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…
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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
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.
- 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
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
- 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.
- 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.
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.
- 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
“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.
- 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.
- 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.
- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
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.
- 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.
- 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
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-citationIonotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors
Hanada, T. (2020) · Biomolecules · doi:10.3390/biom10030464 · Cited by 252
“Similarly, it is accepted that ketamine inhibits GABAergic interneuron activity and causes a surge of extracellular glutamate after administration in animals and humans [71,72].”
BackgroundHare, B. D., Shinohara, R., Liu, R. J., Pothula, S., DiLeone, R. J., & Duman, R. S. (2019) · Nature Communications · doi:10.1038/s41467-018-08168-9 · Cited by 217
Brain NMDA Receptors in Schizophrenia and Depression
Adell, A. (2020) · Biomolecules · doi:10.3390/biom10060947 · Cited by 225
“Although no direct measure of brain glutamate level can be determined from the brain of schizophrenics, some indirect estimates have implicated increased activation of prefrontal cortex in first-episode schizophrenia [62–64] and after ketamine administration [65,66], which can be taken as suggestive of increased gluta…”
BackgroundNeurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine
Deyama, S., & Duman, R. S. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172837 · Cited by 186
Beck, K., Hindley, G., Borgan, F., Ginestet, C. E., McCutcheon, R. A., Brugger, S. P., Driesen, N. R., Ranganathan, M., D’Souza, D. C., Taylor, M. J., et al. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.4693 · Cited by 201
Self-citationThe Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder
Abdallah, C. G., Averill, L. A., Akiki, T. J., Raza, M., Averill, C. L., Gomaa, H., Adikey, A., & Krystal, J. H. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021701 · Cited by 179
Self-citationGlutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder
Sarawagi, A., Soni, N. D., & Patel, A. B. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.637863 · Cited by 184
Glutamatergic dysfunction in Schizophrenia
Kruse, A. O., & Bustillo, J. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02253-w · Cited by 162
“Consistent with the NMDA hypofunction model, in healthy controls and depressed subjects, systemic ketamine induced increased Glu/Gln cycling in the prefrontal cortex [139].”
BackgroundKohtala, S. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00232-4 · Cited by 155
“These findings correspond well to other findings suggesting increased glutamate neurotransmission in the prefrontal cortex of healthy and depressed subjects receiving ketamine [198, 199].”
ResultKetamine: Mechanisms and Relevance to Treatment of Depression
Kim, J., Suzuki, K., Kavalali, E. T., & Monteggia, L. M. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-051322-120608 · Cited by 131
General Anesthesia: A Probe to Explore Consciousness
Bonhomme, V. L., Staquet, C., Montupil, J., Defresne, A., Kirsch, M., Martial, C., Vanhaudenhuyse, A., Chatelle, C., Larroque, S. K., Raimondo, F., et al. (2019) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2019.00036 · Cited by 127
“Magnetic resonance spectroscopy studies looking at in vivo neurotransmission will probably offer new insights soon (Abdallah et al., 2018).”
BackgroundSynaptic Mechanisms Regulating Mood State Transitions in Depression
Parekh, P. K., Johnson, S. B., & Liston, C. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-110920-040422 · Cited by 101
Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaa087 · Cited by 99
Oxidative Stress at the Crossroads of Aging, Stroke and Depression
Shao, A., Lin, D., Wang, L., Tu, S., Lenahan, C., & Zhang, J. (2020) · Aging and Disease · doi:10.14336/ad.2020.0225 · Cited by 101
“Particularly, ketamine is involved in inducing the rapid antidepressant effects through increasing the release of glutamate in the body [265] and affecting energy metabolism in MDD [256].”
BackgroundJelen, L. A., & Stone, J. M. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2020.1854194 · Cited by 112
“This disinhibition of glutamatergic neurons results in an acute cortical glutamate surge (Abdallah et al., 2018; Milak et al., 2016; Moghaddam et al., 1997) and subsequent activation of post-synaptic a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors appears to be a crucial…”
BackgroundThe opioid system in depression
Jelen, L. A., Stone, J. M., Young, A. H., & Mehta, M. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104800 · Cited by 108
“This disinhibition of pyramidal neurons appears to cause an acute glutamate surge (Moghaddam et al., 1997; Abdallah et al., 2018), subsequent activation of post-synaptic AMPA receptors, resulting in activation of neuroplastic signalling pathways and synaptogenesis (Lener et al.”
