Mechanisms of ketamine and its metabolites as antidepressants

In the paper

“Notably, this study did not observe rapid antidepressant effects.”

What the sources say

• Disputed

  The Results for the single-dose 100 mg study report an antidepressant signal at 1 hour and on a mood scale at 4 hours. Although the study did not find a statistically significant MADRS difference at 24 hours, that does not support the broader claim that it observed no rapid antidepressant effects. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Sanacora et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies.”

What the sources say

• Partly supported

  The Introduction (page unavailable) says several studies have shown antidepressant efficacy with ketamine and notes the limitations of existing antidepressant therapies. It does not establish that sub-anesthetic doses of racemic ketamine work within hours in people resistant specifically to monoaminergic drugs. This trial instead studies intranasal esketamine, the S-enantiomer. (LLM, conf=0.86)

  cites Daly et al., 2018 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Zarate, Singh, Carlson, et al., 2006

In the paper

“A large phase III study that utilized a 12-week treatment course totaling 15 treatments in patients with major depression failed to observe an improvement in MADRS scores relative to placebo”

What the sources say

• Partly supported

  The Abstract and Discussion describe 15 lanicemine infusions over 12 weeks, and the Efficacy Outcomes section reports no significant MADRS-score difference from placebo. However, the Abstract and Introduction explicitly identify this as a phase IIb study, not phase III. (LLM, conf=0.93)

  cites Sanacora et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“Notably, the magnitude of Mg2+ block and Ca2+ permeability is dependent on the subunit composition of the receptor”

What the sources say

• Supported

  The introductory passage reports NR2-specific differences in fractional Ca2+ currents and voltage-dependent Mg2+ block. The Results further show that NR2A- or NR2B-containing channels are more strongly blocked by Mg2+ than NR2C- or NR2D-containing channels. The paper reports the calcium-current finding from prior work rather than measuring Ca2+ permeability itself. (LLM, conf=0.86)

  cites Kuner & Schoepfer, 1996 source
• Partly supported

  The section “Functionality of NR3B in neurons: dominant effects on Ca²⁺ permeability” reports that adding NR3B changes the receptor’s measured Ca²⁺ permeability. The passages do not establish that the magnitude of Mg²⁺ block depends on subunit composition (searched for magnesium and Mg²⁺ block). No page number is available in our copy. (LLM, conf=0.86)

  cites Matsuda et al., 2003 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Monyer et al., 1992 source

In the paper

“However, another NMDAR channel blocker AZD6765 (lanicemine, 150 mg i.v.), transiently improved MADRS scores at 80- and 110-minutes post-treatment in patients with major depression that were otherwise unmedicated”

What the sources say

• Supported

  The Results > Efficacy section reports significantly lower MADRS scores with AZD6765 at 80 and 110 minutes; the Discussion describes the improvement as transitory. Methods and Materials > Study design specifies a 150 mg intravenous dose after a two-week drug-free period and says participants received no other psychotropic medications during the study. Page numbers are not available in our copy. (LLM, conf=0.94)

  cites Zarate et al., 2013 source

In the paper

“there is evidence that NMDAR antagonism is responsible for ketamine’s dissociative and psychotomimetic effects”

What the sources say

• ?Not checked — no full text of the sourcecites Krystal et al., 1994 source
• Partly supported

  In “Are NMDARs the entire ketamine story?” (page unavailable), the paper says NMDAR involvement in ketamine’s psychotomimetic effects is relatively uncontroversial and notes that other NMDAR blockers reproduce those effects. In “Ketamine and NMDARs: alternative views” (page unavailable), it reports dissociative symptoms from a selective NMDAR antagonist in humans, but does not directly establish that NMDAR antagonism causes ketamine’s dissociative effects. (LLM, conf=0.82)

  cites Zorumski et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Another study also observed that lanicemine (100 mg i.v.) when administered every other day for three weeks as an adjunctive treatment improved MADRS scores in patients with major depression starting at the second week of treatment through two weeks post-treatment”

What the sources say

• Supported

  The Methods and Results for the adjunctive multiple-infusion trial describe 100 mg IV lanicemine given three times weekly on non-consecutive days for three weeks alongside existing antidepressants. The Results report a significant MADRS benefit by week 2 that persisted to week 5, two weeks after the last infusion. Page numbers were not supplied. (LLM, conf=0.91)

  cites Sanacora et al., 2014 source

In the paper

“ketamine is rapidly metabolized resulting in neuroactive products that are likely to contribute to its therapeutic effects”

What the sources say

• Supported

  The ketamine-metabolism section reports rapid conversion to hydroxynorketamines, detected within minutes after dosing in animals and after infusion in humans (page unavailable). The Introduction describes these metabolites as potentially mediating ketamine’s antidepressant effects, and the Behavioral Effects section reports evidence for a role in sustained antidepressant-like effects in mice. (LLM, conf=0.90)

  cites Highland et al., 2021 source
• ?Not matched

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

  cites Zanos et al., 2018

In the paper

“Further, patients who were in remission were more likely to relapse when switched to a placebo nasal spray in conjunction with an oral antidepressant”

