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)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
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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)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly 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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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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- Based: passes — The paper gives a reason why it holds.
- Supported
- 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
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Self-citationA randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
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Energetic basis of brain activity: implications for neuroimaging
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Self-citationTargeting glutamate signalling in depression: progress and prospects
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Research works printed but not linked: 1
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Cited by
Sorted by citations
Items 101–200 of 226
Gärtner, M., Weigand, A., Scheidegger, M., Lehmann, M., Wyss, P. O., Wunder, A., Henning, A., & Grimm, S. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01377-2 · Cited by 13
“[30] reported that ketamine increases prefrontal glutamate–glutamine cycling, thereby providing the most direct evidence in humans that ketamine increases glutamate release in the prefrontal cortex.”
BackgroundDoes mismatch negativity have utility for NMDA receptor drug development in depression?
Murphy, N., Lijffijt, M., Ramakrishnan, N., Vo-Le, B., Vo-Le, B., Iqbal, S., Iqbal, T., O'Brien, B., Smith, M. A., Swann, A., et al. (2021) · Revista Brasileira de Psiquiatria · doi:10.1590/1516-4446-2020-1685 · Cited by 11
A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine
Elmeseiny, O. S. A., & Müller, H. K. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107081 · Cited by 14
Marcatili, M., Sala, C., Dakanalis, A., Colmegna, F., D’Agostino, A., Gambini, O., Dell’Osso, B. M., Benatti, B., Conti, L., & Clerici, M. (2020) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125320968331 · Cited by 13
Moore, T. M., Walker, K. C., Tung, E., Teed, A. R., Hell, F., Kinreich, S., Jung, R., Abdel, F., Hanson, R. W., & Ahmed, S. S. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.04.041 · Cited by 13
Grados, M. A., Salehi, M., Lotfi, A., Dua, S. S., & Xie, I. Y. (2024) · Frontiers in Drug Delivery · doi:10.3389/fddev.2024.1364037 · Cited by 14
Yang, C., Ali, T., Li, A., Gao, R., Yu, X., Li, S., & Li, T. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110156 · Cited by 11
Kang, J. S., Kim, H., Baek, J. H., Song, M., Park, H., Jeong, W., Chung, H. J., Yoo, D. Y., Lee, D. K., Park, S. W., et al. (2025) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01441-2 · Cited by 12
“These fi ndings have been reinforced by other reports [20 – 24].”
Kim, J., Sapio, M. R., Vazquez, F. A., Maric, D., Loydpierson, A. J., Ma, W., Zarate, C. A., Iadarola, M. J., & Mannes, A. J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.892345 · Cited by 14
“, 2019b), increased glutamate neurotransmission (Abdallah et al., 2018), and increased hippocampal synaptic potentiation (Nosyreva et al.”
BackgroundKojic, M., Saelens, J., Kadriu, B., Zarate, C. A., & Kraus, C. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_313 · Cited by 12
Brakatselos, C., Polissidis, A., Ntoulas, G., Asprogerakas, M.-Z., Tsarna, O., Vamvaka-Iakovou, A., Nakas, G., Delis, A. D., Tzimas, P., Skaltsounis, A., et al. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01977-1 · Cited by 10
Moccia, L., TOFANI, A., Mazza, M., Covino, M., Martinotti, G., Schifano, F., Janiri, L., & Nicola, M. D. (2019) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2019.1578444 · Cited by 10
“…administration of NMDA antagonists, including KET, results in a massive glutamate surge and changes in activities within DLPFC and other prefrontal brain regions (Breier et al. 1997; Abdallah et al. 2018), a mechanism that has been postulated to be central to drug-induced positive symptomatology.”
BackgroundZhang, T., Deng, D., Huang, S., Fu, D., Wang, T., Xu, F., Ma, L., Ding, Y., Wang, K., Wang, Y., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1140275 · Cited by 11
“However, other studies have demonstrated that ketamine application increases synaptic glutamate release (Abdallah et al., 2018; Lisek et al., 2017).”
BackgroundSajid, S., Galfalvy, H., Keilp, J. G., Burke, A. K., Mann, J. J., & Grunebaum, M. F. (2024) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae017 · Cited by 12
“…neurons, leading to a glutamate spike that potentially triggers increased synaptic formation and strengthening, which is thought to reverse depression-induced synaptic loss (Abdallah et al., 2018; Zanos and Gould, 2018; Matveychuk et al., 2020; Milak et al., 2020; Rosenbaum et al., 2023).”