Amidfar, M., Woelfer, M., Réus, G. Z., Quevedo, J., Walter, M., & Kim, Y. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109668 · Cited by 95
Ketamine triggers a switch in excitatory neuronal activity across neocortex
Cichon, J., Wasilczuk, A. Z., Looger, L. L., Contreras, D., Kelz, M. B., & Proekt, A. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01203-5 · Cited by 87
Imaging the effect of ketamine on synaptic density (SV2A) in the living brain
Holmes, S. E., Finnema, S. J., Naganawa, M., DellaGioia, N., Holden, D., Fowles, K., Davis, M., Ropchan, J., Emory, P., Ye, Y., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01465-2 · Cited by 78
Self-citationLazarevic, V., Yang, Y., Flais, I., & Svenningsson, P. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01246-3 · Cited by 81
The anterior cingulate cortex as a key locus of ketamine’s antidepressant action
Alexander, L., Jelen, L. A., Mehta, M. A., & Young, A. H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.05.003 · Cited by 83
“Studies in rodents have shown that NMDAR blockade can cause a glutamate surge acutely, likely in circuits predominated by interneurons, followed by mammalian target of rapamycin (mTOR)-mediated neuroplastic changes over several hours to days (Abdallah et al., 2018; Lener et al., 2017).”
Kang, M. J. Y., Hawken, E., & Vazquez, G. H. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.860882 · Cited by 77
“Supporting this, ketamine induced an increase in prefrontal glutamate release in humans, measured by 13Cglutamine labeling of glutamine, which were more prominent than 13C-glutamate (40).”
BackgroundAbdallah, C. G., Dutta, A., Averill, C. L., McKie, S., Akiki, T. J., Averill, L. A., & William Deakin, J. F. (2018) · Chronic Stress · doi:10.1177/2470547018796102 · Cited by 70
Self-citationKrystal, J. H., Kaye, A. P., Jefferson, S., Girgenti, M. J., Wilkinson, S. T., Sanacora, G., & Esterlis, I. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2305772120 · Cited by 83
Self-citationPicard, N., Takesian, A. E., Fagiolini, M., & Hensch, T. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0341-9 · Cited by 71
Structural neural plasticity evoked by rapid-acting antidepressant interventions
Liao, C., Dua, A. N., Wojtasiewicz, C., Liston, C. M., & Kwan, A. C. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00876-0 · Cited by 81
“Magnetic resonance spectroscopy shows elevated prefrontal glutamate and glutamine metabolite levels in individuals with depression after ketamine treatment 65 and after ECT 66 .”
Banasr, M., Sanacora, G., & Esterlis, I. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.04.004 · Cited by 71
Self-citationRodent ketamine depression-related research: Finding patterns in a literature of variability
Polis, A. J., Fitzgerald, P. J., Hale, P. J., & Watson, B. O. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112153 · Cited by 63
Neurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities
Shinohara, R., Aghajanian, G. K., & Abdallah, C. G. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.006 · Cited by 54
Self-citationNogo, D., Jasrai, A. K., Kim, H., Nasri, F., Ceban, F., Lui, L. M. W., Rosenblat, J. D., Vinberg, M., Ho, R., & McIntyre, R. S. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06105-9 · Cited by 54
“Ketamine may act on the glutamatergic NMDA receptors, which leads to increased glutamate release and AMPA receptor expression, thereby increasing glutamate neurotransmission (Abdallah et al. 2018; Weckmann et al. 2019).”
BackgroundSex differences in resilience: Experiential factors and their mechanisms
Fallon, I. P., Tanner, M. K., Greenwood, B. N., & Baratta, M. V. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14639 · Cited by 62
Rothman, D. L., de Graaf, R. A., Hyder, F., Mason, G. F., Behar, K. L., & De Feyter, H. M. (2019) · NMR in Biomedicine · doi:10.1002/nbm.4172 · Cited by 53
Self-citationPillinger, T., Rogdaki, M., McCutcheon, R. A., Hathway, P., Egerton, A., & Howes, O. D. (2019) · Psychopharmacology · doi:10.1007/s00213-019-5188-5 · Cited by 53
“…of ketamine found increased prefrontal glutamate release (a ‘glutamate surge’), and loss of neurotransmission fidelity (i.e. a mismatch between pre-synaptic glutamate release and post-synaptic activity) which was associated with the induction of psychotomimetic experiences (Abdallah et al. 2018).”