What the sources say

• Supported

  The Maintenance Phase describes a switch from esketamine to placebo nasal spray while oral antidepressant treatment continued. The Efficacy Results report relapse in 45.3% of patients in stable remission assigned to antidepressant plus placebo, versus 26.7% assigned to continue esketamine plus antidepressant. (LLM, conf=0.94)

  cites Daly et al., 2019 source

In the paper

“NMDAR antagonism may not fully explain the antidepressant effects of ketamine”

What the sources say

• Supported

  The paper’s Abstract reports that blocking AMPA receptors abolished ketamine’s antidepressant-like behavioural response, and its summary identifies eEF2 kinase and BDNF translation as steps in the response. Thus, NMDAR antagonism initiates the mechanism but does not, by itself, fully explain the observed effects in the mouse models studied. (LLM, conf=0.88)

  cites Autry et al., 2011 source
• Supported

  The Conclusions state that other NMDAR antagonists do not replicate ketamine’s clinical profile, suggesting that NMDAR inhibition is not its antidepressant mechanism, or not the complete mechanism. The Pharmacology of Rapid-Acting Antidepressants section likewise says ketamine may act at least partly through a mechanism distinct from NMDAR inhibition. (LLM, conf=0.95)

  cites Gould et al., 2019 source
• Supported

  The Introduction (page not available) reports that ketamine produced an antidepressant-like profile in rats while the selective NMDA receptor antagonist MK-801 produced a stimulant-like profile. The Discussion (page not available) relates these differences to NMDA receptor affinity. These preclinical findings support the hedged claim that NMDA receptor antagonism alone may not fully explain ketamine’s antidepressant effects. (LLM, conf=0.84)

  cites Hillhouse & Porter, 2014 source

In the paper

“Ketamine was initially characterized as an NMDAR antagonist”

What the sources say

• Supported

  The Results report that ketamine selectively reduced responses to N-methyl-aspartate in cat and rat neurones and call it an “NMA-antagonist.” The Discussion likewise describes ketamine as an NMA antagonist, supporting the citing sentence’s characterization. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites Anis et al., 1983 source
• Supported

  The Introduction (page not provided) says that studies in the 1980s established ketamine as a noncompetitive NMDAR antagonist. This supports the citing sentence’s characterization of its early understanding. (LLM, conf=0.88)

  cites Zorumski et al., 2016 source

In the paper

“In support, memantine, which blocks the NMDAR ion channel at the same site as ketamine, failed to exert antidepressant effects in patients with depression”

What the sources say

• ?Not checked — no full text of the sourcecites Omranifard et al., 2014
• Partly supported

  The Abstract Conclusions and Discussion report no significant benefit over placebo when memantine was used to augment antidepressants in a small trial of patients with major depressive disorder who had responded poorly to conventional treatment. They do not establish that memantine has no antidepressant effect in patients with depression generally. The copy identifies both drugs as NMDA antagonists but does not say they block the ion channel at the same site. (LLM, conf=0.86)

  cites Smith et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Zarate, Singh, Quiroz, et al., 2006 source

In the paper

“knockdown of GluN2B in SST interneurons mimicked the effects of ketamine on SST Ca2+ dynamics and pyramidal neuron dendrites.”

What the sources say

• Supported

  The Results section, “Ketamine’s effect on dendrites rely on GluN2B in SST neurons,” reports that GluN2B knockdown in SST interneurons reduced their baseline calcium-event activity, mimicking ketamine, and increased spontaneous calcium events in pyramidal dendritic spines. Additional ketamine had no detectable effect on either measure. (LLM, conf=0.94)

  cites Ali et al., 2020 source

In the paper

“using a genetic knockdown approach in mice found that loss of GluN2B in medial PFC (mPFC GABAergic interneurons, and specifically in those expressing somatostatin (SST) and parvalbumin (PV), occluded the antidepressant-like effects of ketamine in the forced swim test (Gerhard et al., 2020).”

What the sources say

• Supported

  The Results sections on Sst and Pvalb interneurons report GluN2B knockdown in the mPFC and no further reduction in forced-swim-test immobility after ketamine in the knockdown mice. The Discussion likewise concludes that GluN2B knockdown in Gad1, Sst, and Pvalb interneurons occluded or blocked ketamine’s antidepressant behavioral effects. Page numbers were not provided in our copy. (LLM, conf=0.93)

  cites Gerhard et al., 2020 source

In the paper

“The genetic manipulation alone appeared to reduce immobility relative to controls to a point where ketamine could not elicit a further reduction.”

What the sources say

• Partly supported

  The results section reports that GluN2B knockdown in Gad1 interneurons reduced baseline immobility relative to controls and that ketamine produced no further reduction. But the Discussion (p. 1345) reports that another antidepressant reduced immobility in the manipulated mice, ruling out a floor effect. Thus the paper supports the observed lack of further ketamine response, not the suggestion that immobility had fallen to a point where no further reduction was possible. (LLM, conf=0.90)

  cites Gerhard et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“Importantly, in the absence of Mg2+, the IC50 values of ketamine are lower for GluN2A/B/C/D (0.33, 0.31, 0.51, and 0.83 μM respectively).”

