The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index; 32 of the 44 sources its claims cite were checked for support.
The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects
Open accessAbstract
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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14 Own result · 12 Partly supported · 8 Own method · 8 Own interpretation · 7 Supported · 2 Supported so far · 2 Sources not found · 2 No full text of the sources · 1 Couldn’t confirm · accuracy not yet measured
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In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [14] Hare B, Ghosal S, Duman R. Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chronic Stress. 2017;1:1–16. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
Section 6 (Clinical Biomarkers of RAADs) explicitly identifies a main limitation of the earlier approaches: they do not distinguish presynaptic glutamate release from postsynaptic activation. The same passage says postsynaptic activation appears critical for RAAD effects; Section 4 links it specifically to ketamine's RAAD effects. The supplied passages do not give page numbers. (LLM, conf=0.95)
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In the paper
“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.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
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In the paper
“13 C MRS is presently the only method that provides direct dynamic measurements of glutamate-glutamine cycling in the human brain [10].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The Introduction says ¹H MRS tracked medial prefrontal Glx during a 40-minute ketamine infusion. The Results report significantly higher Glx during infusion than at baseline, and the Discussion explains that MRS measures total tissue levels rather than neurotransmitter transmission or movement between compartments. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [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
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In the paper
“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.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
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In the paper
“a dysconnectivity that is normalized 24 h post-ketamine treatment [37,57].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Supportedcites [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 Introduction reports a pattern of normalization of pre-treatment prefrontal connectivity alterations 24 hours after ketamine. The Results section, “GBCr in TRD & Post-ketamine,” also reports a significant increase in connectivity in the affected prefrontal clusters after treatment in patients with treatment-resistant depression. (LLM, conf=0.93)
- Supportedcites [57] Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42:1210–9. source
The Abstract reports that patients were scanned 24 hours after ketamine and that the dysconnectivity pattern appeared to normalize after treatment. The Discussion says prefrontal connectivity largely normalized at 24 hours, although cerebellar abnormalities only partially normalized. (LLM, conf=0.90)
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In the paper
“While these processes are highly coupled under normal conditions, preclinical 13 C MRS data suggest disproportionate changes following ketamine administration [16,17].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
The Results and Discussion report that subanesthetic ketamine increased 13C labeling of glutamate, glutamine, and GABA in rat medial prefrontal cortex, suggesting increases in neurotransmitter cycling and oxidative metabolism. The passages do not establish that the changes in these coupled processes were disproportionate to one another. (LLM, conf=0.78)
- Supportedcites [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 Introduction (page not provided) describes the rat prefrontal-cortex ¹³C NMR measurements as informing both neurotransmitter cycling and energy metabolism. In the Results’ dose-response section (page not provided), ketamine increased glutamine-C4 enrichment by 38% but glutamate-C4 enrichment by 9% relative to vehicle, supporting the hedged claim of disproportionate changes. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“At subanesthetic doses, ketamine induces a paradoxical increase in glutamate neurotransmission [14,49].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Supportedcites [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 describes a “rapid paradoxical burst of glutamate” after ketamine, while the Circuit Level Response section discusses the effects of a single low dose. Together, these support the paraphrase; the cited paper specifies the medial prefrontal cortex as the site of the glutamate burst. Page numbers were not available in our copy. (LLM, conf=0.90)
- Supportedcites [49] Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH. Ketamine’s mechanism of action: a path to rapid-acting antidepressants. Depress Anxiety. 2016;33:689–97. source
The Antidepressant Mechanism of Action of Ketamine section contrasts decreased prefrontal glutamate neurotransmission at anesthetic doses with a paradoxical increase in glutamate cycling and extracellular glutamate at subanesthetic doses. It identifies this as a finding reliably shown in preclinical studies, particularly in the prefrontal cortex. (LLM, conf=0.93)
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In the paper
“It also highlights the role of prefrontal synaptic plasticity-i.e., the increased density and connectivity evident at 24 h post treatment and lasting for a week [4,56].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Not checked — no full text of the sourcecites [4] Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472–86. source
- Partly supportedcites [56] Zanos P, Gould TD. Intracellular signaling pathways involved in (S)- and (R)-ketamine antidepressant actions. Biol Psychiatry. 2018;83:2–4. sourceExperimental — accuracy not yet measured
The main text (page not provided) says ketamine-related signaling may produce synaptic plasticity changes that mediate prolonged antidepressant effects, and discusses signaling in the prefrontal cortex. It does not report increased synaptic density or connectivity at 24 hours, or establish that those changes last a week. (LLM, conf=0.86)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“The ketamine-induced subacute increases in prefrontal connectivity were positively associated with the antidepressant response [57].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Supportedcites [57] Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42:1210–9. source
The Discussion reports that prefrontal global brain connectivity largely normalized 24 hours after ketamine and that responders showed more robust prefrontal increases than nonresponders. This supports an association between the subacute connectivity increase and antidepressant response. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“By 18 min after the injection, both prefrontal 13 C glutamate (~13%) and glutamine (~35%) enrichment increased [17].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