BackgroundKim, J., & Monteggia, L. M. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112378 · Cited by 56
“levels in the prefrontal cortex following ketamine treatment that correlates with schizophrenic symptoms [70, 71].”
BackgroundThe neurophysiology of ketamine: an integrative review
McMillan, R. L., & Muthukumaraswamy, S. D. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0090 · Cited by 51
Abram, S. V., Roach, B. J., Fryer, S. L., Calhoun, V. D., Preda, A., van Erp, T. G. M., Bustillo, J., Lim, K. O., Loewy, R. L., Stuart, B. K., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01502-0 · Cited by 49
“The ketamine dose was comparable to doses from studies showing altered prefrontal function during infusion in healthy individuals [46, 48], and the lamotrigine dose (300mg) was chosen based on safety considerations and evidence showing that this lamotrigine dose attenuated ketamine’s behavioral effects [44].”
BackgroundSelf-citationRantamäki, T., & Kohtala, S. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018697 · Cited by 45
“…ofNMDARspresent onGABAergic interneurons, which leads to decreased inhibition of excitatory pyramidal neurons and increased glutamatergic signaling (Homayoun and Moghaddam, 2007), as demonstrated in animals (Moghaddam et al., 1997; Chowdhury et al., 2017) and humans (Abdallah et al., 2018a).”
BackgroundInfluentialKohtala, S., Alitalo, O., Rosenholm, M., Rozov, S. V., & Rantamäki, T. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107741 · Cited by 47
Deyama, S., & Kaneda, K. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109335 · Cited by 46
Mehta, M. A., & Hawkins, P. C. T. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-820480-1.00068-1 · Cited by 42
Imaging synaptic density in depression
Holmes, S. E., Abdallah, C., & Esterlis, I. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01368-4 · Cited by 39
“Importantly, the relationship between EPC and synaptic fidelity was demonstrated using pharmacoimaging challenges in healthy and MDD participants [14].”
BackgroundInfluentialSelf-citationSala, N., Paoli, C., Bonifacino, T., Mingardi, J., Schiavon, E., Via, L. L., Milanese, M., Tornese, P., Datusalia, A. K., Rosa, J., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.759626 · Cited by 38
“Furthermore, increased PFC glutamate release after acute ketamine was also demonstrated by carbon-13 (13C) magnetic resonance spectroscopy, in both healthy and depressed subjects (Milak et al., 2016; Abdallah et al., 2018).”
BackgroundJelen, L. A., Lythgoe, D. J., Stone, J. M., Young, A. H., & Mehta, M. A. (2025) · Nature Medicine · doi:10.1038/s41591-025-03800-w · Cited by 41
“For the self-report measures, there was a significant effect of time for the QIDS–SR ( F 1,74 = 96.43, P < 0.001) and for the M3VAS scores ( F 1,74 = 47.98, P < 0.001), with reductions in mean QIDS–SR scores (placebo-plus-ketamine (mean = −6.54, s.d. = 5.43); naltrexone-plus-ketamine condition (mean = −5.73, utilizing…”
InfluentialNeurobiological biomarkers of response to ketamine
Kadriu, B., Ballard, E. D., Henter, I. D., Murata, S., Gerlus, N., & Zarate, C. A. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.05.003 · Cited by 36
“Abdallah and colleagues found that the ratio of carbon-13 (13C) MRS glutamate/glutamine —a putative measure of neurotransmission strength that correlated with Clinician Administered Dissociative States Scale (CADSS) scores—was enriched during ketamine infusion, providing further evidence that ketamine increases glutam…”
BackgroundResultMaffioletti, E., Minelli, A., Tardito, D., & Gennarelli, M. (2020) · Genes · doi:10.3390/genes11091089 · Cited by 36
Garel, N., Drury, J., Lévesque, J. T., Goyette, N., Lehmann, A., Looper, K. J., Erritzøe, D., Dames, S., Turecki, G., Rej, S., et al. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1268832 · Cited by 39
“Studies in humans have also found ketamine to transiently alter cerebral GABA and glutamate concentrations (59, 60), increase neural activity in areas associated with reward processing (61), and potentially normalize default mode network connectivity abnormalities of depression (62).”
BackgroundKetamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression
Dai, D., Lacadie, C. M., Holmes, S. E., Cool, R., Anticevic, A., Averill, C., Abdallah, C., & Esterlis, I. (2020) · Chronic Stress · doi:10.1177/2470547020980681 · Cited by 34
Self-citationO’Brien, B., Lijffijt, M., Wells, A., Swann, A. C., & Mathew, S. J. (2019) · Pharmaceuticals · doi:10.3390/ph12030133 · Cited by 33
“Ketamine’s antidepressant effect has been related to pre- and post-synaptic NMDAR blockade, enhancing prefrontal [10] and hippocampal [11] glutamate concentrations which activate the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), enhancing synaptic plasticity via AMPAR-induced elevation of brai…”
BackgroundAbdallah, C. G., Ahn, K.-H., Averill, L. A., Nemati, S., Averill, C. L., Fouda, S., Ranganathan, M., MORGAN, P. T., D’Souza, D. C., Mathalon, D. H., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00864-9 · Cited by 33
Self-citationIntrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review
Demchenko, I., Tassone, V. K., Kennedy, S. H., Dunlop, K., & Bhat, V. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.864902 · Cited by 29
“, between-network) connectivity within the CEN caused by a glutamate surge, indicative of a therapeutic effect of ketamine on top-down executive control that is impaired in depression (213).”
BackgroundFrontal Lobe Circuitry in Posttraumatic Stress Disorder
Selemon, L. D., Young, K. A., Cruz, D. A., & Williamson, D. E. (2019) · Chronic Stress · doi:10.1177/2470547019850166 · Cited by 34
Tricklebank, M. D., Robbins, T. W., Simmons, C., & Wong, E. H. F. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05787-x · Cited by 30
Lijffijt, M., Murphy, N., Iqbal, S., Green, C. E., Iqbal, T., Chang, L. C., Haile, C. N., Hirsch, L. C., Ramakrishnan, N., Fall, D. A., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01242-9 · Cited by 31
The potential of 1H-MRS in CNS drug development
Egerton, A. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05344-7 · Cited by 30
“Research into the development of glutamatergic drugs for depression, schizophrenia or other disorders has revealed inverted U or non-linear dose-response relationships (Abdallah et al. 2018b; Foss-Feig et al. 2017).”
BackgroundMagalhães, R. J. D. S., Novais, A., Barrière, D. A., Marques, P., Marques, F., Sousa, J. C., Cerqueira, J., Cachia, A., Jay, T. M., Bottlaender, M., et al. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.2192-18.2019 · Cited by 29
“The value of MRS and MRI in understanding the role of altered glutamatergic and GABAergic metabolism in the pathophysiology of depression in patients has been demonstrated previously (Sanacora et al., 2002; Abdallah et al., 2014, 2018).”
Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?
Carboni, E., Carta, A. R., Carboni, E., & Novelli, A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.657714 · Cited by 33
Holmes, S. E., Asch, R. H., Davis, M. T., DellaGioia, N., Pashankar, N., Gallezot, J.-D., Nabulsi, N., Matuskey, D., Sanacora, G., Carson, R. E., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.10.018 · Cited by 27
Self-citationBiermann, L., Wunram, H. L., Pokorny, L., Breitinger, E., Großheinrich, N., Jarczok, T. A., & Bender, S. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02539-9 · Cited by 30
Depression and the Glutamate/GABA-Glutamine Cycle
Mamelak, M. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240815120244 · Cited by 29
Chen, S., Hsieh, C.-P., Lee, M.-Y., Chen, L.-C., Huang, C.-M., Chen, H., & Chan, M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112369 · Cited by 28
Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine
Zavaliangos‐Petropulu, A., Al‐Sharif, N., Taraku, B., Leaver, A. M., Sahib, A. K., Espinoza, R. T., & Narr, K. L. (2022) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2022.11.005 · Cited by 31
Chen, H., Ding, X., Xiang, G., Xu, L., Liu, Q., Fu, Q., & Li, P. (2023) · BMC Anesthesiology · doi:10.1186/s12871-023-02135-8 · Cited by 26
“One of the non-negligible side effects of clinical induction doses of esketamine is the neuropsychiatric reaction during the awakening period, which is due to the ability of esketamine to activate prefrontal glutamate neurotransmission [19].”
