CoChat
Sign Up
Cited by 108Treatment of Major DepressionElectroconvulsive Therapy StudiesTryptophan and brain disorders

Ketamine in neuropsychiatric disorders: an update

Open access
Johnston, Jenessa N., Kadriu, Bashkim, Kraus, Christoph, Henter, Ioline D., Zarate, Carlos A.·2024·Neuropsychopharmacology
DOI 10.1038/s41386-023-01632-1PMC PMC10700638
Open this paper in CoChat — free accountOpen PDF

Abstract

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of-or further research with-subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review updates the evidence for subanesthetic ketamine and esketamine across neuropsychiatric disorders, emphasizing rapid antidepressant and transdiagnostic effects alongside mechanistic and clinical-practice issues. It concludes that efficacy is broad but often supported by small or preliminary studies, with long-term safety and misuse data still limited.

Key findings

  • Subanesthetic ketamine/esketamine can produce rapid effects in depression and bipolar disorder, often within hours, peaking near 24 h and declining over 10–12 days; intranasal esketamine received FDA approval for treatment-resistant depression in 2019 and for major depression with acute suicidal ideation or behavior in 2020.
  • Real-world effectiveness estimates include a meta-analytic mean response rate of 55.3% and remission rate of 28.9%, community-practice response/remission of roughly 50%/30%, and 6-month intranasal esketamine response/remission of 47.8%/37%; a telehealth sublingual ketamine trial (n = 1247) reported PHQ-9 remission of 32.6% and GAD-7 remission of 31.3%.
  • For suicidal ideation, meta-analyses show reductions from one day up to six weeks, partly independent of mood effects; one crossover trial (n = 37) found 69% complete remission after six infusions maintained with weekly maintenance, and an emergency-department RCT (n = 18) reported 88% remission between 90 and 180 min after treatment.
  • Evidence in other conditions is mixed: a multicenter PTSD trial (n = 158) found no effect on PTSD symptoms despite reduced depressive symptoms; OCD trials are mostly positive but one open-label study (n = 10) found no OCD effect; alcohol-use trials suggest increased abstinence, while cocaine self-administration fell by 67% at 24 h but the effect faded; (R)-ketamine did not separate from placebo at 24 h in a Phase 2a trial (n = 102).

Methods

  • Narrative review synthesizing pharmacology, hypothesized mechanisms, clinical use, and recent clinical findings (2019–2023) across psychiatric disorders, with Table 1 summarizing selected studies.
  • Draws on preclinical work, meta-analyses, randomized controlled trials, open-label pilots, case series, and neuroimaging modalities including EEG, MEG, MRS, fMRI, and PET; neurological conditions such as Alzheimer’s, Huntington’s, and Parkinson’s disease are excluded.
  • No primary data collection or formal systematic meta-analysis is reported.

Limitations

  • The authors state that many trials are pilot studies or case series, often uncontrolled or with small samples, and that larger, more rigorous trials are needed; efficacy for several conditions rests on few trials and participants.
  • The authors also note high placebo response rates in depression and suicidality research, outcome measures such as MADRS being designed for longer intervals than rapid-acting effects, and scarce long-term safety, relapse, and misuse-liability data.
  • Evident from the text: as a narrative review without a systematic search or risk-of-bias assessment, study selection and synthesis may be non-exhaustive, and heterogeneity in dose, route, frequency, and formulation complicates comparisons.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41386-023-01632-1

Cites

223 of 223 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

119 of 231 cited sources checked · 53 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    In that case series, there were only minor changes in ED-related symptomology.

    “though there were only minor changes in ED-related symptomology [123]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [123] Schwartz T, Trunko ME, Feifel D, Lopez E, Peterson D, Frank GKW, et al. A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment-resistant depression. Clin Case Rep. 2021;9:e03869. source

      The Results describe mild or limited eating-disorder improvement in Cases 1 and 4, but the claim that changes were only minor across the case series conflicts with the Discussion (page unavailable). It reports robust, sustained improvements in relevant eating-disorder measures for Cases 1 and 2, and full remission of the eating disorder in Case 2. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    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]”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802. source
    • cites [6] Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939–46. source
    • cites [7] Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64. source

      The COMMENT section reports a robust antidepressant response to ketamine in treatment-resistant depression. The PATIENT SELECTION section says patients with bipolar disorder were excluded, so this paper does not support the bipolar-disorder part of the sentence. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
  • Premisecitation

    Ketamine produces an open-channel block that stops ions from passing through the NMDAR channel.

    “Ketamine then creates an open-channel block that prevents ions from traveling through the channel [17].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Huettner JE, Bean BP. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci. 1988;85:1307–11. source

      The introduction (page unavailable) identifies ketamine as an antagonist of NMDA responses, and the Discussion says it competes for the MK-801 binding site. But the Discussion's open, nonconducting channel model is for MK-801; our copy does not establish that ketamine itself produces an open-channel block that prevents ion flow. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    One trial found that remission rates after ketamine were inferior to those after ECT.

    “For instance, one trial found that remission rates post-ketamine were inferior to those post-ECT [69]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [69] Eckstrand J, Fattah C, Persson M, Cheng T, Nordanskog P, Åkeson J, et al. Racemic ketamine as an alternative to electroconvulsive therapy for unipolar depression. A randomized, open-label, non-inferiority trial (KetECT). Int J Neuropsychopharmacol. 2022;25:339–49. source
  • Premisecitation

    Both theories converge on increased AMPAR transmission downstream, activating signaling pathways thought central to ketamine's rapid effects, including BDNF expression and mTORC1 activation.

    “Both theories converge on a downstream increase in αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) transmission, which activates cellular signaling pathways proposed to be integral to ketamine's rapid-acting therapeutic effects such as increases in BDNF expression and mechanistic target of rapamycin complex 1 (mTORC1) activation [28].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801–11. source
  • May combine two claims. 76
  • Classified as probably not a substantial claim. 29
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Ketamine is metabolized within minutes to norketamine, mainly by cytochrome P450 liver enzymes.

    “Ketamine is metabolized within minutes after administration by nitrogen-mediated demethylation to norketamine, mediated primarily by cytochrome P450 liver enzymes [18,19].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [18] Desta Z, Moaddel R, Ogburn ET, Xu C, Ramamoorthy A, Venkata SL, et al. Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica. 2012;42:1076–87. source

      The Introduction identifies N-demethylation to norketamine as a major ketamine metabolic pathway, and the Results identify CYP2B6 as its primary mediator in human liver microsomes. The cited passages do not establish that this conversion occurs within minutes after administration; the clinical observations concern later sampling times. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] Rao LK, Flaker AM, Friedel CC, Kharasch ED. Role of cytochrome P4502B6 polymorphisms in ketamine metabolism and clearance. Anesthesiology. 2016;125:1103–12. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Long-term unregulated ketamine use has been reported to cause ulcerative cystitis and memory impairment, although dependence rates among recreational users are relatively low.

    “While dependence rates are relatively low amongst recreational users, long-term unregulated use has been reported to lead to issues such as ulcerative cystitis and memory impairment [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A review of ketamine abuse and diversion. Depress Anxiety. 2016;33:718–27. source

  • May combine two claims.

    Premisecitation

    Ketamine is effective for treatment-refractory symptoms including suicidality, anxiety, and anhedonia, and it affects motivation-related functional circuits.

