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Cited by 229Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchElectroconvulsive Therapy Studies

The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects

Open access
Abdallah, Chadi G., De Feyter, Henk M., Averill, Lynnette A., Jiang, Lihong, Averill, Christopher L., Chowdhury, Golam M. I., Purohit, Prerana, de Graaf, Robin A. +7 more·2018·Neuropsychopharmacology
DOI 10.1038/s41386-018-0136-3PMC PMC6098048
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Abstract

The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy ( 13 C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal 13 C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate-glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two 13 C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate-glutamine cycling, as indicated by a 13% increase in 13 C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by 13 C glutamate enrichment. During ketamine infusion, the ratio of 13 C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = -0.54, p = 0.048). The…

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Crossref · 10.1038/s41386-018-0136-3

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

32 of 44 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A main limitation of previous methods is the lack of distinction between presynaptic glutamate release and postsynaptic activation.

    “A main limitation of previous methods is the lack of distinction between presynaptic glutamate release and postsynaptic activation, the latter has been related to the RAAD effects of ketamine [14,15].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Hare B, Ghosal S, Duman R. Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chronic Stress. 2017;1:1–16. source

      The ‘Role of BDNF Translation and Signaling’ section (page unavailable) says ketamine’s antidepressant response requires AMPA receptor activity, supporting the sentence’s link between receptor activation and rapid antidepressant effects. But neither that section nor ‘Critical Microcircuits in Rapid Antidepressant Responses’ (page unavailable) says that previous methods could not distinguish presynaptic glutamate release from postsynaptic activation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [15] Abdallah CG, Sanacora G, Duman RS, Krystal JH. The neurobiology of depression, ketamine and rapid-acting antidepressants: is it glutamate inhibition or activation? Pharmacol Ther. 2018. https://doi.org/10.1016/j.pharmthera.2018.05.010 . source
  • Premisecitation

    Rodent studies have shown that ketamine and other NMDA receptor antagonists transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex.

    “Rodent studies employing carbon-13 magnetic resonance spectroscopy ( 13 C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Chowdhury GM, Behar KL, Cho W, Thomas MA, Rothman DL, Sanacora G. 1H-[13C]-nuclear magnetic resonance spectroscopy measures of ketamine’s effect on amino acid neurotransmitter metabolism. Biol Psychiatry. 2012;71:1022–5. source

      The Discussion (page not supplied) reports that subanesthetic ketamine acutely increased carbon-13 labeling of glutamate and glutamine in rodent medial prefrontal cortex, suggesting increased glutamate–glutamine cycling. The paper did not use these spectroscopy methods to show the same effect for other NMDA receptor antagonists; its Introduction instead discusses transient glutamate increases reported by microdialysis studies. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [17] Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–6. source

      The Results and Discussion report that carbon-13 NMR measures of glutamate–glutamine cycling increased in rat medial prefrontal cortex after ketamine and the NMDA receptor antagonist Ro 25-6981. The Discussion establishes that ketamine’s effect was transient, but explicitly says Ro 25-6981’s time course was not examined, so the source does not establish that its increase was transient. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    13C MRS is presently the only method that provides direct dynamic measurements of glutamate-glutamine cycling in the human brain.

    “13 C MRS is presently the only method that provides direct dynamic measurements of glutamate-glutamine cycling in the human brain [10].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Rothman DL, De Feyter HM, de Graaf RA, Mason GF, Behar KL. 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed. 2011;24:943–57. source

      The Introduction says that following 13C label into glutamate and glutamine, combined with metabolic modeling, allows measurement of neurotransmitter cycling rates in the human brain. The Summary and Conclusions calls 13C MRS the only *non-invasive* method for measuring this cycling. The claim omits that qualification and describes the measurement as direct, whereas the paper says it depends on metabolic modeling. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    1H MRS shows changes in tissue content of glutamate and/or glutamine during ketamine infusion.