BackgroundAverill, L. A., Jiang, L., Purohit, P., Coppoli, A., Averill, C. L., Roscoe, J., Kelmendi, B., Feyter, H. M. D., de Graaf, R. A., Gueorguieva, R. V., et al. (2022) · Chronic Stress · doi:10.1177/24705470221092734 · Cited by 23
“The aim of this PTSD study is to investigate energy-per-cycle (EPC; ie, the VTCAn/VCycle ratio) as a putative biomarker directly related to glutamatergic synaptic strength.(8) Preclinical studies suggest that trauma and chronic stress reduce glutamate synaptic density, downregulate postsynaptic ionotropic glutamate re…”
BackgroundMethodResultInfluentialSelf-citationPerisynaptic astrocytes as a potential target for novel antidepressant drugs
Frizzo, M. E., & Ohno, Y. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.11.002 · Cited by 25
Weigand, A., Gärtner, M., Scheidegger, M., Wyss, P. O., Henning, A., Seifritz, E., Stippl, A., Herrera-Meléndez, A. L., Bajbouj, M., Aust, S., et al. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac049 · Cited by 22
“(Abdallah et al., 2018) reported that ketamine increased prefrontal Glu-Gln cycling, thereby providing the most direct evidence in humans that ketamine increases Glu release in the prefrontal cortex, a mechanism implicated in the induction of rapid antidepressant effects.”
BackgroundSapienza, J., Agostoni, G., Dall’Acqua, S., Sut, S., Nasini, S., Martini, F., Marchesi, A., Bechi, M., Buonocore, M., Cocchi, F., et al. (2023) · Schizophrenia Research · doi:10.1016/j.schres.2023.12.005 · Cited by 25
Hossam, Y., & Fahim, I. S. (2023) · Frontiers in Sustainable Food Systems · doi:10.3389/fsufs.2023.1220324 · Cited by 22
Caldwell, S., & Rothman, D. L. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.701170 · Cited by 23
Self-citationBrito, M. A., Li, D., Fields, C. W., Rybicki-Kler, C., Dean, J. G., Liu, T., Mashour, G. A., & Pal, D. (2021) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000005835 · Cited by 20
Lijffijt, M., Green, C. E., Balderston, N. L., Iqbal, T., Atkinson, M. E., Vo‐Le, B., Vo-Le, B., O’Brien, B., Grillon, C., Swann, A. C., et al. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00846 · Cited by 21
“This response has been associated with activation of α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPAR) (79) or activation of fast-spiking gamma-aminobutyric acid (GABA)ergic parvalbumin interneurons (80) following a ketamine-driven increase in prefrontal glutamate (81).”
BackgroundPan, S., Pan, Y., Tang, Y., Zuo, N., Zhang, Y., Jia, K., & Kong, L. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15489 · Cited by 21
Gallay, C. C., Forsyth, G., Can, A., Dutton, M., Jamieson, D., Jensen, E., Hermens, D. F., Bennett, M. R., & Lagopoulos, J. (2021) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2021.111369 · Cited by 21
Safety of general anaesthetics on the developing brain: are we there yet?
Robinson, E. J., Lyne, T. C., & Blaise, B. J. (2022) · BJA Open · doi:10.1016/j.bjao.2022.100012 · Cited by 20
Kohtala, S., & Rantamäki, T. (2021) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13598 · Cited by 16
Murphy, N., Tamman, A. J. F., Lijffijt, M., Amarneh, D. Y., Iqbal, S., Swann, A. C., Averill, L. A., O’Brien, B., & Mathew, S. J. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01586-4 · Cited by 24
“A sub-anesthetic dose of ketamine generates an antidepressant effect by modulating the coordination of glutamatergic communication and the release of brain-derived neurotrophic factor (BDNF) and the activation of mammalian target of rapamycin (mTOR) in the frontal network [8].”
BackgroundSelf-citationBoucherie, D. E., Reneman, L., Ruhé, H. G., & Schrantee, A. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2023.103517 · Cited by 23
“While SSRIs and SNRIs are generally considered safe and effective, not all patients respond to treatment with these types of medication (Al-Harbi, 2012).”
BackgroundSun, Q., Fan, T. W. ‐., Lane, A. N., & Higashi, R. M. (2019) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2019.115676 · Cited by 19
Wang, X., Daley, C., Gakhar, V., Lange, H. S., Vardigan, J. D., Pearson, M. S., Zhou, X., Warren, L., Miller, C. O., Belden, M., et al. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.119.263483 · Cited by 19
“This technique has been successfully applied to characterize the physiologic process underlying ketamine’s rapid antidepressant-like effect in preclinical models and in human (Chowdhury et al., 2012; Abdallah et al., 2018).”