    “ketamine has been found to be effective for traditionally treatment-refractory symptoms such as suicidality, anxiety, and anhedonia, and to impact functional circuitries related to motivation [8,9].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Monteggia LM, Zarate CAJ. Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol. 2015;30:139–43. source

      The Introduction (page not supplied) reports a rapid antidepressant response in treatment-resistant depression and rapid antisuicidal effects. It does not report efficacy for anxiety or anhedonia, or an effect on motivation-related functional circuits. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Mkrtchian A, Evans JW, Kraus C, Yuan P, Kadriu B, Nugent AC, et al. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol Psychiatry. 2021;26:3292–301. source

      The Introduction describes anhedonia as a treatment-resistant depressive symptom that ketamine can improve. The Discussion reports improved anhedonia and altered fronto-striatal connectivity after ketamine in participants with treatment-resistant depression. Our copy does not establish ketamine’s effectiveness for suicidality or anxiety, so those parts of the attributed claim are unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    After an acute ketamine dose, antidepressant effects usually begin within hours, peak near 24 hours, and then decline over about 10 to 12 days.

    “The antidepressant effects of an acute dose of ketamine are typically thought to occur within hours, peak around 24 h then gradually decline over a period of 10-12 days [10].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46:1459–72. source

  • May combine two claims.

    Premisecitation

    A randomized controlled trial of 154 participants with treatment-resistant depression found that acute ketamine (0.5 mg/kg) plus automated self-association training over four days significantly reduced depression scores over 30 days, whereas ketamine plus sham training showed increasing scores over 30 days.

    “A large, randomized, controlled trial of 154 participants with TRD found that those who received an acute dose of ketamine (0.5 mg/kg) in conjunction with “automated selfassociation training” (ASAT) over four days had significantly reduced depression scores over a 30-day period; in contrast, the scores of those who received ketamine and a sham ASAT steadily increased over 30 days [56].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] Price RB, Spotts C, Panny B, Griffo A, Degutis M, Cruz N, et al. A novel, brief, fully automated intervention to extend the antidepressant effect of a single ketamine infusion: a randomized clinical trial. Am J Psychiatry. 2022;179:959–68. source

  • May combine two claims.

    Premisecitation

    A large open-label effectiveness trial (n=1247) found that sublingual ketamine monitored via telehealth was safe and effective for anxiety and depression, with 32.6% and 31.3% of participants remitted on PHQ-9 and GAD-7, respectively.

    “a recent, large, open-label effectiveness trial (n = 1247) found that sublingual ketamine monitored over telehealth applications was safe and effective for treating the symptoms of anxiety and depression [66]; 32.6% and 31.3% of participants were classified as remitted on the Patient Health Questionnaire 9 (PHQ-9) and the Generalized Anxiety Disorder 7-item Checklist (GAD-7), respectively.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [66] Hull TD, Malgaroli M, Gazzaley A, Akiki TJ, Madan A, Vando L, et al. At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: findings from a large, prospective, open-label effectiveness trial. J Affect Disord. 2022;314:59–67. source

      The Patients section reports 1,247 participants with sufficient follow-up data, and Table 2 reports remission rates of 32.6% on PHQ-9 and 31.3% on GAD-7 at session 4. The table calculates those rates from the participants with available session-4 scores (553 and 501, respectively), not from all 1,247 participants as the citing sentence could imply. The Background and Discussion describe the telehealth treatment and report low adverse-event rates. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    One meta-analysis found that racemic ketamine produced a greater overall antidepressant response and fewer dropouts than esketamine.

    “One meta-analysis found that racemic ketamine elicited a greater overall antidepressant response and had fewer dropouts across studies than esketamine [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Bahji A, Vazquez GH. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542–55. source

  • May combine two claims.

    Premisecitation

    Ketamine also acts as an opioid and dopamine receptor agonist, inhibits monoamine reuptake, and antagonizes muscarinic receptors.

    “In addition to glutamatergic modulation, ketamine is also an opioid (mu, kappa, delta) and dopamine receptor agonist, inhibits monoamine reuptake, and antagonizes muscarinic receptors [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay M-A, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:2045125320916657. source

      The ‘Antidepressant mechanisms of ketamine and potential biochemical biomarkers’ section (page unavailable) lists opioid (mu, delta and kappa), monoaminergic, and muscarinic receptors or transporters as possible binding targets. It does not establish that ketamine is an opioid or dopamine receptor agonist, inhibits monoamine reuptake, or antagonizes muscarinic receptors; it describes the opioid system’s role as unclear and controversial. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Two studies (n=134 and n=157) found that intermittent low-dose ketamine (0.3 mg/kg before each ECT session) improved cognitive functioning and reduced psychiatric complications after ECT.

    “However, two studies (n = 134 and n = 157, respectively) found that intermittent low-dose ketamine (0.3 mg/kg, administered before each ECT treatment) improved cognitive functioning and reduced psychiatric complications after ECT [50,51].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [50] Dong J, Min S, Qiu H, Chen Q, Ren L. Intermittent administration of low dose ketamine can shorten the course of electroconvulsive therapy for depression and reduce complications: a randomized controlled trial. Psychiatry Res. 2019;281:112573. source
    • cites [51] Zou W, Min S, Chen Q, Li X, Ren L. Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients—a randomized, double‐blind, controlled clinical study. Brain Behav. 2021;11:e01775. source

      The Abstract Methods describe 157 enrolled elderly patients receiving 0.3 mg/kg ketamine with each ECT treatment. The Results (Cognitive impairments) report less cognitive impairment in the ketamine group during treatment, but no difference in MMSE scores at the end of ECT. The Results (Adverse events) report no significant reduction in psychiatric adverse events, so the claim about reduced psychiatric complications is unsupported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Synaptic NMDAR transmission promotes cell survival, whereas extrasynaptic NMDARs promote cell death through p38MAPK inhibition and activation, respectively.

    “research suggests that synaptic NMDAR transmission promotes cell survival and that extra-synaptic NMDARs promote cell death through p38MAPK inhibition and activation, respectively [25].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010;11:682–96. source

      The ‘NMDAR paradox’ section says synaptic NMDAR signalling promotes neuronal survival whereas extrasynaptic signalling promotes death. ‘Calpain activation and STEP cleavage’ identifies p38 activation as an extrasynaptic pro-death pathway, but does not support synaptic p38 inhibition as the survival mechanism; it notes that neuroprotective synaptic activity can also activate p38. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Preclinical research initially suggested that conversion to (2S,6S;2R,6R)-HNK was necessary for ketamine's antidepressant-like effects and that (2R,6R)-HNK could have its own antidepressant effects in mice.

    “Preclinical research first suggested that metabolism to (2S,6S;2R,6R)-HNK was essential for ketamine's antidepressantlike effects and that (2R,6R)-HNK could exert its own antidepressant effects in mice [45,46].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [45] Zanos P, Highland JN, Liu X, Troppoli TA, Georgiou P, Lovett J, et al. (R)-Ketamine exerts antidepressant actions partly via conversion to (2R,6R)-hydroxynorketamine, while causing adverse effects at sub-anaesthetic doses. Br J Pharm. 2019;176:2573–92. source

      The Introduction reports earlier preclinical evidence that conversion to (2S,6S;2R,6R)-HNK was necessary for ketamine’s full antidepressant-relevant effects in mice, and that (2R,6R)-HNK had antidepressant-like effects in animal tests. But “essential” overstates the first point: the Discussion concludes that conversion increases (R)-ketamine’s potency, while also describing effects independent of the metabolite. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [46] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source

  • May combine two claims.

    Premisecitation

    Recent research found that ketamine significantly improved full remission rates in people presenting with severe acute suicidal ideation, although the effect differed by primary diagnosis.

    “recent research demonstrating that ketamine significantly improved full remission rates for those presenting with severe acute suicidal ideation, though this effect differed based on primary diagnosis [76].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [76] Abbar M, Demattei C, El-Hage W, Llorca P-M, Samalin L, Demaricourt P, et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022;376:e067194. source

  • May combine two claims.

    Premisecitation

    Multiple meta-analyses and systematic reviews have shown that ketamine significantly reduces suicidal ideation from one day up to six weeks, and this effect appears at least partly independent of its mood effects.