What the sources say

• Partly supported

  The Results report that adding 1 mM Mg²⁺ right-shifted ketamine concentration–inhibition curves for all four NR1/2 subtypes, supporting lower IC₅₀ values without Mg²⁺. The passages available from our copy do not give the four claimed values (0.33, 0.31, 0.51, and 0.83 μM), so those numbers cannot be verified. (LLM, conf=0.84)

  cites Kotermanski & Johnson, 2009 sourceExperimental — accuracy not yet measured

In the paper

“When phosphorylated, this site selectively increases extrasynaptic insertion of AMPARs which can then diffuse to the synapse to promote long-term potentiation (LTP)”

What the sources say

• ?Not checked — no full text of the sourcecites Derkach et al., 2007 source
• ?Not matched

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

  cites Oh et al., 2006
• Partly supported

  The Discussion (page unavailable) describes increased extrasynaptic GluR1 insertion through D1 receptor–PKA signaling, followed by movement into synapses after NMDA receptor activation; it suggests this sequence may facilitate LTP. The copy does not identify S845 as the phosphorylation site, and it says PKA phosphorylation alone is insufficient for synaptic delivery. (LLM, conf=0.86)

  cites Sun et al., 2005 sourceExperimental — accuracy not yet measured

In the paper

“For instance, GluN2C/D-containing NMDARs expressed in HEK293T cells appear to be more susceptible to ketamine block (IC50 of 1.18 and 2.95 μM, respectively) in the presence of physiological 1 mM Mg2+, 1 mM glutamate, 100 μM glycine, and pH 7.2 relative to GluN2A/B (5.35 and 5.08 μM, respectively) containing NMDARs”

What the sources say

• Partly supported

  The Results and Discussion report that, in 1 mM Mg2+, ketamine preferentially inhibits NR1/2C and NR1/2D receptors over NR1/2A and NR1/2B. The Methods confirm HEK293T cells, 1 mM glutamate, 100 μM glycine, and pH 7.2. The passages available from our copy do not give the four quoted ketamine IC50 values, so those numbers cannot be verified. (LLM, conf=0.84)

  cites Kotermanski & Johnson, 2009 sourceExperimental — accuracy not yet measured

In the paper

“others have established that ketamine (20 μM, 30-minute bath application) potentiates AMPAR-mediated evoked neurotransmission in the CA1 of mice independent of changes in presynaptic release probability”

What the sources say

• Partly supported

  The paper reports that 20 μM ketamine applied at rest potentiated subsequent evoked synaptic responses in hippocampal slices (section labeled Abstract, Fig. 3e); Methods specify a 30-minute application and CA1 recordings. But Methods identify the slices as rat, not mouse, and the passages do not establish that presynaptic release probability was unchanged. (LLM, conf=0.88)

  cites Autry et al., 2011 sourceExperimental — accuracy not yet measured
• Supported

  The section on NMDAR blockade at rest reports that 30 minutes of ketamine at 20 μM potentiated AMPAR-mediated evoked responses at CA3–CA1 synapses in hippocampal slices. The Discussion states that potentiation was not accompanied by a change in paired-pulse facilitation, arguing against increased presynaptic release probability; the paper also identifies the experimental slices as coming from mice. (LLM, conf=0.91)

  cites Nosyreva et al., 2013 source

In the paper

“Additionally, lowering pH from 7.6 to 6.9 reduced the IC50 values of ketamine at all NMDAR subunits (2A, 0.537; 2B, 0.239; 2C, 0.66; 2D, 1.23 μM).”

What the sources say

• Supported

  The Results (Table 2) report that lowering pH from 7.6 to 6.9 reduced (+/−)ketamine IC50 at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D. All four pH 6.9 values match those in the citing sentence. (LLM, conf=0.95)

  cites Dravid et al., 2007 source

In the paper

“First, a study using rat hippocampal slices observed that ketamine (1 μM, 20-minute bath application) enhanced the action potential probability in CA1 measured through a disinhibition of pyramidal neurons”

What the sources say

• Supported

  The Methods describe CA1 recordings in rat hippocampal slices and comparison of a 10-minute baseline with the last five minutes of drug application. The Results report that bath-applied 1 μM ketamine increased synaptically driven action-potential probability in CA1 pyramidal cells, consistent with disinhibition; the recording intervals indicate a 20-minute application. Page numbers were not available in our copy. (LLM, conf=0.90)

  cites Widman & McMahon, 2018 source

In the paper

“association and dissociation rate constants for (2R,6R)-HNK were slower relative to ketamine.”

What the sources say

• Partly supported

  The ‘Inhibitory Effect of HNK on NMDA Receptor Currents’ section explicitly describes both apparent rate constants as slower for HNK than for ketamine. However, Table 2 in the Discussion lists a higher dissociation rate constant for HNK (1.3 s⁻¹) than for ketamine (0.7 s⁻¹), contradicting the paper’s own description of slower dissociation. (LLM, conf=0.86)

  cites Abbott & Popescu, 2020 sourceExperimental — accuracy not yet measured

In the paper

“Production of the 6-HNKs is important for the full antidepressant-like behavioral effects of ketamine (Zanos, Highland, Liu, et al., 2019; Zanos et al., 2016; Zheng et al., 2021).”