    “1 H MRS, a method capable of estimating total-but not dynamic cycling of-prefrontal glutamate and glutamine levels show changes in tissue content of glutamate and/or glutamine during ketamine infusion [32,[41][42][43], but also see [44].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [32] Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS, et al. Utility of imaging-based biomarkers for glutamate-targeted drug development in psychotic disorders: a randomized clinical trial. JAMA Psychiatry. 2018;75:11–9. source
    • cites [41] Milak MS, Proper CJ, Mulhern ST, Parter AL, Kegeles LS, Ogden RT, et al. A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol Psychiatry. 2016;21:320–7. source
    • cites [42] Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry. 2005;162:394–6. source
  • Interpretationcitation

    The alteration of EPC acutely post injection may reflect a transient reduction in postsynaptic activation due to blockade of postsynaptic NMDAR by ketamine and its metabolite, norketamine.

    “The alteration of EPC acutely post injection may reflect a transient reduction in postsynaptic activation [9] due to blockade of postsynaptic NMDAR by ketamine and its metabolite, norketamine.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Abdallah CG, Jiang L, De Feyter HM, Fasula M, Krystal JH, Rothman DL, et al. Glutamate metabolism in major depressive disorder. Am J Psychiatry. 2014;171:1320–7. source

      The Discussion (page unavailable) proposes reduced glutamatergic synaptic strength in depressed subjects and links synaptic strength to AMPA and NMDA receptor transmission. That lends support to the cited idea of reduced postsynaptic activation, but the paper does not address a transient change after ketamine injection; its ketamine mentions appear in the References. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    Glutamate enrichment primarily reflects oxidative energy production through the TCA cycle, while the rate of glutamine enrichment primarily reflects glutamate neurotransmitter cycling.

    “Accordingly, the glutamate enrichment primarily reflects oxidative energy production through the TCA cycle, while the rate of glutamine enrichment primarily reflects glutamate neurotransmitter cycling [8,10].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] de Graaf RA, Rothman DL, Behar KL. State of the art direct 13C and indirect 1H-[13C] NMR spectroscopy in vivo. A practical guide. NMR Biomed. 2011;24:958–72. source
    • cites [10] Rothman DL, De Feyter HM, de Graaf RA, Mason GF, Behar KL. 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed. 2011;24:943–57. source

  • Classified as probably not a substantial claim.

    Premisecitation

    13C MRS is a unique, noninvasive method to measure neurotransmitter cycling and cell-specific neuroenergetics.

    “Carbon-13 magnetic resonance spectroscopy ( 13 C MRS) is a unique, noninvasive method to measure neurotransmitter cycling and cell-specific neuroenergetics [8][9][10].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [8] de Graaf RA, Rothman DL, Behar KL. State of the art direct 13C and indirect 1H-[13C] NMR spectroscopy in vivo. A practical guide. NMR Biomed. 2011;24:958–72. source
    • cites [9] Abdallah CG, Jiang L, De Feyter HM, Fasula M, Krystal JH, Rothman DL, et al. Glutamate metabolism in major depressive disorder. Am J Psychiatry. 2014;171:1320–7. source
    • cites [10] Rothman DL, De Feyter HM, de Graaf RA, Mason GF, Behar KL. 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed. 2011;24:943–57. source

  • May combine two claims.

    Premisecitation

    In healthy subjects, a direct link between prefrontal connectivity and glutamate neurotransmission was demonstrated, while showing an acute ketamine-induced surge in prefrontal connectivity, which is attenuated by a glutamate inhibitor.

    “In healthy subjects, a direct link between prefrontal connectivity and glutamate neurotransmission was demonstrated, while showing an acute ketamine-induced surge in prefrontal connectivity, which is attenuated by a glutamate inhibitor [37].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Abdallah CG, Averill CL, Salas R, Averill LA, Baldwin PR, Krystal JH, et al. Prefrontal connectivity and glutamate transmission: relevance to depression pathophysiology and ketamine treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:566–74. source

      The Results (GBCr & Glutamate Modulators; page unavailable) report that ketamine increased prefrontal connectivity in healthy subjects and that lamotrigine pretreatment significantly reduced those increases. But the Abstract Conclusions call the link to glutamate neurotransmission indirect, and the Discussion notes that the study did not directly show lamotrigine blocking ketamine-induced glutamate transmission in humans. Thus, the claim overstates the evidence by saying a direct link was demonstrated. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The association with BPRS positive symptoms was comparable in effect size, but did not reach statistical significance in this sample of 14 subjects.