    “Multiple meta-analyses and systematic reviews have demonstrated that ketamine significantly reduces suicidal ideation within one day and up to six weeks, an effect that appears to be at least partially independent of its effects on mood [72][73][74][75].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [72] Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150–58. source

      The Abstract Conclusions report reduced suicidal thoughts within one day and for up to one week, with effects partially independent of mood effects. They do not support the claimed duration of up to six weeks; the Discussion says effects beyond one week had not been thoroughly investigated. Page numbers are not provided in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [73] Hochschild A, Grunebaum MF, Mann JJ. The rapid anti-suicidal ideation effect of ketamine: a systematic review. Prev Med. 2021;152:106524. source
    • cites [74] Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: a systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry. 2020;54:29–45. source

      The Results (p. 13) report a significant reduction in suicidal ideation within one day and through 72 hours, but no significant effect after 72 hours; the claimed benefit up to six weeks is not supported. The Discussion (p. 15) says the effects on suicidality and depression may not be completely correlated, supporting the cautious suggestion of partial independence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A double-blind crossover trial (n=37) found that 69% of participants had complete remission of suicidal ideation after six ketamine infusions, and this effect was maintained with weekly maintenance infusions.

    “One double-blind, crossover trial (n = 37) found that 69% of participants had complete remission of suicidal ideation after six ketamine infusions, an effect maintained with weekly maintenance infusions [83].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] Phillips JL, Norris S, Talbot J, Hatchard T, Ortiz A, Birmingham M, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology. 2020;45:606–12. source

      The Abstract and ‘Maintenance ketamine infusions’ section report 37 participants and that 24 participants (69%) had no suicidal ideation after six repeated infusions. However, the double-blind crossover applied only to the initial single-infusion phase; the six-infusion and weekly maintenance phases were open-label. The Discussion says weekly infusions sustained reductions in suicidal ideation among responders, not that the 69% complete-alleviation rate was maintained. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A recent systematic review found that intranasal esketamine did not outperform placebo for reducing suicidal ideation, although this result may have been confounded by a high placebo response rate.

    “However, it should be noted that a recent systematic review found that intranasal esketamine did not perform better than placebo at reducing suicidal ideation [90], though this finding may have been confounded by the high placebo response rate that exists when assessing suicidal ideation [91].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [90] Jollant F, Colle R, Nguyen TML, Corruble E, Gardier AM, Walter M, et al. Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review. Ther Adv Psychopharmacol. 2023;13:20451253231151327. source
    • cites [91] Bloomfield-Clagett B, Ballard ED, Greenstein DK, Wilkinson ST, Grunebaum MF, Murrough JW, et al. A participant-level integrative data analysis of differential placebo response for suicidal ideation and nonsuicidal depressive symptoms in clinical trials of intravenous racemic ketamine. Int J Neuropsychopharmacol. 2022;25:827–38. source

      Citation [91] supports the placebo-response caveat, not the preceding systematic-review finding attributed to [90]. The Discussion reports preliminary evidence of a greater placebo response for suicidal ideation and suggests this may contribute to modest findings in IV ketamine trials. The paper says intranasal esketamine was not the subject of its analysis, so it does not establish that placebo response confounded the esketamine finding. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Only sertraline and paroxetine are currently approved pharmacotherapies for PTSD, and both have high relapse rates.

    “Only two pharmacotherapies are currently approved for PTSD-sertraline and paroxetine-and both have high relapse rates [100]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, et al. Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry. 2015;206:93–100. source

      The discussion of individual drugs (section labelled SKB627 E; page unavailable) treats sertraline and paroxetine as pharmacotherapies for PTSD. The paper does not establish that they are the only approved drugs or report high relapse rates for both; its stated outcome measures are symptom severity and early withdrawal. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Minimal clinical research supports these findings, suggesting risks of dependency are extremely low when ketamine is administered in a medical setting.

    “Minimal clinical research supports these findings, suggesting that risks of dependency are extremely low when ketamine is administered in a medical setting [158-160]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [158] Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CAJ, et al. Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord. 2020;263:568–75. source

      The Results (Cravings/Addiction behaviors; page unavailable) report no observed cravings or addiction behavior during inpatient follow-up of up to three months after a single ketamine infusion. But the Discussion (Strengths and limitations; page unavailable) says dependence was not formally measured and the findings do not cover repeated dosing or other routes. The paper therefore does not establish that dependency risk is “extremely low” across medical settings. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [159] Feifel D, Dadiomov D, Lee KC. Safety of repeated administration of parenteral ketamine for depression. Pharmaceuticals. 2020;13:151. source
    • cites [160] Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2015;76:247–52. source

  • May combine two claims.

    Premisecitation

    Although it does not act as rapidly as ketamine, Auvelity demonstrated a significant difference from placebo at one week and up until six weeks in 327 participants.

    “Although it does not act as rapidly as ketamine, Auvelity demonstrated a significant difference from placebo at one week and up until six weeks (n = 327) [186]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [186] Iosifescu DV, Jones M, O’Gorman C, Streicher C, Feliz S, Fava M, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: A phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83:21m14345. source

      The Discussion reports significantly greater reductions in MADRS scores with AXS-05 than with placebo starting at week 1 and continuing through week 6. Patient Characteristics reports 327 participants randomized, although the efficacy analysis included 318. The paper does not compare how rapidly AXS-05 and ketamine act, so that part of the sentence is unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Metabotropic glutamate receptors have repeatedly been implicated in the pathophysiology of depression, and mGluRs2/3 are known to mediate levels of glutamate and synaptic plasticity.

    “Metabotropic glutamate receptors (mGluRs) have repeatedly been implicated in the pathophysiology of depression, and mGluRs2/3 are known to mediate levels of glutamate and synaptic plasticity [189]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [189] Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist. 2009;15:525–39. source

      Section II.E links mGluRs to depression through animal-model findings, but says data linking mGluR dysfunction to mood disorders are sparse; this qualifies the claim that they have repeatedly been implicated. The Introduction says metabotropic receptors modulate synaptic plasticity, but our copy does not establish specifically that mGluR2/3 mediate glutamate levels and synaptic plasticity. Page numbers were not available in the indexed passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Placebo response rates are high in depression and suicidality research, as well as in trials with rapid-acting antidepressants.

    “placebo response rates are high in depression and suicidality research, as well in trials with rapid-acting antidepressants [104]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [104] Abdallah CG, Roache JD, Gueorguieva R, Averill LA, Young-McCaughan S, Shiroma PR, et al. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology. 2022;47:1574–81. source

      The Discussion (page unavailable) reports an unexpectedly large placebo effect in this ketamine trial and says high placebo response is not uncommon in the field. The trial studied PTSD symptoms in veterans and active-duty military personnel; these passages do not establish high placebo response rates specifically in depression or suicidality research, or across rapid-acting antidepressant trials generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Auvelity is hypothesized to work via NMDAR antagonism of dextromethorphan, which is prolonged by bupropion, a norepinephrine-dopamine reuptake inhibitor.

    “Auvelity is hypothesized to work via the NMDAR antagonism of dextromethorphan, which is prolonged by bupropion, a norepinephrine-dopamine reuptake inhibitor [187]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [187] Stahl SM. Dextromethorphan/bupropion: a novel oral NMDA (N-methyl-d-aspartate) receptor antagonist with multimodal activity. CNS Spectr. 2019;24:461–66. source

  • The quote only partly states this claim.

    Premisecitation

    Inhaled 50% nitrous oxide had significant and rapid-acting antidepressant effects in a small cohort of three participants with PTSD.