What the sources say

• Supported

  The Introduction states that conversion of racemic ketamine to its 6-HNK metabolite was necessary for its full antidepressant-relevant actions in mice. The Discussion adds this paper’s finding that conversion of (R)-ketamine to (2R,6R)-HNK increases its potency in mouse behavioural tests. Together, these support the claim in the context of mouse antidepressant-like behaviour. (LLM, conf=0.90)

  cites Zanos, Highland, Liu, et al., 2019 source
• Supported

  In “Antidepressant actions of HNK” (page not provided), the paper reports that hindering ketamine’s metabolism to (2S,6S;2R,6R)-HNK eliminated its sustained antidepressant-like effects in the mouse forced-swim and learned-helplessness tests. This supports the claim that producing these metabolites is important for ketamine’s full behavioral effects. (LLM, conf=0.93)

  cites Zanos et al., 2016 source
• Supported

  The Results and Discussion (page not supplied) report that selectively targeting 6-hydroxynorketamine fully reversed ketamine’s effect in a rodent forced-swim test. The authors conclude that 6-hydroxynorketamine activity is a necessary component of ketamine’s antidepressant-like activity in rodent models, supporting the cited claim in that behavioral context. (LLM, conf=0.91)

  cites Zheng et al., 2021 source

In the paper

“its inability to displace MK-801 binding to NMDARs (10 μM).”

What the sources say

• Partly supported

  Results §3.3 reports that (2R,6R)-HNK had very weak affinity in an MK-801 displacement assay (Ki >100 μM), consistent with little displacement at 10 μM. It does not report a displacement result specifically for (2R,6R)-HNK at 10 μM; Methods §2.6 uses 10 μM for unlabeled MK-801, not HNK. (LLM, conf=0.84)

  cites Moaddel et al., 2013 sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s NMDA-receptor activity discussion reports that (2R,6R)-HNK showed only 24% inhibition of MK-801-site binding at 100 μM, consistent with little activity at clinically relevant concentrations. It does not report the claimed result at 10 μM, so the specific concentration is not verified by our copy. (LLM, conf=0.82)

  cites Morris et al., 2017 sourceExperimental — accuracy not yet measured
• Supported

  The “(2R,6R)-HNK effects on glutamate receptors” section states that (2R,6R)-HNK does not displace [3H]-MK-801 binding to NMDARs in vitro. The “MK-801 displacement binding” Methods section specifies that the tested concentrations extended to 10 μM. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites Zanos et al., 2016 source

In the paper

“GluN2A containing NMDARs in PV interneurons are necessary for the rapid actions of ketamine on evoked firing of visual cortex pyramidal neurons and gamma-band oscillations in mice (Picard et al., 2019).”

What the sources say

• Supported

  The Results section ('NMDA-GluN2A receptors on PV-cells underlie rapid ketamine action') reports that deleting GluN2A specifically from PV cells prevented the significant increase in maximal evoked responses and abolished the ketamine-induced increase in gamma-band oscillations. The Introduction identifies the evoked activity as pyramidal-cell activity in mouse primary visual cortex. (LLM, conf=0.93)

  cites Picard et al., 2019 source

In the paper

“the inhibitory effects of (2R,6R)-HNK (500 μM) were enhanced at negative holding potentials, much like ketamine and Mg2+.”

What the sources say

• Supported

  The Chemicals section identifies the HNK used as 2R,6R-hydroxynorketamine. In “Inhibitory Effect of HNK on NMDA Receptor Currents” (Fig. 3A), the paper reports voltage-dependent inhibition at the stated HNK concentration, with greater current block at negative potentials, similar to ketamine and Mg²⁺. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites Abbott & Popescu, 2020 source

In the paper

“the inhibitory effects of (2R,6R)-HNK at a very high and pharmacologically not relevant concentration of 500 μM at GluN2A-containing NMDARs in HEK-293 cells in the presence of glutamate and glycine was enhanced by 84 and 87% at pH 6.8 and 7.2, respectively (Abbott & Popescu, 2020).”

What the sources say

• Partly supported

  The ‘Inhibitory Effect of HNK on NMDA Receptor Currents’ section reports 84% and 87% inhibition at pH 6.8 and 7.2, respectively, in GluN1/GluN2A-expressing HEK-293 cells exposed to glutamate and glycine. Those are inhibition levels, not increases of 84% and 87%. Our copy also renders the HNK dose as ‘500 mM,’ so it does not verify the claimed 500 μM dose. (LLM, conf=0.86)

  cites Abbott & Popescu, 2020 sourceExperimental — accuracy not yet measured

In the paper

“HNKs, which also have antidepressant-like effects in preclinical models, may not require NMDARs for their long-lasting effects on behavior or synaptic plasticity in the hippocampus (Gould et al., 2017; Riggs et al., 2020; Zanos et al., 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites Gould et al., 2017 source
• Partly supported

  The Introduction and Results report antidepressant-like effects of (2R,6R)-HNK in preclinical models and show that its acute potentiation of hippocampal synaptic transmission occurs despite NMDAR blockade. The Discussion explicitly distinguishes those acute effects from the sustained adaptations associated with persistent behavioral effects. This paper therefore does not establish that NMDARs are unnecessary for the long-lasting behavioral or hippocampal plasticity effects, and it studies (2R,6R)-HNK rather than HNKs generally. (LLM, conf=0.87)

  cites Riggs et al., 2020 sourceExperimental — accuracy not yet measured
• Supported

