ketamine, intravenous ketamine, esketamine for anaesthesia/analgesia/sedation), wrong comparator, non-randomized design, reviews, protocol-only reports, relapse-prevention/maintenance-withdrawal designs (a different estimand), and open-label safety studies.

Eligibility is not based on whether the abstract reports the target outcome. If an otherwise eligible trial does not report the MADRS change from baseline as a per-arm mean and standard deviation (in the abstract or in eligible structured registry results), it is declared absent rather than substituted with another endpoint or timepoint or an imputed variance.

## Outcomes
Primary outcome:
- Change from baseline in MADRS total score at approximately 4 weeks (Day 28 of the double-blind induction phase), including phrasings such as MADRS, Montgomery-Asberg / Montgomery-Åsberg Depression Rating Scale, change from baseline in MADRS, and the double-blind induction endpoint.

The estimand is the mean difference (MADRS points) in the change from baseline, esketamine versus placebo, at the induction endpoint. Pooling is random-effects inverse-variance on the mean difference; a single included trial is presented as that trial's own effect, not a random-effects pool.

## Sources and verification
- Per-arm change-from-baseline mean and standard deviation are taken verbatim from the trial's primary report or its structured ClinicalTrials.gov posted results (paramType MEAN with a Standard-Deviation dispersion), never a least-squares mean with a standard error, and never imputed from a figure. The full-analysis-set (FAS/mITT) induction-endpoint values are used; a trial reporting only a least-squares-mean difference with a standard error, or only a mixed-model estimate, is declared absent rather than pooled (the reported model estimate is noted where it differs).
- The estimand is the CHANGE from baseline (not the final value); a final-value mean is not mixed with a change-from-baseline mean. All timepoints are aligned to the induction endpoint (~Day 28).
- Every pooled number is verified against the committed source span before it is pooled.

## Comparator
- Published open-access meta-analysis of intranasal esketamine for treatment-resistant depression reporting the MADRS change, for trial-set overlap and reporting comparison only. An identical estimate on an identical trial set is arithmetic, not corroboration; the overlap is stated on the page.

Search

Source status (which adapters ran)

Citation chase: RAN_OK · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: RAN_OK · PubMed: RAN_OK · Registry-first (AACT): RAN_ERROR — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

esketamine nasal spray treatment-resistant depression randomized double-blind MADRS

"esketamine"[Title] AND "treatment-resistant depression" AND placebo AND randomized

intranasal esketamine oral antidepressant treatment resistant depression randomized

ClinicalTrials.gov

{"cond": "treatment resistant depression", "intr": "esketamine"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 136 records: agreement 126/136, disagreement 7.4% (10 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-12T11:20:57Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

136 records screened; 14 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['31109201'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['29656663'] recovered by the search and correctly EXCLUDED [] by rule (same drug/design, wrong topic).

Results

Change in MADRS (primary)

k = 2: the 2 trial(s) named below were pooled; 12 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Adverse events

Comparator

Change in MADRS: 1.44 (RR), 95% CI 1.2–1.74

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 0 of 2 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 2 are pooled but have no registry match (31109201, NCT02422186) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT registry fields). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults with treatment-resistant depression, does intranasal esketamine added to an oral antidepressant reduce the MADRS depression score versus placebo added to an oral antidepressant? (Randomized double-blind trials; mean difference in MADRS points at the ~4-week induction endpoint.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 5e2b43c6f3d8); a registry-first search was screened by two independent rule screeners with adjudication (136 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave MD -4.07 (95% CI -21.22 to 13.08), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was -21.22 to 13.08. 12 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 5e2b43c6f3d8) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 2 trials gave MD -4.07 (95% CI -21.22 to 13.08), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was -21.22 to 13.08.

Risk-of-bias sensitivity. 0 of 2 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 5e2b43c6f3d8) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py esketamine-trd-madrs

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 2 vs the comparable same-scope comparator k = 4 — GAP. Comparator (Front Psychiatry 2026, PMID 42490943) acute MADRS-change-from-baseline Day-28 primary pooled 4 RCTs (N=937, MD -2.99 [-5.10,-0.88]; verified in its own results table '937 (4 RCTs)'). We pool 2 (TRANSFORM-2 flexible-dose [positive], TRANSFORM-3 elderly). The 2 gap trials (TRANSFORM-1 and the phase-2 dose-finding) are 3-arm FIXED-DOSE (56/84 mg) designs: our multi-arm continuous guard refuses per-arm extraction because we pool the approved FLEXIBLE-dose estimand, not a single fixed-dose arm. Both are in the corpus, declared-absent with reason - design/estimand exclusion, not a search miss.