    “The association with the Brief Psychiatric Rating Scale (BPRS) positive symptoms was comparable in effect size, but did not reach statistical significance in this sample of 14 subjects [54,55].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [54] Fukumoto K, Kato T, Li X-Y, Duman R. Role of BDNF/mTORC1 signaling in the long-lasting antidepressant effects of (2R,6R)-hydroxynorketamine. Neuropsychopharmacology. 2017;43:S111.

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

    • cites [55] Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, et al. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry. 2018;83:29–37. source

      The Results section reports scopolamine responses in mice, and Methods and Materials describes animal behavioral tests and statistical analyses; neither addresses BPRS positive symptoms. Searches for BPRS, a 14-subject sample, and the stated nonsignificant association found no supporting passage in our copy. No page numbers were provided for these passages. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In rodents, approximately 9 min after intraperitoneal injection, ketamine induces a rise in prefrontal 13C glutamine enrichment (~20%) with no changes in 13C glutamate (~1%).

    “In particular, approximately 9 min after intraperitoneal injection in rodents, ketamine induces a rise in prefrontal 13 C glutamine enrichment (~20%) with no changes in 13 C glutamate (~1%) [17]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–6. source

      The Results (time-dependence section; page unavailable) report increased prefrontal 13C glutamine enrichment during the first 0.5–8.5 minutes after intraperitoneal ketamine in rats; 13C glutamate increased significantly only during the later 10–18-minute interval. This supports the early glutamine rise and lack of a significant early glutamate change, but our copy does not state the claimed approximate 20% and 1% values. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The changes in 13C-glutamine (13%) were more prominent than 13C-glutamate (1%), comparable to preclinical findings.

    “Comparable to preclinical findings with 13 C MRS [17], the changes in 13 C-glutamine (13%) were more prominent than 13 C-glutamate (1%).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–6. source

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

    Premisecitation

    Other studies have employed pharmacoimaging paradigms to demonstrate a relationship between ketamine-induced prefrontal activation/connectivity and its transient behavioral disturbances.

    “Other studies have employed pharmacoimaging paradigms to demonstrate a relationship between ketamine-induced prefrontal activation/connectivity and its transient behavioral disturbances [29][30][31][32][33][34][35][36]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [29] Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry. 1997;154:805–11. source
    • cites [30] Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D’Souza DC, et al. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry. 2013;18:1199–204. source
    • cites [31] Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D’Souza DC, et al. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology. 2013;38:2613–22. source

  • May combine two claims.

    Premisecitation

    Preclinical studies have found that the NMDAR antagonist ketamine blocks glutamate neurotransmission, but only at high anesthetic doses.

    “Preclinical studies have found that the NMDAR antagonist ketamine blocks glutamate neurotransmission, but only at high anesthetic doses [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7. source

      The section “Effect of ketamine on extracellular glutamate levels in the PFC” reports that an anesthetic dose of 200 mg/kg significantly decreased extracellular glutamate, while subanesthetic doses increased it. The paper measures and reports decreased glutamate levels at the anesthetic dose; it does not establish that ketamine blocks glutamate neurotransmission altogether. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Interpretationcitation

    The approach parallels extant preclinical data, which facilitates the translatability of the biomarker between species.

    “The approach parallels extent preclinical data [16,17], which facilitates the translatability of the biomarker between species.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] Chowdhury GM, Behar KL, Cho W, Thomas MA, Rothman DL, Sanacora G. 1H-[13C]-nuclear magnetic resonance spectroscopy measures of ketamine’s effect on amino acid neurotransmitter metabolism. Biol Psychiatry. 2012;71:1022–5. source

      The Discussion (page unavailable) reports that ketamine increased glutamate-related cycling in rats, consistent with earlier preclinical studies. It does not establish that the biomarker translates between species; instead, it says species and methodological differences limit comparisons across studies. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [17] Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–6. source

  • May combine two claims.