The Results section on time dependence reports that, following ketamine injection in rats, both mPFC glutamate-C4 and glutamine-C4 13C labeling increased during the 10–18-minute interval. Our copy does not give the claimed ~13% and ~35% increases for that interval; a separate dose-response result reports 9% and 38%, respectively. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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In the paper
“The acute surge in glutamate transmission increases prefrontal synaptic connectivity, through enhanced activity-dependent brain-derived neurotrophic factor (BDNF) and related downstream signaling [14].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Supportedcites [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 Figure 2 caption in “Critical Microcircuits in Rapid Antidepressant Responses” states that increased prefrontal glutamatergic transmission facilitates BDNF- and mTORC1-mediated synaptic strengthening. The same section describes a glutamate burst leading to activity-dependent BDNF release and downstream synapse formation, while presenting the pathway as a proposed mechanism. (LLM, conf=0.90)
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In the paper
“During placebo infusion, there were no significant correlations between any of the metabolites and psychotomimetic measures (p > 0.1).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
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In the paper
“but not with BPRS Positive (r = -0.43,n = 14, p = 0.13; Cohen's d = 1.0;Fig. 5b)”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
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In the paper
“Otherwise, there were no significant correlations between 13 C glutamine or 13 C glutamate enrichment and any of CADSS, BPRS Positive, or BPRS Negative scores (p > 0.1).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
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In the paper
“but not with glutamine enrichment (r = -0.38,n = 14, p = 0.19; Cohen's d = 0.8).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
plainn = 14- Asserted: passes — The authors put it forward as true.
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In the paper
“To examine whether the cycling surge differed in MDD, we conducted an exploratory analysis, which showed a comparable effect size in healthy (d = 0.48) and MDD (d = 0.78), with no statistically significant differences between groups (p = 0.85; Fig. 4).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
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In the paper
“We found no evidence of ketamine effects on oxidative energy production, as reflected by 13 C glutamate enrichment.”
- Also stated in: § RESULTS · plain
“but no significant effect of ketamine on 13 C glutamate enrichment was seen (t = 0.2, df = 20, p = 0.81; Fig. 3).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
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In the paper
“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).”
- Also stated in: § RESULTS · plain
“In the current study, the 13 C glutamine enrichment was 13% greater during ketamine infusion than with placebo (t = 2.4, df = 20, p = 0.02; Fig. 3)”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
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In the paper
“Compared to placebo, ketamine in the healthy group induced significant increases in CADSS [mean difference (SEM) = 28 (4.1), t = 6.9, df = 13, p < 0.001]”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
plaindirectn = 14 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“or BPRS Negative symptoms (r = 0.02, n = 14, p = 0.96; Cohen's d = 0.03).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
plainn = 14- Asserted: passes — The authors put it forward as true.
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In the paper
“but not BPRS Negative symptoms [mean difference (SEM) = 1 (0.6), t = 1.7, df = 13, p = 0.10].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
plainn = 14- Asserted: passes — The authors put it forward as true.
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In the paper
“and BPRS Positive symptoms [mean difference (SEM) = 10 (1.8), t = 5.5, df = 13, p < 0.001]”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > RESULTS
plaindirectn = 14 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“demonstrating the longhypothesized ketamine-induced glutamate surge”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
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In the paper
“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).”
- Also stated in: § RESULTS · plain
“During the ketamine infusion, the 13 C glutamate/glutamine enrichment ratio was negatively correlated with CADSS (r = -0.54,n = 14, p = 0.048; Cohen's d = 1.3;Fig. 5a)”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
plaincorrelationaln = 14 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
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- Rests on an assumption: There are not yet direct measures of glutamate neurotransmission in vivo in humans to support the hypothesis that ketamine activates prefrontal glutamate neurotransmission.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is consistent with the occurrence of an acute ketamine-induced glutamate surge in humans, using a paradigm that is readily translated between animals and humans.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
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In the paper
“Together, the human evidence is consistent with the findings from preclinical models, with particular focus on the essential role of acute and subacute prefrontal synaptic neurotransmission and connectivity in the mechanism of ketamine and perhaps other RAADs.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“In humans, functional global brain connectivity was previously used to provide a well-replicated evidence of reduced prefrontal connectivity in individuals with MDD [37,[57][58][59]”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Not matchedcites [37,[57][58][59]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, the preclinical evidence to date underscores the critical role of acute prefrontal glutamate neurotransmission in the mechanism of action of various RAADs.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, due to limitations that may include biological variability and low spatial resolution of 13 C MRS, the application of the 13 C-glutamate/glutamine ratio may be limited to alterations in glutamate neurotransmission in groups of individuals or within”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus far, this study provided first-level pilot evidence about the potential utility of the 13 C MRS pharmacoimaging paradigm in human models of schizophrenia”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.”