  The Antidepressant actions of HNK section reports sustained antidepressant-like effects of (2R,6R)-HNK in mice. The glutamate-receptor results report persistent hippocampal synaptic potentiation, and Methods > Field recordings specifies that NMDARs were blocked during those recordings. The Discussion describes the antidepressant mechanism as independent of NMDAR inhibition, consistent with the citing sentence’s cautious wording. (LLM, conf=0.90)

  cites Zanos et al., 2016 source

In the paper

“when (2R,6R)-HNK was applied prior to glutamate, the inhibitory effects on whole-cell NMDAR currents were increased relative to when it was co-applied with glutamate which suggests (2R,6R)-HNK preferentially binds inactive receptors.”

What the sources say

• Supported

  In the State Dependence of HNK Block section, the authors compare HNK applied before glutamate with HNK coapplied with it. Table 3 shows greater peak-current inhibition with preapplication, and the authors say its effectiveness before channel opening strongly indicates an affinity for resting receptors. The table does not report a direct statistical test between the two application timings. (LLM, conf=0.88)

  cites Abbott & Popescu, 2020 source

In the paper

“This disinhibition theory posits that ketamine blocks NMDARs on GABAergic interneurons, thus reducing their firing rate and removing the breaks on glutamatergic neurons (Grunze et al., 1996).”

What the sources say

• Partly supported

  The Discussion reports that NMDA receptor antagonists reduce inhibitory transmission and says this is consistent with NMDA receptors on inhibitory interneurons. The paper also models increased spread of excitation when inhibitory plasticity is blocked. It does not show that ketamine specifically reduces interneuron firing; its experiments used other antagonists. (LLM, conf=0.87)

  cites Grunze et al., 1996 sourceExperimental — accuracy not yet measured

In the paper

“ketamine treatment (0.5 μM) facilitated BDNF release from primary cortical neurons 15, 60, and 360 minutes post-treatment”

What the sources say

• Supported

  The Results section, “Ketamine Treatment Increases BDNF Release in Primary Neuronal Cultures,” reports significantly increased BDNF release from cortical neurons incubated with 0.5 µM ketamine for 15 minutes, 60 minutes, or 6 hours (360 minutes). The paper describes these as incubation durations, rather than measurements after treatment ended. (LLM, conf=0.94)

  cites Lepack et al., 2014 source

In the paper

“long-term treatment (21 days) with SSRIs or SNRIs, which enhance serotonin and norepinephrine signaling, increase the expression of BDNF mRNA in the hippocampus of rats (Nibuya et al., 1996).”

What the sources say

• Partly supported

  The Chronic antidepressant administration section reports that chronic fluoxetine increased BDNF mRNA in rat hippocampal cell layers, and Figure 3 specifies a 21-day treatment. The paper does not report a 21-day BDNF mRNA result for an SNRI; the other drug in that figure, tranylcypromine, is identified as a monoamine oxidase inhibitor. (LLM, conf=0.86)

  cites Nibuya et al., 1996 sourceExperimental — accuracy not yet measured

In the paper

“chronic electroconvulsive seizure treatment can also increase BDNF mRNA expression in the hippocampus (Nibuya et al., 1995).”

What the sources say

• Supported

  The Results report that chronic ECS increased BDNF mRNA in hippocampal subfields, although the response varied by subfield. The Discussion also reports prolonged BDNF mRNA elevation in the dentate gyrus after chronic ECS. (LLM, conf=0.93)

  cites Nibuya et al., 1995 source

In the paper

“The effects of (2R,6R)-HNK in the forced swim test and novelty suppressed feeding were blocked in mice containing the BDNF Val66Met allele (heterozygous Val/Met and homozygous Met/Met mice) (Fukumoto et al., 2019).”

What the sources say

• Supported

  The Results section states that (2R,6R)-HNK had significant effects in the forced swim test (FST) and novelty-suppressed feeding test (NSFT) in Val/Val mice, but that these effects were blocked in both Val/Met and Met/Met mice. The Fig. 2 caption reports the same finding. (LLM, conf=0.95)

  cites Fukumoto et al., 2019 source

In the paper

“Ketamine restored dendritic spines that were specifically lost during the CORT exposure.”

What the sources say

• Supported

  The Results section, “Antidepressant-dose ketamine selectively restores lost spines,” reports that new spines formed near sites of spines lost during chronic CORT exposure more often than in controls or by chance. This supports selective restoration, though the same section notes that a majority of lost spines were not restored. (LLM, conf=0.91)

  cites Moda-Sava et al., 2019 source

In the paper

“LY341495 (3 mg/kg i.p.) in rats was sufficient to reverse anhedonia produced by a chronic unpredictable stress model of depression and measured using the sucrose preference test at 48 hours post-treatment (Dwyer et al., 2013).”