    “and in a small cohort (n = 3) of participants with PTSD [178]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [178] Varias A, van Roessel P, Parsiani M, Filippou-Frye M, Neylan TC, Nagele P, et al. Does nitrous oxide help veterans with post-traumatic stress disorder (PTSD)? A case series. J Clin Psychiatry. 2020;81:20I13393. source

      The Method section describes three participants with PTSD inhaling 50% nitrous oxide. The Results report rapid improvement in PTSD symptoms in two participants, but do not report antidepressant outcomes or a statistically significant effect; the authors also caution that this was an uncontrolled case series. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Preclinically, (R)-ketamine does not induce conditioned place preference, deficits in prepulse inhibition, or hyperlocomotion.

    “Preclinically, (R)-ketamine does not induce conditioned place preference, deficits in prepulse inhibition, or hyperlocomotion [155-157]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [155] Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solis O, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021;26:6704–22. source

      The Results section reports no conditioned place preference with (R)-ketamine in male mice. It does not report a prepulse-inhibition test. Contrary to the hyperlocomotion claim, the Results state that 20 mg/kg (R)-ketamine increased locomotor activity; the finding absent for (R)-ketamine was locomotor sensitization over days (page not specified in our copy). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [156] Chang LC, Zhang K, Pu Y, Qu Y, Wang S-M, Xiong Z, et al. Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharm Biochem Behav. 2019;181:53–59. source
    • cites [157] Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5:e632. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More recent research is investigating adjunctive D-cycloserine for indications such as OCD, PTSD, and MDD.

    “More recent research is investigating adjunctive D-cycloserine for indications such as OCD, PTSD, and MDD [172-174]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [172] Cole J, Sohn MN, Harris AD, Bray SL, Patten SB, McGirr A. Efficacy of adjunctive D-cycloserine to intermittent theta-burst stimulation for major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2022;79:1153–61. source
    • cites [173] Farrell LJ, Waters AM, Tiralongo E, Mathieu S, McKenzie M, Garbharran V, et al. Efficacy of D-cycloserine augmented brief intensive cognitive-behavioural therapy for paediatric obsessive-compulsive disorder: a randomised clinical trial. Depress Anxiety. 2022;39:461–73. source

      The Discussion describes this paper as a randomized trial of D-cycloserine–augmented CBT for pediatric OCD, supporting the OCD example. The References list a review covering PTSD, but this paper does not investigate PTSD, and no passage found addresses D-cycloserine for MDD. Pages are not specified in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [174] Inslicht SS, Niles AN, Metzler TJ, Lipshitz SAL, Otte C, Milad MR, et al. Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. Neuropsychopharmacology. 2022;47:1945–52. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Auvelity has received a fast-track designation from the FDA to treat Alzheimer's disease.

    “Auvelity has also received a fast-track designation from the FDA to treat Alzheimer's disease”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [188] Lepkowsky CM. Auvelity as a potential treatment for Alzheimer’s disease. Med Res Arch. 2022;10. https://doi.org/10.18103/mra.v10i10.3206. source

      The 'Auvelity: A Novel Antidepressant' section reports FDA approval for major depressive disorder, while the Discussion and Conclusion describes treatment of Alzheimer’s disease as hypothetical. Neither section reports an FDA fast-track designation for Alzheimer’s disease; the absence of approval for that indication does not settle whether a fast-track designation was granted. Searches for 'fast-track designation' and 'fast track FDA designation' found no passage addressing it. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Broadly, these agents demonstrated no significant antidepressant efficacy and an adverse events profile that led to early terminations of some clinical trials in MDD, TRD, and Parkinson's disease.

    “Broadly, these agents demonstrated no significant antidepressant efficacy and an adverse events profile that led to the early terminations of some clinical trials in indications such as MDD, TRD, and Parkinson's disease [169,170]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [169] Nutt JG, Gunzler SA, Kirchhoff T, Hogarth P, Weaver JL, Krams M, et al. Effects of a NR2B selective NMDA glutamate antagonist, CP‐101,606, on dyskinesia and parkinsonism. Mov Disord. 2008;23:1860–66. source

      The Results (Adverse Events; page unavailable) report abnormal thinking, depersonalization, and amnesia in patients with Parkinson’s disease receiving CP-101,606. The paper does not report antidepressant efficacy in MDD or TRD, or say that adverse events led to early termination of a trial. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [170] Kadriu B, Musazzi L, Henter ID, Graves M, Popoli M, Zarate CA Jr. Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol. 2019;22:119–35. source

      The MK-0657 (CERC-301) and JNJ40411813/ADX71149 sections report trials without significant antidepressant efficacy. The CP-101,606/Traxoprodil section reports adverse effects and discontinuation of that compound’s development, but it also reports significant antidepressant effects; it does not say a clinical trial ended early. The passages do not substantiate early trial terminations across MDD, TRD, and Parkinson’s disease. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These findings were not replicated with other NMDAR antagonists or with 6,6-d2-(R,S)-ketamine.

    “These findings were not replicated with other NMDAR antagonists or with 6,6-d2-(R,S)-ketamine [193]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [193] Zanos P, Highland JN, Stewart BW, Georgiou P, Jenne CE, Lovett J, et al. (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc Natl Acad Sci USA. 2019;116:6441–50. source

  • May combine two claims.

    Premisecitation

    Co-administration of ketamine and an mGluR2/3 antagonist sustained antidepressant-like responses in another animal model, supporting mGluR2/3 antagonists as effective adjunctive therapies.

    “Co-administration of ketamine and an mGluR2/3 antagonist also sustained antidepressant-like responses in another animal model [197], which further supports mGluR2/3 antagonists as effective adjunctive therapies.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [197] Rafało-Ulińska A, Brański P, Pałucha-Poniewiera A. Combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 induces rapid and sustained effects in the CUMS model of depression via a TrkB/BDNF-dependent mechanism. Pharmaceuticals. 2022;15:125. source

  • May combine two claims.

    Premisecitation

    RO4995819 (decoglurant), an mGluR2/3 NAM, completed Phase 1 and a Phase 2 trial in partially refractory MDD, but no significant differences were observed between decoglurant and placebo.

    “RO4995819 (decoglurant), an mGluR2/3 NAM, has also completed Phase 1 clinical trials and a Phase 2 trial in partially refractory MDD, but no significant differences were observed between decoglurant and placebo [195]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [195] Umbricht D, Niggli M, Sanwald-Ducray P, Deptula D, Moore R, Grünbauer W, et al. Randomized, double-blind, placebo-controlled trial of the mGlu2/3 negative allosteric modulator decoglurant in partially refractory major depressive disorder. J Clin Psychiatry. 2020;81:18m12470. source

  • May combine two claims.

    Premisecitation

    AMPAR PAMs appeared well-tolerated in early-phase clinical trials, but failures to improve cognition and mood have consistently been observed.

    “While AMPAR PAMs appeared to be well-tolerated in earlyphase clinical trials, failures to improve cognition and mood have consistently been observed [201,202]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [201] Chappell AS, Gonzales C, Williams J, Witte MM, Mohs RC, Sperling R. AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Neurology. 2007;68:1008–12. source
    • cites [202] Trzepacz PT, Cummings J, Konechnik T, Forrester TD, Chang C, Dennehy EB, et al. Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer’s disease. Int Psychogeriatr. 2013;25:707–19. source

      The Results (Safety evaluation; page not provided) say mibampator was well tolerated. The Results (Efficacy; page not provided) report no treatment-group advantage on the cognitive measure or depression scale, although apathy improved significantly with mibampator. This trial of one AMPA receptor potentiator does not establish that failures to improve cognition and mood were consistently observed across AMPAR PAMs. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Another resting-state fMRI study found that ketamine increased frontostriatal connectivity in participants with TRD, an effect that was disrupted when ketamine was administered to healthy volunteers.

    “Another restingstate fMRI study found that ketamine increased frontostriatal connectivity in participants with TRD, an effect that was disrupted when ketamine was administered to healthy volunteers [9]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Mkrtchian A, Evans JW, Kraus C, Yuan P, Kadriu B, Nugent AC, et al. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol Psychiatry. 2021;26:3292–301. source

  • May combine two claims.