- Also stated in: § DISCUSSION · boosted
“The study results provide the most direct evidence yet in humans of a ketamine-induced increase in prefrontal glutamate release, based on the detection of increased 13 C labeling of glutamine.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § DISCUSSION · boosted
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The findings, taken together with published observations, suggest the possibility of a positive relationship between prefrontal glutamate cycling and global connectivity.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The ketamine-induced acute glutamate surge also plays an important role in the psychotomimetic effects of the drug, behavioral alterations that are believed to capture core phenomenology of the pathophysiology of schizophrenia [28].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [28] Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37:4–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Early studies have shown that inhibitors of glutamate release attenuate the ketamine-induced psychotomimetic symptoms [20][21][22][23].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [20] Deakin JF, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008;65:154–64. source
- Not checked — no full text of the sourcecites [21] Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl). 2005;179:303–9. source
- Not checked — no full text of the sourcecites [22] Krystal JH, Mathew SJ, D’Souza DC, Garakani A, Gunduz-Bruce H, Charney DS. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs. 2010;24:669–93. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 14
- Probably not a substantial claim. 10
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Supportedcites [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
In Methods, under “[1-13C]-glucose and [1,6-13C2]-glucose” (page unavailable), the paper says glutamate label transfer indicates the TCA-cycle rate, while subsequent transfer to glutamine reflects the glutamate–glutamine neurotransmitter cycle. This supports the claim in the context of the labeled-glucose experiments discussed there. (LLM, conf=0.90)
- Supportedcites [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 (page unavailable) says that tracing label into glutamate and glutamine, together with metabolic modeling, measures cell-specific TCA-cycle rates and neurotransmitter cycling. Section 3.1 (page unavailable) specifically derives the neuronal TCA-cycle rate from isotopic turnover of the large glutamate pool; Sections 2.1 and 2.3 identify neurotransmitter cycling as the major source of glutamine under normal conditions. The claim is supported as a description of these labeling measurements, rather than enrichment alone being a direct rate measurement. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Carbon-13 magnetic resonance spectroscopy ( 13 C MRS) is a unique, noninvasive method to measure neurotransmitter cycling and cell-specific neuroenergetics [8][9][10].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Supportedcites [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
The Abstract describes 13C NMR with labeled-substrate infusion as a noninvasive way to measure metabolic fluxes. The Methods (Metabolic modeling; page not available in our copy) explain that the measurements can be used to calculate neurotransmitter-cycle fluxes and separate neuronal and astroglial TCA-cycle fluxes, supporting the cell-specific neuroenergetics claim. (LLM, conf=0.91)
- Supportedcites [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 Results section describes 13C MRS as providing unique information on dynamic metabolism and neurotransmission, including a measure of glutamate/glutamine cycling. The Discussion explains that kinetic modeling can separate measures of energy production among neuronal and glial compartments in vivo. The paper’s method uses an intravenous tracer infusion, but this does not contradict the description of MRS measurement as noninvasive. (LLM, conf=0.90)
- Supportedcites [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 in vivo MRS is unique in measuring cell-type-specific energetics and neuronal/glial neurotransmitter cycles. The Summary and Conclusions describes 13C MRS as the only noninvasive method for measuring neuronal and glial energy metabolism and glutamate and GABA neurotransmitter cycling. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Not matchedcites [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.
- Could not verifycites [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. sourceExperimental — accuracy not yet measured
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)
plaincorrelationaln = 14- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Comparable to preclinical findings with 13 C MRS [17], the changes in 13 C-glutamine (13%) were more prominent than 13 C-glutamate (1%).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Supportedcites [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 (dose-response effects) report that ketamine increased 13C-glutamine enrichment by 38% and 13C-glutamate enrichment by 9% in rat mPFC. This supports the cited comparison: the preclinical glutamine change was more prominent. The 13% and 1% figures describe the citing study’s own results, not figures attributed to this source. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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]”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The Results report that ketamine-induced changes in functional connectivity predicted positive symptoms, including in a cluster extending from the orbital frontal cortex. This supports the cited sentence’s claim of a relationship between prefrontal connectivity and transient behavioral disturbances; the paper measures connectivity, not activation. (LLM, conf=0.90)
- Supportedcites [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
The Discussion reports that ketamine impaired spatial working-memory performance, reduced prefrontal activation and task-related connectivity, and that the activation and connectivity reductions were related to performance. The Performance section also describes associations between ketamine-related brain changes and performance decrements. The behavioral relationship demonstrated here is specifically with working-memory performance. (LLM, conf=0.90)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Preclinical studies have found that the NMDAR antagonist ketamine blocks glutamate neurotransmission, but only at high anesthetic doses [48].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The approach parallels extent preclinical data [16,17], which facilitates the translatability of the biomarker between species.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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 Introduction describes a preclinical approach measuring glutamate cycling in rat prefrontal cortex with ¹H-[¹³C]-NMR spectroscopy. The Conclusion explicitly says this approach can be relatively easily translated to human studies, supporting the claimed cross-species translatability; it does not report human validation. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > INTRODUCTION
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [19] Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 2004;27:489–95. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > DISCUSSION
plaincorrelationaln = 14 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 13C glutamate/glutamine ratio reflects low EPC (excitatory postsynaptic current/glutamate cycling).