    Premisecitation

    Under normal conditions, neuronal energy largely supports postsynaptic neuronal activation and functional increments are consistently proportional to changes in glutamate-glutamine cycling, resulting in a largely constant EPC ratio across species and functional conditions.

    “Under normal conditions, neuronal energy largely supports postsynaptic neuronal activation and functional increments are consistently proportional to changes in glutamate-glutamine cycling, resulting in a largely constant EPC ratio across species and functional conditions [18,19].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [18] Hyder F, Rothman DL, Bennett MR. Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels. Proc Natl Acad Sci USA. 2013;110:3549–54. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [19] Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 2004;27:489–95. source

  • May combine two claims.

    Findingown data

    In the current report, CADSS scores significantly correlated with the 13C glutamate/glutamine ratio (r = -0.54, n = 14, p = 0.048; Cohen's d = 1.3), indicating that reduced neuroenergetics relative to neurotransmitter cycling is associated with the psychotomimetic effects of ketamine in healthy participants.

    “it is intriguing that CADSS scores significantly correlated with glutamate/glutamine ratio (r = -0.54,n = 14, p = 0.048; Cohen's d = 1.3)”
    • Also stated in: § Limitations · hedged
      “presenting pilot evidence associating the psychotomimetic effects of ketamine with reduced EPC, as estimated by the 13 C glutamate/ glutamine ratio.”
    • Also stated in: § Limitations · plain
      “Reduced neuroenergetics relative to neurotransmitter cycling, as measured by the 13 C-glutamate/ 13 C-glutamine ( 13 C Glu/Gln) ratio, is associated with the psychotomimetic effects of ketamine, as measured by the Clinician-Administered Dissociative States Scale (CADSS).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 13C glutamate/glutamine ratio reflects low EPC (excitatory postsynaptic current/glutamate cycling).

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

    Study design and conductnone given

    The overlap between glutamine and aspartate peaks prevented the individual fitting of aspartate and glutamine.

    “Moreover, the overlap between glutamine and aspartate peaks prevented the individual fitting of aspartate and glutamine.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study used a single-blind, placebo-controlled, fixed-order within-subject design.

    “Two 13 C MRS scans, separated by at least 1 week, were performed using a single-blind, placebo-controlled, fixed-order within-subject design (Fig. S2).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study had a small sample size, requiring replication in larger studies.

    “Other limitations include the small sample size, which requires replication in larger studies”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other putative RAADs (e.g., scopolamine and (2R,6R)-Hydroxynorketamine) show a comparable acute surge in prefrontal glutamate and enhanced BDNF signaling.

    “Other putative RAADs (e.g., scopolamine and (2R,6R)-Hydroxynorketamine) show a comparable acute surge in prefrontal glutamate [17,[50][51][52][53] and enhanced BDNF signaling”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17,[50][51][52][53]

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

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

    Study design and conductnone given

    The study used fixed-order acquisition, requiring future test-retest reliability data or randomized parallel groups design.

    “and the fixed-order acquisition, which requires future test-retest reliability data or randomized parallel groups design.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The 13C MRS measures showed relatively low variability between sessions, with ratios of 7.3 for 13C glutamine enrichment and 11 for 13C glutamate enrichment.

    “We found relatively low variability, with ratios of 7.3 for 13 C glutamine enrichment and 11 for 13 C glutamate enrichment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Study design and conductreasoning

    The study should be considered a first-level pilot study implementing a novel technique, rather than a confirmatory study.

    “Considering that this is a first-inhuman study, this study should be considered a first-level pilot study implementing a novel technique, rather than a confirmatory study.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The psychotomimetic effects of ketamine were assessed using the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS).

    “The psychotomimetic effects of ketamine were assessed using the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) (Fig. S2).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Cramer-Rao Lower Bounds were used to estimate the quality of individual measurements, averaging 3% for glutamate and 11% for glutamine.