    Premisecitation

    PET imaging studies found that increased 5-HT1B receptor binding was associated with ketamine response in participants with TRD and correlated with depression symptom ratings at baseline.

    “PET imaging studies found that increased 5-HT 1B receptor binding was associated with ketamine response in participants with TRD and correlated with depression symptom ratings at baseline [207]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [207] Tiger M, Veldman ER, Ekman C-J, Halldin C, Svenningsson P, Lundberg J. A randomized placebo-controlled PET study of ketamine´ s effect on serotonin1B receptor binding in patients with SSRI-resistant depression. Transl Psychiatry. 2020;10:159. source

      The Discussion reports that baseline ventral-striatal 5-HT1B receptor binding correlated with both ketamine-related symptom change and pretreatment depression ratings. But it says larger treatment effects occurred in patients with lower—not increased—pretreatment binding. The reported increase in hippocampal binding after ketamine was a separate finding, not an association with response. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Another study found similar baseline differences between healthy volunteers and individuals with MDD but did not replicate differences in global brain connectivity after ketamine versus placebo.

    “another study found similar baseline differences between healthy volunteers and individuals with MDD but did not replicate differences in global brain connectivity after ketamine versus placebo [210]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [210] Kraus C, Mkrtchian A, Kadriu B, Nugent AC, Zarate CA Jr, Evans JW. Evaluating global brain connectivity as an imaging marker for depression: influence of preprocessing strategies and placebo-controlled ketamine treatment. Neuropsychopharmacology. 2020;45:982–89. source

  • May combine two claims.

    Premisecitation

    TS-161, an mGluR2/3 antagonist, completed a Phase 1 evaluation and was found to be safe and well-tolerated with high rates of conversion to its active metabolite and sufficient CSF penetration for pharmacological effects.

    “TS-161, an mGluR2/3 antagonist, completed a Phase 1 evaluation of its safety profile, tolerability, and pharmacokinetics and was found to be safe and well-tolerated with high rates of conversion to its active metabolite and sufficient CSF penetration for pharmacological effects [194]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [194] Watanabe M, Marcy B, Hiroki A, Watase H, Kinoshita K, Iijima M, et al. Evaluation of the safety, tolerability, and pharmacokinetic profiles of TP0473292 (TS-161), a prodrug of a novel orthosteric mGlu2/3 receptor antagonist TP0178894, in healthy subjects and its antidepressant-like effects in rodents. Neuropsychopharmacology. 2022;25:106–17. source

  • May combine two claims.

    Interpretationcitation

    That pattern mirrored measurements from healthy volunteers after a placebo infusion, suggesting that ketamine normalized function.

    “this pattern mirrored measurements from healthy volunteers after a placebo infusion [212], suggesting that ketamine normalized function.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [212] Reed JL, Nugent AC, Furey ML, Szczepanik JE, Evans JW, Zarate CA Jr. Effects of ketamine on brain activity during emotional processing: diferential findings in depressed versus healthy control participants. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:610–18. source

  • May combine two claims.

    Premisecitation

    An mGluR2/3 agonist-induced hypothermic assay demonstrated that racemic ketamine and (2R,6R)-HNK prevented increases in body temperature induced by an mGluR2/3 orthostatic agonist (LY379628), implicating mGluR2/3 antagonism in ketamine's antidepressant effects.

    “an mGluR2/3 agonistinduced hypothermic assay demonstrated that racemic ketamine and (2R,6R)-HNK prevented the increases in body temperature induced by an mGluR2/3 orthostatic agonist (LY379628), implicating mGluR2/3 antagonism in ketamine's antidepressant effects [193]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [193] Zanos P, Highland JN, Stewart BW, Georgiou P, Jenne CE, Lovett J, et al. (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc Natl Acad Sci USA. 2019;116:6441–50. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Gamma oscillations are closely regulated by GABA A modulation and AMPAR-mediated depolarization, making them a valuable measure of excitatory/inhibitory balance.

    “A key area of interest for elucidating ketamine's underlying mechanisms of action has been measuring changes in gamma oscillations, as they are closely regulated by GABA A modulation and AMPAR-mediated depolarization, making them a valuable measure of excitatory/inhibitory balance [204]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [204] Gandal MJ, Sisti J, Klook K, Ortinski PI, Leitman V, Liang Y, et al. GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry. 2012;2:e142. source

      The Introduction and Results (‘Reduced gamma signal-to-noise ratio’; page unavailable) link gamma activity to excitatory–inhibitory balance and describe gamma abnormalities as a potential biomarker. The Discussion (‘Baclofen mechanism of action’; page unavailable) links GABA release and GABAA-mediated spike timing to gamma synchrony. Our copy does not establish the claimed role of AMPAR-mediated depolarization. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Few studies have examined drug-drug interactions between ketamine and monoaminergic-based therapeutics.

    “few studies have yet examined drug-drug interactions between ketamine and monoaminergic-based therapeutics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Many neurobiological mechanisms involved in ketamine's effects remain unclear.

    “many of the involved neurobiological mechanisms remain unclear”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Ketamine is a non-competitive NMDAR antagonist that produces rapid therapeutic effects and has changed neuropsychopharmacology.

    “Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist with rapid-acting therapeutic effects, has created a paradigm shift in the field of neuropsychopharmacology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ketamine is highly water- and lipid-soluble and can rapidly cross the blood-brain barrier.

    “As a phencyclidine derivative, ketamine is a highly water-and lipid-soluble agent that can rapidly cross the blood-brain barrier [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42. source

  • May combine two claims.

    Premisereasoning

    The FDA approved intranasal esketamine for adults with treatment-resistant depression in 2019 and for major depression with acute suicidal ideation or behavior in 2020; the European Union approved the same indications.

    “Based on significant clinical evidence, the Food and Drug Administration (FDA) approved the use of intranasal esketamine (Spravato TM )-the (S+) enantiomer of ketamine-for adults with TRD in 2019; in 2020, it was approved to treat adults with major depression and acute suicidal ideation or behavior.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because ketamine has varied pharmacological actions, it may also be effective in neuropsychiatric disorders beyond depression.

    “Although subanesthetic-dose ketamine was first studied for its antidepressant effects, its varied pharmacological actions suggested that it could also be effective in other neuropsychiatric disorders.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Ketamine has known clinical side effects including sedation, dizziness, dissociation, and psychotomimetic symptoms.

    “In addition to its known clinical side effects-including sedation, dizziness, dissociation, and psychotomimetic symptoms -ketamine also has a relatively long history of recreational substance misuse.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ketamine binds deep inside the NMDAR channel, and the magnesium block must be removed before binding can occur.

    “Like phencyclidine, ketamine binds to a site located deep within the NMDAR channel, necessitating the removal of the magnesium block before binding [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] MacDonald JF, Miljkovic Z, Pennefather P. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J Neurophysiol. 1987;58:251–66. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A direct comparison between racemic ketamine and (R)-ketamine has not yet been conducted.

    “Although a direct comparison between racemic ketamine and (R)-ketamine has yet to be conducted”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ketamine's elimination rate is close to liver blood flow, and its half-life is about two to three hours.

    “The elimination rate of ketamine is nearly equal to that of liver blood flow, with a half-life of approximately two to three hours [20,21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Domino EF, Domino SE, Smith RE, Domino LE, Goulet JR, Domino KE, et al. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharm Ther. 1984;36:645–53. source
    • cites [21] Schüttler J, Stanski DR, White PF, Trevor A, Horai Y, Verotta D, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm. 1987;15:241–53. source

  • May combine two claims.

    Premisecitation

    A study found that ketamine significantly reduced depressive symptoms in 53 older adults, with a 27% remission rate after four infusions, but it was associated with transient increases in hypertension.