- Also stated in: § Limitations · hedged
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the overlap between glutamine and aspartate peaks prevented the individual fitting of aspartate and glutamine.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Study population
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Other limitations include the small sample size, which requires replication in larger studies”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
What the sources say
- Not matchedcites [17,[50][51][52][53]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“and the fixed-order acquisition, which requires future test-retest reliability data or randomized parallel groups design.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We found relatively low variability, with ratios of 7.3 for 13 C glutamine enrichment and 11 for 13 C glutamate enrichment.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Study population
plainn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The psychotomimetic effects of ketamine were assessed using the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) (Fig. S2).”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Study population
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cramer-Rao Lower Bounds were used to estimate the quality of the individual measurements, averaging 3% for glutamate and 11% for glutamine.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Study population
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
In the citing paper
“In human MDD patients, ketamine administration similarly increases glutamate/glutamine cycling in PFC 225.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [225]
In the citing paper
“when MRS is combined with infusion of carbon-13 non-radioactive isotopes ( 13 C MRS), we can estimate the overall glutamate release and cycling (V Cycle ), neuronal energetic consumption (V TCAn ) and the energy-percycle ratio (V TCAn /V Cycle )”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [21]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Study population
“Due to the overlap, we analyzed the combined aspartate and glutamate peaks.”
§ The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects > Limitations
“Moreover, the overlap between glutamine and aspartate peaks prevented the individual fitting of aspartate and glutamine.”
Citations
Cites
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
Self-citationA randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766
Krystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330
Self-citationMoghaddam, B., Adams, B., Verma, A., & Daly, D. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-08-02921.1997 · Cited by 1,793
Moghaddam, B., & Javitt, D. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.181 · Cited by 1,035
Energetic basis of brain activity: implications for neuroimaging
Shulman, R. G., Rothman, D. L., Behar, K. L., & Hyder, F. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.06.005 · Cited by 590
Self-citationTargeting glutamate signalling in depression: progress and prospects
Murrough, J. W., Abdallah, C. G., & Mathew, S. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.16 · Cited by 482
Self-citationAnand, A., Charney, D. S., Oren, D. A., Berman, R. M., Hu, X. S., Cappiello, A., & Krystal, J. H. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.3.270 · Cited by 426
Self-citationVollenweider, F. X., Leenders, K. L., Øye, I., Hell, D., & Angst, J. (1997) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(96)00042-9 · Cited by 413
(1997) · American Journal of Psychiatry · doi:10.1176/ajp.154.6.805 · Cited by 392
Research works printed but not linked: 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.
Cited by
Sorted by citations
Dopamine and glutamate in schizophrenia: biology, symptoms and treatment
McCutcheon, R. A., Krystal, J. H., & Howes, O. D. (2020) · World Psychiatry · doi:10.1002/wps.20693 · Cited by 612
Self-citationKetamine: A Paradigm Shift for Depression Research and Treatment
Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.005 · Cited by 455
Self-citationHare, B. D., & Duman, R. S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0685-9 · Cited by 366
“indicative of immediate circuit level effects [15].”
BackgroundYan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300
“In human MDD patients, ketamine administration similarly increases glutamate/glutamine cycling in PFC [225].”
BackgroundKetamine and rapid antidepressant action: New treatments and novel synaptic signaling mechanisms
Krystal, J. H., Kavalali, E. T., & Monteggia, L. M. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-023-01629-w · Cited by 262
“…a 13 C-MRS involving the infusion of 13 C-glucose as a metabolic tracer, in a mixed group of healthy subjects ( n = 14) and MDD patients ( n = 7), described a 13% increase in 13 C-glutamine enrichment, i.e., an increase in V Cycle , that correlated with the emergence of dissociation symptoms [70].”
BackgroundMethodInfluentialSelf-citation
Metadata
- 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
- Published
- 2018-06-28
- Volume
- 43
- Issue
- 10
- Pages
- 2154-2160
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- 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
- bronze
- doi.org
- 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 (medical) › 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
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.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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