BackgroundShen, M., Lv, D., Li, S., Zhang, Y., Wang, Z., Zhao, C., Chen, X., & Wang, C. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy324 · Cited by 10
Belloch, F. B., Beltrán, E., Vénzala, E., Montalt‐Tordera, J., Diaz-Perdigón, T., Cecon, E., Puerta, E., Delagrange, P., & Tordera, R. M. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.12.012 · Cited by 10
Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain
Gärtner, M., Weigand, A., Keicher, C., Meiering, M. S., Weigner, D., Carstens, L., Hertrampf, R., Beckmann, C. F., Mennes, M., Wunder, A., et al. (2023) · Neuropsychobiology · doi:10.1159/000528315 · Cited by 11
Treatment response with ketamine in chronic suicidality: An open label functional connectivity study
Can, A., Hermens, D. F., Mohamed, A. Z., Shan, Z., Dutton, M., Gallay, C. C., Forsyth, G., Jamieson, D., & Lagopoulos, J. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.03.064 · Cited by 10
Bednařík, P., Spurny‐Dworak, B., Silberbauer, L., Svátková, A., Handschuh, P. A., Reiter, B., Konadu, M. E., Stimpfl, T., Spies, M., Bogner, W., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.609485 · Cited by 9
Poulia, N., Delis, F., Brakatselos, C., Ntoulas, G., Asprogerakas, M.-Z., & Antoniou, K. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.746935 · Cited by 9
The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders
(2023) · International Review of Neurobiology · doi:10.1016/bs.irn.2022.10.007 · Cited by 8
Self-citationThe effect of low-dose esketamine on maternal depression after cesarean delivery
Shang, Y., Li, S., Zheng, Q., Mi, T., Lv, Y.-Z., Han, L., & Wang, B.-R. (2025) · Journal of Psychosomatic Obstetrics and Gynaecology · doi:10.1080/0167482x.2025.2527659 · Cited by 9
“…studies demonstrate ketamine’s effects are amplified in individuals with baseline glutamatergic dysfunction, a hallmark of major depression [24]; (2) Recent trials of perioperative ketamine in surgically-naïve depressed patients show larger effect sizes (cohen’s d = 0.8–1.2) than observed…”
InfluentialSynaptic priming: A framework for pharmacotherapy in depression
Brown, K. A., Ajibola, M. I., Medeiros, G. C., & Gould, T. D. (2025) · Neuron · doi:10.1016/j.neuron.2025.09.010 · Cited by 11
Biological embedding of early trauma: the role of higher prefrontal synaptic strength
Tamman, A. J. F., Jiang, L., Averill, C. L., Mason, G. F., Averill, L. A., & Abdallah, C. G. (2023) · European Journal of Psychotraumatology · doi:10.1080/20008066.2023.2246338 · Cited by 9
Self-citationTheilmann, W., Rosenholm, M., Hampel, P., Löscher, W., & Rantamäki, T. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235046 · Cited by 8
“Ketamine provokes cortical excitability by increasing glutamatergic neurotransmission [74,75].”
BackgroundPepe, M., Nicola, M. D., Cocciolillo, F., Chiappini, S., Martinotti, G., Calcagni, M. L., & Sani, G. (2024) · Pharmaceuticals · doi:10.3390/ph17040452 · Cited by 8
“…reporting the role of glutamatergic dysfunctions in corticostriatal networks in the development of addiction [72], as well as the relationship between drug-induced psychotic symptoms and alterations in multiple brain regions following the acute administration of NMDA receptor antagonists [73].”
BackgroundThe therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine
Park, D., Lee, G., Lee, W.-G., Kim, B. S., Lee, Y., & Kim, J. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03100-2 · Cited by 11
“2A, left) [15, 59, 60, 91 – 93].”
Cortical Mechanisms Contributing to Ketamine-Induced Dissociation
Bera, K., Looger, L. L., Proekt, A., & Cichon, J. (2025) · The Neuroscientist · doi:10.1177/10738584251403946 · Cited by 9
Trenado, C., Seifritz, E., Olbrich, S., & Ferrea, S. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120751 · Cited by 8
Exploring effects and experiences of ketamine in group couples therapy
Cornfield, M., McBride, S., Torre, J. T. L., Zalewa, D., Gallo, J., Mahammadli, M., & Williams, M. T. (2024) · Journal of Psychedelic Studies · doi:10.1556/2054.2024.00302 · Cited by 8
“Ketamine targets glutamate pathways, increasing the synaptic release of glutamate while also promoting neuroplasticity (Abdallah et al., 2018).”