    “Cramer-Rao Lower Bounds were used to estimate the quality of the individual measurements, averaging 3% for glutamate and 11% for glutamine.”
    Quote in the paperNot a substantial claim
20 of 20

  • The paper relies on this without support.

    There are not yet direct measures of glutamate neurotransmission in vivo in humans to support the hypothesis that ketamine activates prefrontal glutamate neurotransmission.

    “However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses.”

  • The paper relies on this without support.

    A major obstacle in this field is the lack of biomarkers that directly reflect synaptic glutamate neurotransmission.

    “A major obstacle in this field is the lack of biomarkers that directly reflect synaptic glutamate neurotransmission.”

  • The paper relies on this without support.

    Not a single RAAD or glutamate-based antipsychotic has been approved to treat depression or schizophrenia.

    “However, to date not a single RAAD or glutamate-based antipsychotic has been approved to treat depression or schizophrenia, although two decades have passed since the RAAD and psychotomimetic effects of ketamine were first reported in the 1990s [3,7].”

  • The authors state this as an assumption.

    In the model, healthy individuals with high sensitivity to ketamine (i.e., NMDAR hypofunction) would have higher blockade of synaptic NMDAR, leading to reduced postsynaptic activation per glutamate cycle, and subsequent increase in psychotomimetic symptoms.

    “In this model, healthy individuals with high sensitivity to ketamine (i.e., NMDAR hypofunction) would have higher blockade of synaptic NMDAR, leading to reduced postsynaptic activation per glutamate cycle, and subsequent increase in psychotomimetic symptoms.”

  • The paper relies on this without support.

    The 13C glutamate/glutamine ratio reflects low EPC (excitatory postsynaptic current/glutamate cycling).

    “A possible explanation is that the low glutamate/glutamine enrichment ratio reflects low EPC.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

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.

  • Conflicting identification of the peak combined with aspartate

    Minor

    The methods say the overlapping signal was analyzed as aspartate plus glutamate, but the limitations say the overlap prevented separate fitting of aspartate and glutamine. These statements identify different metabolites as sharing the unresolved peak.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Fukumoto K, Kato T, Li X-Y, Duman R. Role of BDNF/mTORC1 signaling in the long-lasting antidepressant effects of (2R,6R)-hydroxynorketamine. Neuropsychopharmacology. 2017;43:S111.

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Authors
Abdallah, C. G., De Feyter, H. M., Averill, L. A., Jiang, L., Averill, C. L., Chowdhury, G. M. I., Purohit, P., de Graaf, R. A., Esterlis, I., Juchem, C., Pittman, B. P., Krystal, J. H., Rothman, D. L., Sanacora, G., & Mason, G. F.
Affiliations
  • United States Department of Veterans Affairs (US)
  • Yale University (US)
Corresponding author
Abdallah, Chadi G.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2018-06-28
Volume
43
Issue
10
Pages
2154-2160
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-018-0136-3
PMC
PMC6098048
OpenAlex
W2811499691
Semantic Scholar
55fa8fbd96aca1f390b69b197fb8ea34b15c3494
Cited by
229
References
58
Citations by year
2026: 25 · 2025: 33 · 2024: 25 · 2023: 30 · 2022: 39 · 2021: 27 · 2020: 26 · 2019: 20 · 2018: 4
FWCI
12.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH101498)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Keywords
ketamine, prefrontal cortex, glutamatergic neurotransmission, depression, NMDA receptor antagonists, 13C NMR, psychotomimetic effects, antidepressant effects, dissociative states
MeSH terms
Adult, Aged, Antidepressive Agents, Depressive Disorder, Energy Metabolism, Female, Glutamates, Hallucinogens, Humans, Ketamine, Male, Middle Aged, Synaptic Transmission, Magnetic Resonance Spectroscopy, Pilot Projects, Prefrontal Cortex, Excitatory Amino Acid Antagonists, Young Adult, Healthy Volunteers

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