    “Another study found that ketamine significantly decreased depressive symptoms in 53 older adults, with a 27% remission rate after four infusions, but was associated with transient increases in hypertension [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Lipsitz O, Di Vincenzo JD, Rodrigues NB, Cha DS, Lee Y, Greenberg D, et al. Safety, tolerability, and real-world effectiveness of intravenous ketamine in older adults with treatment-resistant depression: a case series. Am J Geriatr Psychiatry. 2021;29:899–913. source

  • May combine two claims.

    Premisecitation

    (S)-ketamine has a higher demethylation and clearance rate and a wider distribution pattern than (R)-ketamine or racemic ketamine.

    “Notable differences in metabolism exist between the two enantiomers: (S)-ketamine has a higher demethylation and clearance rate, as well as a wider distribution pattern than either (R)-ketamine or racemic (R,S)-ketamine [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Geisslinger G, Menzel-Soglowek S, Kamp HD, Brune K. Stereoselective high-performance liquid chromatographic determination of the enantiomers of ketamine and norketamine in plasma. J Chromatogr. 1991;568:165–76. source

  • May combine two claims.

    Interpretationcitation

    A small controlled trial (n=10) found similar results, indicating that larger trials are needed to clarify (R)-ketamine's antidepressant potential.

    “Another recent, small, controlled trial (n = 10) obtained similar results [44], suggesting that larger clinical trials are needed to elucidate (R)-ketamine's antidepressant potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Leal GC, Souza-Marques B, Mello RP, Bandeira ID, Caliman-Fontes AT, Carneiro BA, et al. Arketamine as adjunctive therapy for treatment-resistant depression: a placebo-controlled pilot study. J Affect Disord. 2023;330:7–15. source

  • May combine two claims.

    Premisenone given

    Norketamine is rapidly further metabolized to dehydronorketamine and hydroxynorketamine, which may contribute to ketamine's therapeutic effects.

    “Subsequent metabolism of norketamine to dehydronorketamine (DHNK) and hydroxynorketamine (HNK) also occurs rapidly, potentially contributing to its therapeutic effects (described below).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Repeated ketamine doses did not show decreased therapeutic efficacy, suggesting that chronic ketamine administration may help maintain antidepressant effects.

    “In addition, no decreases in therapeutic efficacy were observed with repeated doses, suggesting that chronic ketamine administration could be useful in maintaining antidepressant effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodgrigues NB, Ceban F, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;151:693–709. source

  • May combine two claims.

    Interpretationcitation

    Low-dose ketamine may reduce complications in patients receiving ECT, but mixed meta-analytic results for anesthetic-dose ketamine call for caution.

    “This suggests that low-dose concentrations of ketamine may reduce complications in patients also receiving ECT, though mixed results from meta-analyses of anesthetic-dose ketamine suggest that cautious interpretation is warranted [49,52,53].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [49] Zheng W, Li X-H, Zhu X-M, Cai D-B, Yang X-H, Ungvari GS, et al. Adjunctive ketamine and electroconvulsive therapy for major depressive disorder: a meta-analysis of randomized controlled trials. J Affect Disord. 2019;250:123–31. source
    • cites [52] Li D-J, Wang F-C, Chu C-S, Chen T-Y, Tang C-H, Yang W-C, et al. Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: a meta-analysis. Eur Neuropsychopharmacol. 2017;27:29–41. source
    • cites [53] McGirr A, Berlim MT, Bond DJ, Neufeld NH, Chan PY, Yatham LN, et al. A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability. J Psychiatr Res. 2015;62:23–30. source

  • May combine two claims.

    Premisecitation

    An initial open-label pilot trial found that (R)-ketamine produced significant antidepressant effects in seven people with treatment-resistant depression and few dissociative symptoms.

    “Clinically, an initial open-label pilot trial found that (R)-ketamine exerted significant antidepressant effects in seven individuals with TRD and, furthermore, was associated with few dissociative symptoms [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Leal GC, Bandeira ID, Correia-Melo FS, Telles M, Mello RP, Vieira F, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatr Clin Neurosci. 2021;271:577–82. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Whether NMDAR inhibition is required for ketamine's antidepressant effects is still unknown.

    “However, the necessity of NMDAR inhibition for ketamine's antidepressant effects remains unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A study comparing intranasal esketamine with intravenous racemic ketamine (n=62) found no significant differences in response or remission, but more treatments were needed for remission with intranasal esketamine.

    “Another study comparing intranasal esketamine with intravenous racemic ketamine (n = 62) also found no significant differences in rates of response and remission, though the number of treatments needed to achieve remission was significantly higher for intranasal esketamine [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Singh B, Kung S, Pazdernik V, Schak KM, Geske J, Schulte PJ, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in clinical practice among patients with treatment-refractory depression: an observational study. J Clin Psychiatry. 2023;84:22m14548. source

  • May combine two claims.

    Premisecitation

    One study (n=220) found that adjunctive ketamine performed worse than ketamine monotherapy on suicidality, with no differences on other measures of depression, anxiety, or functional impairment.

    “Interestingly, one study found that adjunctive ketamine performed worse on measures of suicidality than ketamine monotherapy, though no differences were observed on other measures of depression, anxiety, or functional impairment (n = 220) [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Di Vincenzo JD, Lipsitz O, Rodrigues NB, Lee Y, Gill H, Kratiuk K, et al. Ketamine monotherapy versus adjunctive ketamine in adults with treatment-resistant depression: results from the Canadian Rapid Treatment Centre of Excellence. J Psychiatr Res. 2021;143:209–14. source

  • May combine two claims.

    Premisecitation

    Steady-state concentrations of metabolites such as HNK are affected stereoselectively, which could contribute to enantiomer-specific therapeutic effects.

    “In addition, steady-state concentrations of metabolites such as HNK are also impacted in a stereoselective manner, which could contribute to enantiomer-specific therapeutic effects [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Weiss M, Siegmund W. Pharmacokinetic modeling of ketamine enantiomers and their metabolites after administration of prolonged‐release ketamine with emphasis on 2, 6‐hydroxynorketamines. Clin Pharm Drug Dev. 2022;11:194–206. source

  • May combine two claims.

    Premisecitation

    A comparison of intravenous esketamine 0.25 mg/kg (n=34) and racemic ketamine 0.5 mg/kg (n=29) found no significant differences in remission or safety at 24 hours, with a slight trend favoring racemic ketamine on MADRS and response rates at 72 hours and seven days.

    “Another recent comparison of intravenous esketamine (0.25 mg/kg) (n = 34) and racemic ketamine (0.5 mg/kg) (n = 29) found no significant differences in remission rates or safety profile at 24 h after an acute infusion, though there was a slight trend towards decreased MADRS scores and increased response rates in those who received racemic ketamine at 72 h and seven days [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527–34. source

  • May combine two claims.

    Premisecitation

    Multiple studies found that ketamine improves ECT outcomes most when given with another anesthetic, with no significant effects when ketamine was given alone.

    “Multiple studies have now tested the effects of adjunctive ketamine on ECT outcomes and found that ketamine most effectively improves ECT outcomes when it is administered together with another anesthetic; no significant effects were found with ketamine administration alone [49].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Zheng W, Li X-H, Zhu X-M, Cai D-B, Yang X-H, Ungvari GS, et al. Adjunctive ketamine and electroconvulsive therapy for major depressive disorder: a meta-analysis of randomized controlled trials. J Affect Disord. 2019;250:123–31. source

  • May combine two claims.

    Premisecitation

    Ketamine inhibits NMDAR-dependent bursting in lateral habenula neurons, reversing depression-associated increases in bursting and theta-band synchronization.

    “Ketamine also inhibits NMDAR-dependent bursting activity of lateral habenula neurons, reversing the increases in bursts and thetaband synchronization observed in depression [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22. source

  • May combine two claims.