BackgroundEffect of Ketamine Treatment on Social Withdrawal in Autism and Autism-Like Conditions
Ralston, M. J., Osman, A., Suryadevara, P., & Cleland, E. (2024) · Clinical Neuropharmacology · doi:10.1097/wnf.0000000000000591 · Cited by 6
Shinohara, R., & Furuyashiki, T. (2022) · Neuroscience Research · doi:10.1016/j.neures.2022.12.015 · Cited by 7
Cao, Y., Chen, T., Xia, H., Zhu, H. L., Hou, H., Guo, Z., Wei, F., & Liu, X. (2023) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.5910 · Cited by 5
Gold, N. D., Mallard, A. J., Hermann, J. C., Zeifman, R. J., Pagni, B. A., Bogenschutz, M. P., & Ross, S. (2023) · Journal of Palliative Medicine · doi:10.1089/jpm.2022.0604 · Cited by 6
“121 While ketamine blocks glutamate directly at NMDA receptor sites at high anesthetic doses, it induces an acute surge of glutamate activity at sub-anesthetic, or psychedelic, doses, 122 and it is not understood how this acute surge may affect ALS pathology.”
The Meaning of Glutamate and the Quest for Biomarkers in the Transition to Psychosis
Bustillo, J., Gaudiot, C., & Lenroot, R. (2018) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2018.3251 · Cited by 6
Ketamine plasmonic sensor using polyaniline-rGO-Fe3O4 nanocomposite thin layer
Sadrolhosseini, A. R., Hamidi, S. M., Kazemzad, M., Rafiei, A., Amouyan, F., & Sadeghi, S. (2022) · Sensors and Actuators A Physical · doi:10.1016/j.sna.2022.113896 · Cited by 5
Grice, A. B., Sloofman, L. G., Levy, T., Walker, H., Ganesh, G., Santos, M. R. D. L., Amini, P., Buxbaum, J. D., Kolevzon, A. L., Kostić, A., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03005-8 · Cited by 5
Abdallah, C. G., & Mason, G. F. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01122-2 · Cited by 5
Self-citationCircadian neuromarkers of mood disorders
Agnorelli, C., & Fagiolini, A. M. (2022) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2022.100384 · Cited by 6
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Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy HumansPreprint
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“In humans, intravenous administration of ketamine increases resting brain activity as measured by positron emission tomography (PET) (20-23), resting fMRI functional connectivity (24), an MRS-based measure of glutamate release (25), and a PET indirect estimate of glutamate release (26-28).”
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“At sub-anesthetic doses in humans, it induces an hypofunction of NMDA receptors and increases the release of glutamate in cortical structures [112,113].”
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“4,16 Although several mechanisms may contribute to the rapid antidepressant effect of these drugs, their impact on glutamate transmission is thought to be central.”
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Exploring Psychedelics for Unmet Needs in Women’s Reproductive Health
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“Findings in ketamine studies suggest that NMDA antagonism can increase Glx in specific brain regions[29,30].”
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“Similarly, clinical studies using carbon-13 magnetic resonance spectroscopy ( 13 C MRS) methods confirmed that ketamine increased glutamate-glutamine cycling in the prefrontal cortex in depressed patients [59], as well as in the hippocampus in healthy volunteers [60].”
ResultThe role of ketamine as an antidepressant agent
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“Adaptions in neurotransmitter content were reported with elevated glutamatergic levels in the medial prefrontal cortex (Abdallah et al. 2018) and decreased GABA levels in the hippocampus (Silberbauer et al. 2020).”
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“In addition to these two glutamatergic mechanisms, ketamine can increase glutamate-glutamine cycling in neurons and glial cells, leading to extracellular glutamate levels in the PFC of animal models and human patients [73,74].”
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Interventional Mental Health: A Transdisciplinary Approach to Novel Psychiatric Care Delivery
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“Additionally, brainderived neurotrophic factor (BDNF), a “master-regulator” molecule with key roles in promoting neuroplasticity, expression is significantly reduced in patients with depression [21-24].”
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“Then, the TrkB receptor is stimulated and causes mTORC1 activation and motivates the synthesis of dendritic spines that share a temporal profile with antidepressant effects (34).”
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“The glutamate ‘surge’ induced by psychedelic doses of ketamine is generally thought to be acute, 52,53 not extending beyond the drug’s presence in the body, as previous studies did not detect significant changes in glutamate concentrations at 1–2 days post-ketamine in either healthy subjects or…”
From Bench to Bedside: Understanding General Anesthetics' Impact on PTSD
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Pharmacotherapy for Cocaine Use Disorders
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Ketamine and Other Glutamate Receptor Antagonists As Fast-Actin
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Perspective Chapter: Ketamine, Depression, and Gender Bias
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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
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