What the sources say

• Supported

  The Methods describe rats exposed to chronic unpredictable stress, then given a single 3 mg/kg intraperitoneal injection of LY341495 and tested for sucrose preference. The Results and discussion report a significant reversal of stress-induced decreased sucrose preference at 48 hours after treatment. (LLM, conf=0.95)

  cites Dwyer et al., 2013 source

In the paper

“(2R,6R)-HNK (30 mg/kg i.p.) produced antidepressant-like effects in mice tested in the forced swim test and female urine sniffing test 24 hours post-treatment”

What the sources say

• Supported

  The Results section reports testing intraperitoneal (2R,6R)-HNK at doses including 30 mg/kg and a significant forced-swim effect 24 hours after dosing. It also reports an antidepressant effect with 30 mg/kg in the female urine sniffing test one day after dosing; the Fig. 1 caption corroborates both time points. (LLM, conf=0.93)

  cites Fukumoto et al., 2019 source

In the paper

“ketamine rescued the increase in immobility produced by CORT exposure during the tail suspension test starting at three hours to one-week post-treatment.”

What the sources say

• Supported

  The Results section reports that ketamine reversed CORT-induced immobility in the tail suspension test. Its time-course section says the behavioral effect began 3 hours after treatment and persisted for up to a week. Page numbers were not provided in our copy. (LLM, conf=0.93)

  cites Moda-Sava et al., 2019 source

In the paper

“serotonin receptor agonists appear to have differential effects on BDNF expression depending on the brain region with significant decreases in the dentate gyrus of the hippocampus and increases in the parietal, frontal, and temporal cortex of rats (Vaidya et al., 1997).”

What the sources say

• Supported

  The Results section reports that DOI, a 5-HT2A/2C receptor agonist, significantly decreased BDNF mRNA in the dentate gyrus and increased it in parietal cortex, with increases also seen in frontal and temporal cortex. The Figure 2 caption identifies the treated animals as rats. The finding concerns BDNF mRNA after DOI administration, not every serotonin receptor agonist. (LLM, conf=0.93)

  cites Vaidya et al., 1997 source

In the paper

“intracellular and extracellular D-serine levels in PC-12 cell cultures were reduced by (2R,6R; 2S,6S)-HNK with IC50 values of 0.68 ± 0.09 nM and 0.18 ± 0.04 nM respectively (Singh et al., 2016).”

What the sources say

• Partly supported

  Table 2 (Results) gives 0.68 ± 0.09 nM for (2R,6R)-HNK and 0.18 ± 0.04 nM for (2S,6S)-HNK, but both values refer to intracellular D-serine. The Results section on extracellular D-serine reports an IC50 of 0.21 ± 0.08 nM for (2S,6S)-HNK, not 0.18 ± 0.04 nM; the claim misassigns the values to the two compartments. (LLM, conf=0.92)

  cites Singh et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Activation of AS-PaRac1 three hours post-treatment did not impact tail suspension test behavior 48 hours post-treatment, which is prior to the onset of spine formation by ketamine 12 hours post-treatment.”

What the sources say

• Partly supported

  The Results section on prefrontal spinogenesis reports that activating AS-PaRac1 3 hours after ketamine did not affect immobility behavior when tested 2 days after treatment. It also reports that increased spine formation became detectable at 12–24 hours. The 3-hour activation preceded spine formation, but the sentence incorrectly describes the 48-hour behavioral test as occurring before it. (LLM, conf=0.88)

  cites Moda-Sava et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“The neurotrophic factor theory of depression, in part, emerged from several clinical and preclinical studies that showed significant gross structural changes in the hippocampus and PFC linked to neuronal atrophy (Deyama & Duman, 2020).”

What the sources say

• Supported

  In the ‘Neuronal atrophy and decreased levels of neurotrophic factors in depressed subjects’ section (page not provided), the review says evidence of neuronal atrophy in the PFC and hippocampus supports the neurotrophic hypothesis and reports reduced volume in both regions in depressed patients. The companion rodent-model section describes stress-related atrophy in those regions as consistent with the clinical findings. (LLM, conf=0.91)

  cites Deyama & Duman, 2020 source

In the paper

“specific deletion of the newly formed spines 24 hours post-treatment via activated synapse-targeting photoactivatable Rac1 (AS-PaRac1), which collapses newly formed spines through light stimulation, reversed the effects of ketamine in the tail suspension test 48 hours post-treatment.”

What the sources say

• Supported

  The Results section, “Prefrontal spinogenesis sustains the remission of depression-related behavior over time,” states that AS-PaRac1 was photoactivated one day after ketamine treatment and behavior was tested two days after treatment. It reports that deleting newly formed spines this way blocked ketamine’s long-term effect in the tail suspension test. The same section explains that blue-light photoactivation causes spine shrinkage and collapse. (LLM, conf=0.94)

  cites Moda-Sava et al., 2019 source

In the paper

“a lack of D-serine might preferentially impact GluN2B containing NMDARs as D-serine restricts their diffusion within membranes and reduces synaptic expression (Ferreira et al., 2017).”

What the sources say

• Supported

  The Results (pages not provided) report that exogenous D-serine reduced GluN2B-NMDAR surface diffusion and synaptic content, while GluN2A synaptic content was unaffected. The claim’s suggestion about a lack of D-serine is a hedged inference from those preferential effects, not a reported measurement of D-serine deficiency. (LLM, conf=0.90)

  cites Ferreira et al., 2017 source

In the paper

“a study in mice observed that ketamine (3 mg/kg i.p.) increased expression of BDNF protein in the hippocampus 30 minutes post-treatment (Autry et al., 2011).”