    Premisecitation

    A Phase 2a trial (n=102) found that (R)-ketamine (PCN-101) had no significant effect on baseline MADRS scores at 24 hours, although its safety profile was generally positive.

    “the first large-scale, Phase 2a, proof-of-concept clinical trial (n = 102) (NCT05414422) found that (R)-ketamine (PCN-101) had no significant effect on baseline Montgomery-Asberg Depression Rating Scale (MADRS) scores at 24 h postadministration, though it had a generally positive safety profile [43].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Atai Life Sciences. atai Life Sciences announces results from Phase 2a trial of PCN-101 (R-ketamine) for treatment-resistant depression. 2023. https://www.globenewswire.com/news-release/2023/01/06/2584334/0/en/atai-Life-Sciences-Announces-Results-from-Phase-2a-Trial-of-PCN-101-R-ketamine-for-Treatment-Resistant-Depression.html.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisenone given

    Ketamine has repeatedly been shown to reduce symptoms of major depressive disorder and bipolar disorder.

    “Ketamine has repeatedly been shown to effectively reduce the symptoms of major depressive disorder (MDD) and BD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A recent meta-analysis found that ketamine has substantial real-world effectiveness, with a mean response rate of 55.3% and a remission rate of 28.9%, although remission rates varied across patient groups.

    “A recent meta-analysis [59] found that ketamine had substantial real-world effectiveness, with a mean response rate of 55.3% and a remission rate of 28.9%, but differences in remission rates varied across patient groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodgrigues NB, Ceban F, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;151:693–709. source

  • May combine two claims.

    Premisecitation

    A different study found that repeated ketamine infusions had no effect on depressive symptom severity or suicidal ideation; the 26 participants had severe major depressive disorder with chronic suicidal ideation, suggesting that a higher dose or more infusions may have been needed.

    “Although a different study found that repeated ketamine infusions had no effect on severity of depressive symptoms or suicidal ideation, the 26 participants in that study had severe MDD with chronic suicidal ideation, suggesting that a higher ketamine dose or an increased number of infusions may have been necessary to see an effect [87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Ionescu DF, Bentley KH, Eikermann M, Taylor N, Johnson-Akeju O, Swee MB, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord. 2019;243:516–24. source

  • May combine two claims.

    Premisecitation

    A network meta-analysis found that ketamine was superior to other pharmacological treatments at two weeks after treatment initiation, while at four, six, and eight weeks quetiapine and risperidone augmentation were the best and second-best treatments.

    “However, a network meta-analysis found that ketamine was superior to other pharmacological treatments at two weeks after treatment initiation; at four, six, and eight weeks, quetiapine and risperidone augmentation were found to be the best and second best treatments, respectively [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N. Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis. Curr Med Res Opin. 2017;33:701–11. source

  • May combine two claims.

    Premisecitation

    Work in mice found no drug-induced sensitization or drug-evoked synaptic plasticity for ketamine, suggesting lower misuse liability than cocaine.

    “work in mice found no drug-induced sensitization or drug-evoked synaptic plasticity for ketamine, suggesting lower misuse liablity than the comparative substance, cocaine [68]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Simmler LD, Li Y, Hadjas LC, Hiver A, van Zessen R, Lüscher C. Dual action of ketamine confines addiction liability. Nature. 2022;608:368–73. source

  • May combine two claims.

    Premisecitation

    A recent systematic review supported ketamine use for OCD, though results varied across studies and require further investigation.

    “a recent systematic review supported ketamine use for the treatment of OCD, though results appeared to vary across studies and require further investigation [117]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Bandeira ID, Lins-Silva DH, Cavenaghi VB, Dorea-Bandeira I, Faria-Guimarães D, Barouh JL, et al. Ketamine in the treatment of obsessive-compulsive disorder: a systematic review. Harv Rev Psychiatry. 2022;30:135–45. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Strategies to mitigate placebo response include increasing study duration, randomizing the run-in period, and addressing functional blinding in rapid-acting antidepressant trials.

    “Strategies to mitigate placebo response include increasing study duration, randomizing the run-in period, and addressing functional blinding in rapid-acting antidepressant trials [162]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Fava M, Evins AE, Dorer DJ, Schoenfeld DA. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom. 2003;72:115–27. source

  • May combine two claims.

    Premisecitation

    In that trial, baseline cerebral blood flow predicted MADRS reductions at 24 h post-nitrous oxide administration, a finding not observed in control groups.

    “baseline cerebral blood flow predicted MADRS reductions at 24 h postnitrous oxide administration, a finding not observed in control groups [179]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Kim WSH, Dimick MK, Omrin D, Mitchell RHB, Riegart D, Levitt A, et al. Proof‐of‐concept randomized controlled trial of single‐session nitrous oxide for refractory bipolar depression: focus on cerebrovascular target engagement. Bipolar Disord. 2022;25:221–32. source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Recent development and/or repurposing of other neuropsychopharmacological interventions provides insight into how different aspects of ketamine's unique pharmacology, such as NMDAR antagonism and AMPAR modulation, may contribute to symptom alleviation.

    “the recent development and/or repurposing of other neuropsychopharmacological interventions provides important insight into how different aspects of ketamine's unique pharmacology, such as NMDAR antagonism and AMPAR modulation, may contribute to symptom alleviation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Dextromethorphan is also a sigma-1 agonist, implicating a novel mechanism of action in rapid-acting antidepressant effects.

    “Dextromethorphan is also a sigma-1 agonist, implicating a novel mechanism of action in rapid-acting antidepressant effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    High placebo response might be due to patients' expectations of benefits in clinical trials with novel substances, behavioral conditioning in research settings, or overlap in neuroanatomical substrates between affected brain regions in MDD and placebo response.

    “This might be due to patients' expectations of benefits in clinical trials with novel substances, behavioral conditioning in research settings, or the striking overlap in neuroanatomical substrates between affected brain regions in MDD and placebo response [161]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov. 2013;12:191–204. source

  • May combine two claims.

    Interpretationreasoning

    Despite early failures in developing other NMDAR modulators as rapid-acting antidepressants, several promising agents are currently under investigation.

    “Thus, despite early failures in the development of other NMDAR modulators as rapidacting antidepressants, several promising agents are currently under investigation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    More data are currently available for ketamine/esketamine than for other rapid-acting agents such as serotonergic psychedelics.

    “more data are currently available for ketamine/ esketamine than for other rapid-acting agents (e.g., serotonergic psychedelics)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Ketamine evidently has great clinical utility, but its direct therapeutic mechanisms are still unclear.

    “While ketamine evidently has great clinical utility, its direct therapeutic mechanisms are still unclear.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The success of therapeutics with well-defined mechanisms of action can provide insight into how ketamine may target each neuropsychiatric disorder discussed.

    “the success of therapeutics with well-defined mechanisms of action can provide insight into how ketamine may target each neuropsychiatric disorder discussed above.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    MIJ-821 is an NR2B negative allosteric modulator that binds to and inhibits NMDAR activity, thereby inhibiting abnormal neurotransmission.

    “MIJ-821 is an NR2B negative allosteric modulator that binds to and inhibits the activity of NMDARs, thereby inhibiting abnormal neurotransmission.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    REL-1017 (esmethadone, d-methadone) is an NMDAR channel blocker that has demonstrated significant promise as a therapeutic.

    “REL-1017 (esmethadone, d-methadone) is an NMDAR channel blocker that has demonstrated significant promise as a therapeutic.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Neuroimaging studies can provide a strong foundation to bridge preclinical and clinical research, allowing a non-invasive way to study changes in brain function.

    “Neuroimaging studies can provide a strong foundation to bridge preclinical and clinical research, allowing a non-invasive way to study changes in brain function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Techniques such as EEG, MEG, MRS, fMRI, and/or PET allow for a macroscopic viewpoint of neurophysiological function.

