Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial
Open accessAbstract
Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample.Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion.Results Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point.Conclusions This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Psychedelics have broad therapeutic potential, demonstrating efficacy for treating depression, PTSD, anxiety disorders, substance abuse disorder, and alcohol use disorder, among others.
“they also appear to have broad therapeutic potential, demonstrating efficacy for treating depression, post-traumatic stress disorder (PTSD), anxiety disorders, substance abuse disorder, and alcohol use disorder, among others”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [170]
The Results > Efficacy section reports that ketamine reduced depressive symptoms versus placebo in patients with bipolar depression. The paper does not establish efficacy for PTSD, anxiety disorders, substance abuse disorder, or alcohol use disorder; its Methods and Materials section excludes recent substance abuse or dependence. The finding for depression therefore supports only part of the broad therapeutic-efficacy claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPsychoplastogens have demonstrated efficacy across a range of neuropsychiatric disorders including depression, PTSD, and addiction.
“these medicines have demonstrated efficacy across a range of neuropsychiatric disorders including depression, PTSD, and addiction (156, 168–172)”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [170]
The Results > Efficacy section reports that ketamine reduced depressive symptoms versus placebo in patients with bipolar depression. This supports the depression portion of the claim, but the paper does not establish efficacy for PTSD or addiction, or for psychoplastogens as a class. No page number is available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredKetamine reduced suicidal ideation within 1-4 hours in bipolar disorder.
“Ketamine, an NMDA glutamate receptor antagonist, reduced suicidal ideation within 1–4 hours in major depression(71–75) and bipolar disorder.(76, 77)”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [76]
Ketamine's strong antidepressant effects were later confirmed in treatment-resistant depression and bipolar disorder.
“Shortly thereafter, ketamine's robust antidepressant effects were confirmed in treatmentresistant depression (TRD) and bipolar disorder (BD) [5][6][7]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [6]
Intravenous ketamine has rapid onset of efficacy.
“Intravenous ketamine (level 3)477, 478 has rapid onset of efficacy”
Results in bipolar disorder support two previous small studies.
“Results in bipolar disorder—a disorder associated with a high suicidal risk and limited options to treat depression27—are highly encouraging and support two previous small studies.8 28”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [28]
Ketamine exerts antidepressant actions in patients with bipolar depression with a similar response rate.
“In addition to the therapeutic effects of ketamine in major depressed patients, ketamine exerts antidepressant actions in patients suffering with bipolar depression, with a similar response rate 20, 21.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [21]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 44 · Cited by 811
Research works printed but not linked: 1
- [32]First MB Spitzer RL Gibbon M Williams AR Structured Clinical Interview for DSM-IV TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) 2001 New York New York State Psychiatric Institute, Biometrics Research
- Authors
- Zarate, C. A., Brutsche, N. E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N., Cravchik, A., Selter, J., Marquardt, C. A., Liberty, V., & Luckenbaugh, D. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Zarate, Carlos A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 71
- Issue
- 11
- Pages
- 939-946
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3343177
- OpenAlex
- W2157040702
- Cited by
- 811
- References
- 44
- Citations by year
- 2026: 13 · 2025: 39 · 2024: 33 · 2023: 48 · 2022: 58 · 2021: 82 · 2020: 71 · 2019: 49 · 2018: 57 · 2017: 50 · 2016: 72 · 2015: 82 · 2014: 75 · 2013: 51 · 2012: 29
- FWCI
- 55.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002857)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, bipolar depression, rapid antidepressant response, NMDA receptor antagonists, suicidal ideation, treatment-resistant depression, intravenous infusion, replication, lithium, valproic acid
- MeSH terms
- Adult, Bipolar Disorder, Depression, Double-Blind Method, Female, Humans, Infusions, Intravenous, Ketamine, Male, Middle Aged, Treatment Outcome, Cross-Over Studies, Excitatory Amino Acid Antagonists, Suicidal Ideation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