Method(2020) · Advances in Pharmacology · doi:10.1016/bs.apha.2020.04.003 · Cited by 18
Self-citationHales, C. A., Bartlett, J., Arban, R., Hengerer, B., & Robinson, E. S. J. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00797-3 · Cited by 20
Alitalo, O., Saarreharju, R., Henter, I. D., Zarate, C. A., Kohtala, S., & Rantamäki, T. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102140 · Cited by 17
In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease
Mandal, P. K., Roy, R. G., Samkaria, A., Maroon, J. C., & Arora, Y. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03538-8 · Cited by 17
“The mechanism of action of ketamine in the prefrontal cortex of healthy controls and depressed patients has been studied [108].”
BackgroundAngelescu, I., Kaar, S. J., Marques, T. R., Borgan, F., Veronesse, M., Sharman, A., Sajjala, A., Deakin, J. F. W., Hutchison, J. B., Large, C. H., et al. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221122031 · Cited by 17
“, 2008), and, when given acutely, induce psychotic and negative symptoms in healthy people and worsen symptoms in patients with schizophrenia (Abdallah et al., 2018; Beck et al., 2019, 2020; Haaf et al., 2018; Thiebes et al., 2017).”
BackgroundDanyeli, L. V., Şen, Z. D., Čolić, L., Kurzweil, L., Gensberger‐Reigl, S., Macharadze, T., Götting, F. N., Refisch, A., Liebe, T., Chand, T., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02346-0 · Cited by 16
“This finding is in line with studies reporting delayed prefrontal glutamatergic modulation in individuals with MDD [67] and healthy participants [33, 34, 67], as well as with a recent study reporting increased Glu levels in the pgACC 24 h after S-ketamine administration [35].”
ResultLi, D., Pan, Q., Xiao, Y., & Hu, K. (2024) · Schizophrenia · doi:10.1038/s41537-024-00485-x · Cited by 17
“Clinical studies have revealed increased activation of the PFC in patients with fi rst-episode SZ 105 and after ketamine administration in healthy individuals, suggesting increased glutamate release in the PFC 106 .”
BackgroundTargeting of Metabotropic Glutamate Receptors for the Development of Novel Antidepressants
Chaki, S., Koike, H., & Fukumoto, K. (2019) · Chronic Stress · doi:10.1177/2470547019837712 · Cited by 16
Yates, J. R. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111107 · Cited by 15
Brown, K. A., Ajibola, M. I., & Gould, T. D. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02085-4 · Cited by 15
“Rapid activation of antidepressant synaptic machinery by ketamine is indicated by a “ glutamate surge ” , which is supported by clinical studies revealing association of antidepressant outcomes with responses indicative of enhanced glutamate release probability in the prefrontal cortex [PFC [8]”
Ketamine plus Alcohol: What We Know and What We Can Expect about This
Kobayashi, N. H. C., Farias, S. V., Luz, D. A., Ferraro, K. M. M. M., da Conceição, B. C., da Silveira, C. C. S. D. M., Fernandes, L. M. P., Cartágenes, S. D. C., Ferreira, V. M. M., Fontes-Júnior, E. A., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147800 · Cited by 17
Carboni, E., & Carta, A. R. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2105144 · Cited by 16
Frizzo, M. E. (2019) · Current Therapeutic Research · doi:10.1016/j.curtheres.2019.100566 · Cited by 16
Fitzgerald, K. C., Morris, B., Soroosh, A. J., Balshi, A., Maher, D. P., Kaplin, A. I., & Nourbakhsh, B. (2020) · Multiple Sclerosis Journal · doi:10.1177/1352458520936226 · Cited by 15
Gonzalez, S., Vasavada, M. M., Njau, S. N., Sahib, A. K., Espinoza, R. T., Narr, K. L., & Leaver, A. M. (2020) · Neurology Psychiatry and Brain Research · doi:10.1016/j.npbr.2020.08.006 · Cited by 14
Sapienza, J., Agostoni, G., Repaci, F., Spangaro, M., Comai, S., & Bosia, M. (2025) · Metabolites · doi:10.3390/metabo15030176 · Cited by 17
Asch, R. H., Abdallah, C. G., Carson, R. E., & Esterlis, I. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-024-01913-3 · Cited by 13
Self-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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