    “Techniques such as electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), fMRI, and/or positron emission tomography (PET) allow for a macroscopic viewpoint of neurophysiological function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A study in healthy volunteers found a distinct time course for neural responses to ketamine.

    “the study was conducted in healthy volunteers, and the results implicated a distinct time course for neural responses to ketamine that should be explored in future research [213].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] McMillan R, Forsyth A, Campbell D, Malpas G, Maxwell E, Dukart J, et al. Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: a simultaneous EEG/fMRI study. J Psychopharmacol. 2019;33:219–29. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Initial research suggests that adverse events occur less frequently with maintenance treatments of intranasal esketamine.

    “initial research has suggested that adverse events occur less freqently with maintenance treatments of intranasal esketamine”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Variation in ketamine dose, administration frequency, and treatment duration can significantly affect results.

    “variance in the dose used, the frequency of administration, and the duration of treatment can significantly impact results”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The unique structure and function of AMPARs allow for multiple approaches to mediate glutamatergic activity and could still hold promise for developing novel therapeutics.

    “the unique structure and function of AMPARs allow for multiple approaches to mediate glutamatergic activity and could still hold great promise for developing novel therapeutics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Deficits in global brain connectivity have been repeatedly implicated in MDD and can be assessed using resting-state fMRI.

    “Deficits in global brain connectivity have also been repeatedly implicated in MDD and can be assessed using resting-state fMRI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased glutamate release activates downstream mechanisms that activate mTORC1 signaling, leading to upregulation of synaptic density, PSD-95, and GluA1-containing AMPAR surface insertion.

    “This increased probability of glutamate release activates downstream mechanisms that activate mTORC1 signaling, leading to upregulation of synaptic density, PSD-95, and GluA1containing AMPAR surface insertion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    A novel approach combining EEG with fMRI suggested that increases in the subgenual anterior cingulate cortex after subanesthetic ketamine administration may be due to physiological noise; however, the study was conducted in healthy volunteers.

    “a novel approach of combining EEG with fMRI suggested that increases in the subgenual anterior cingulate cortex after subanesthetic ketamine administration may be due to physiological noise; however, the study was conducted in healthy volunteers”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Ketamine has repeatedly been shown to increase AMPAR activity and throughput, suggesting that increasing AMPAR signaling itself may facilitate rapid-acting therapeutic effects.

    “ketamine has repeatedly been shown to increase AMPAR activity and throughput, suggesting that increasing AMPAR signaling itself may facilitate rapid-acting therapeutic effects.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    More potent NMDAR antagonism or other mechanisms may be necessary for rapid-acting antidepressant effects.

    “more potent NMDAR antagonism (associated with ketamine's dissociative and psychotomimetic effects) or other mechanisms may be necessary for rapid-acting antidepressant effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Increasing evidence suggests ketamine is a promising treatment for multiple neuropsychiatric conditions, including bipolar disorder, suicidal ideation, anxiety spectrum disorders, eating disorders, chronic pain, migraines, and substance use disorders.

    “increasing evidence has suggested that ketamine is a promising treatment for BD, suicidal ideation, anxiety spectrum disorders, eating disorders, chronic pain, migraines, and substance use disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    One of the hallmarks of most neuropsychiatric disorders is dysregulated neuroplasticity, which interrupts most facets of normal functioning, including normal cognitive, learning, and memory processes.

    “One of the hallmarks of most neuropsychiatric disorders is dysregulated neuroplasticity, which interrupts most facets of normal functioning, including normal cognitive, learning, and memory processes [203]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Kays JL, Hurley RA, Taber KH. The dynamic brain: neuroplasticity and mental health. J Neuropsychiatry Clin Neurosci. 2012;24:118–24. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Preclinical PET imaging provides a valuable tool for translating scientific results, allowing for high-throughput hypothesis testing before recruiting human participants.

    “Preclinical PET imaging also provides a valuable tool for translating scientific results, allowing for high-throughput hypothesis testing before recruiting human participants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other AMPAR PAMs such as S18986, LY392098, and mibampator are thought to function by reducing desensitization of the ion channel.

    “Other AMPAR PAMs, such as S18986, LY392098, and mibampator, which are thought to function by reducing desensitization of the ion channel [199]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Ornstein PL, Zimmerman DM, Arnold MB, Bleisch TJ, Cantrell B, Simon R, et al. Biarylpropylsulfonamides as novel, potent potentiators of 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic acid (AMPA) receptors. J Med Chem. 2000;43:4354–58. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The side effect profiles of ketamine and esketamine as prototypes for rapid-acting substances are now well established.

    “the sideeffect profiles of ketamine and esketamine as prototypes for rapidacting substances are now well established”
    Quote in the paperNot a substantial claim
95 of 95

  • The paper relies on this without support.

    Alcohol and substance misuse are highly prevalent, and current treatments have long-term relapse rates, so novel therapeutic approaches are needed.

    “Alcohol and substance misuse are highly prevalent, and current treatments have long-term relapse rates, necessitating novel therapeutic approaches.”

  • The paper relies on this without support.

    Substance use disorders are often resistant to traditional pharmacotherapy and behavioral interventions.

    “Substance use disorders are often resistant to traditional pharmacotherapy and behavioral interventions.”

  • The paper relies on this without support.

    Glutamatergic dysregulation is implicated across multiple substance use disorders.

    “Glutamatergic dysregulation has been implicated across multiple substance use disorders, leading to interest in the putative therapeutic impact of ketamine.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Ketamine-assisted ECT has opposite reported cognitive outcomes

    Major

    The discussion says both cited studies found improved cognitive functioning, but the table says study [51] found greater cognitive impairment with ketamine-assisted ECT.

  • The anorexia pilot study is assigned conflicting references

    Minor

    The discussion cites the five-person ketamine-plus-ketogenic-diet pilot as [121], but the corresponding table row cites [122]. The discussion uses [122] for a different five-person case series.

  • Duration of the social-anxiety effect differs for study [98]

    Minor

    The table reports an effect lasting up to two weeks, but the discussion says it lasted up to two days.

  • Auvelity's second ingredient changes within the paper

    Minor

    One passage names buprenorphine as an ingredient, while the next identifies bupropion as the ingredient that prolongs dextromethorphan's action.

  • Ketamine is described both as a mu-opioid agonist and as lacking direct mu-opioid binding

    Minor

    The mechanism section calls ketamine a mu-opioid receptor agonist, whereas the opioid-withdrawal section says its action does not involve direct binding to that receptor.

  • Study [94] has different sample sizes in the table and text

    Minor

    The table gives 113 participants for the repeated-ketamine anxiety study, while the discussion gives 201 for study [94].

  • Study [107] has different sample sizes in the table and text

    Minor

    The table lists 41 participants for the PTSD and chronic-pain trial; the discussion lists 40 for the same cited trial.

7 of 7

Cites

Flagged first, then by citations

4 of the 227 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Johnston, J. N., Kadriu, B., Kraus, C., Henter, I. D., & Zarate, C. A.
Affiliations
National Institutes of Health (US)
Corresponding author
Johnston, Jenessa N.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2023-06-20
Volume
49
Issue
1
Pages
23-40
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-023-01632-1
PMC
PMC10700638
OpenAlex
W4381334012
Cited by
108
References
227
Citations by year
2026: 28 · 2025: 41 · 2024: 36 · 2023: 3
FWCI
3.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (ZIAMH002857)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
ketamine, esketamine, subanesthetic ketamine, rapid-acting antidepressants, depression, bipolar disorder, anxiety disorders, substance use disorders, eating disorders, chronic pain, hydroxynorketamine, enantiomers, suicidal ideation, anhedonia, mechanism of action, neuroimaging
MeSH terms
Antidepressive Agents, Anxiety Disorders, Bipolar Disorder, Depression, Humans, Ketamine, Anhedonia

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

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