What the sources say

• Supported

  The Methods (page unavailable) specify that C57BL/6 mice received ketamine at 3.0 mg/kg i.p. and that hippocampal tissue was collected 30 minutes after injection for BDNF quantification. The results passage labeled Abstract (page unavailable) reports significantly increased hippocampal BDNF protein at 30 minutes after treatment. (LLM, conf=0.95)

  cites Autry et al., 2011 source

In the paper

“infusion of an anti-BDNF antibody into the mPFC blocked the antidepressant-like effects of ketamine (10 mg/kg i.p.) in the forced swim test”

What the sources say

• Supported

  The ‘Antidepressant Actions of Ketamine in the FST’ section reports that anti-BDNF antibody infusion into the mPFC completely blocked ketamine’s reduction of immobility in rats. The mPFC cannulation and infusion procedure specifies ketamine at 10 mg/kg i.p.; the Figure 1 caption confirms the same dose and result. Page numbers are not provided in our copy. (LLM, conf=0.95)

  cites Lepack et al., 2014 source

In the paper

“the severity of depressive symptoms, as measured by the HAMD-17, inversely correlated with the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A) labeled with the [11C]UCB-J radioligand and measured via PET scan (Holmes et al., 2019).”

What the sources say

• Supported

  The Results section, “Synaptic density and depressive symptoms,” reports significant negative correlations between HAMD-17 scores and [11C]UCB-J VT, an indicator of SV2A density, in three brain regions. The Introduction identifies [11C]UCB-J as an SV2A-binding radioligand used in PET imaging. (LLM, conf=0.94)

  cites Holmes et al., 2019 source

In the paper

“This effect corresponded with antidepressant-like effects in the forced swim test that were absent in BDNF knockout mice.”

What the sources say

• Supported

  The passage labelled Abstract reports that ketamine reduced forced-swim-test immobility in wild-type controls at 30 minutes and 24 hours, but did not produce antidepressant-like effects in inducible BDNF knockout mice. The Methods passage confirms that both groups underwent the forced swim test after ketamine treatment. (LLM, conf=0.94)

  cites Autry et al., 2011 source

In the paper

“Interestingly, neither enantiomer activated ß-arrestin.”

What the sources say

• Supported

  The Results section on in vitro target engagement states that neither (S)- nor (R)-ketamine activated the β-arrestin pathway in the opioid-receptor signaling assays (Figure 1F). This directly supports the citing sentence. (LLM, conf=0.95)

  cites Bonaventura et al., 2021 source

In the paper

“mutation of the putative transmembrane binding site of TrkB (residue Y433) prevented ketamine’s actions (10 mg/kg) in the forced swim test (treatment two hours before), and extinction of conditioned fear (treatment immediately post-conditioning and two hours prior to extinction sessions).”

What the sources say

• Supported

  The Results section, “Binding to TRKB mediates the behavioral effects of antidepressants,” reports that ketamine at 10 mg/kg reduced forced-swim immobility and promoted conditioned-fear extinction in wild-type mice, but not in TRKB.Y433F mice. It also gives the treatment timing stated in the claim (Figure 6D–H). (LLM, conf=0.94)

  cites Casarotto et al., 2021 source

In the paper

“whereas (R)-ketamine acted as a weak partial agonist at both μ opioid receptors (EC50 = 34 μM, Emax = 39 %) and κ opioid receptors (EC50 > 100 μM, Emax < 50%).”

What the sources say

• Supported

  The Results section on in vitro target engagement explicitly describes (R)-ketamine as a weaker partial agonist at both MOR and KOR in the cAMP assay. It reports the same EC50 and Emax values given in the citing sentence. (LLM, conf=0.95)

  cites Bonaventura et al., 2021 source

In the paper

“fluoxetine (30 mg/kg i.p.) also increased phosphorylation of TrkB one-hour post-treatment in the hippocampus of WT and serotonin transporter knockout mice”

What the sources say

• Supported

  The Results section on serotonin transporter knockout mice and Figure 5A report that fluoxetine increased hippocampal TrkB phosphorylation similarly in wild-type and knockout mice. Another Results passage specifies that acute fluoxetine at 30 mg/kg for one hour induced TrkB phosphorylation in mouse hippocampus, and Materials and Methods states that the mice received drugs by intraperitoneal injection. (LLM, conf=0.88)

  cites Rantamäki et al., 2011 source

In the paper

“many antidepressants, including fluoxetine, imipramine, ketamine, and (2R,6R)-HNK disrupt the interaction between TrkB and the AP-2 protein complex”

What the sources say

• Supported

  In “Antidepressants and BDNF differentially affect the TRKB:AP2M interaction” (page not provided), the paper reports that fluoxetine, imipramine, ketamine, and RR-HNK each reduced the TRKB:AP2M interaction in cell cultures. RR-HNK is identified in the paper as (2R,6R)-hydroxynorketamine. (LLM, conf=0.94)

  cites Fred et al., 2019 source

In the paper

“a study using congenitally learned helpless (cLH) rats observed increased Ca2+ signaling in the lateral habenula (LHb), a brain region involved in negative affective regulation and implicated in depression, relative to WT rats (Klein et al., 2020).”

What the sources say

• Supported

  The Discussion reports that brain-slice imaging showed greater LHb neuronal activity in cLH rats than in WT rats. The Calcium Imaging section identifies the measurement as calcium imaging, supporting the paraphrase about increased Ca2+ signaling. (LLM, conf=0.92)

  cites Klein et al., 2020 source

In the paper

“(S)-ketamine (bolus of 0.11 mg/kg with 0.12 mg/kg maintenance i.v. infusion over 20 min) produced significant increases in overall hippocampal subfield volumes in healthy volunteers 65 minutes following treatment initiation independent of whether the volunteer carried the Met allele (Höflich et al., 2021).”

What the sources say

• Supported

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

  cites Höflich et al., 2021 source

In the paper

“buprenorphine, which is a partial μ-opioid receptor agonist and potent κ-opioid receptor antagonist rescues the increase in immobility in the forced swim test produced by an unpredictable chronic mild stress model of depression in mice (Falcon et al., 2016).”

What the sources say

• Supported

  The Introduction describes buprenorphine as a high-affinity partial μ-opioid receptor agonist and κ-opioid receptor antagonist. In “BPN Reversed UCMS-induced Behavioral Changes” (page unavailable), the paper reports that chronic mild stress increased forced-swim immobility in mice and buprenorphine reversed that increase. (LLM, conf=0.94)

  cites Falcon et al., 2016 source

In the paper

“the opioid receptor antagonist naltrexone (50 mg) attenuated the antidepressant effects of ketamine (0.5 mg/kg i.v. over 40 minutes) one to three days post-treatment as measured by the Hamilton Depression Rating Scale 6 item and 17 item.”

What the sources say

• Supported

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

  cites Williams et al., 2018 source

In the paper

“The effects of ketamine (10 mg/kg i.p.) on spine morphology 24 hours post-treatment, including increased spine number, increased diameter, and reduced length were significantly blunted but not completely abolished in Met/Met mice.”

What the sources say

• Partly supported

  The Results section reports that, 24 hours after 10 mg/kg i.p. ketamine, spine density and head diameter increased in Val/Val mice but not overall in Met/Met mice. It also reports a small diameter increase in a subset of Met/Met spines, supporting 'blunted but not completely abolished.' The copy describes increased spine length as a baseline feature of Met/Met mice, not a ketamine-induced reduction in length. (LLM, conf=0.88)

  cites Liu et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“computational analyses of the predicted interaction between ketamine and its metabolites to the μ and κ-opioid receptor suggested that (2R,6R)-HNK interacted with the orthosteric binding pockets at high affinity (Joseph et al., 2021).”

What the sources say

• Supported

  The Results and Discussion section reports that simulations placed (2R,6R)-HNK in the orthosteric binding pockets of both μ and κ opioid receptors. Its discussion of predicted affinities gives high-affinity calculated KD values for protonated HNK: 5.5 nM for μ and 0.57 nM for κ. The high-affinity result is specifically for the protonated form. (LLM, conf=0.91)

  cites Joseph et al., 2021 source

In the paper

“the antidepressant-like effects of ketamine in the forced swim test (reduced immobility) were absent in Met/Met mice.”

What the sources say

• Supported

  The Results section, “Antidepressant effect of ketamine in the forced swim test (FST) is blocked in Met/Met mice,” reports that ketamine significantly reduced immobility in wild-type mice but not in Met/Met mice. It describes the attenuation of immobility in Met/Met mice as completely abrogated. (LLM, conf=0.95)

  cites Liu et al., 2012 source

In the paper

“if replicated, suggest that (2R,6R)-HNK directly binds to and triggers TrkB signaling to enhance synaptic plasticity.”

What the sources say

• Supported

  In Results (‘Antidepressants bind to TRKB transmembrane domain’; page unavailable), the paper reports that R,R-HNK binds TRKB and suggests TRKB is its direct target. Results (‘Antidepressants promote membrane trafficking of TRKB’; page unavailable) reports that R,R-HNK increases synaptic AMPA-receptor surface exposure, an effect blocked by TRKB inhibitors or mutation, and interprets it as downstream of TRKB activation. This supports the citing sentence’s tentative link to synaptic plasticity. (LLM, conf=0.91)

  cites Casarotto et al., 2021 source

In the paper

“the tricyclic antidepressant imipramine (30 mg/kg i.p.) increased phosphorylation of TrkB (residue Y816) 30 minutes post-treatment in the PFC (Rantamäki et al., 2011).”

What the sources say

• Supported

  Figure 1A in the Results reports that imipramine (30 mg/kg i.p., 30 minutes) induced TrkB phosphorylation in the medial prefrontal cortex of mice. Figure 1B identifies Y816 as the phosphorylated TrkB residue measured. (LLM, conf=0.92)

  cites Rantamäki et al., 2011 source

In the paper

“Val/Val patients were more responsive 4 hours post-treatment (41% reduction in HAM-D score) to ketamine therapy relative to Met allele carriers (24% reduction in HAM-D score) (Laje et al., 2012).”

What the sources say

• Supported

  In “To the Editor,” the paper reports a 41% mean improvement in HAM-D scores for the Val/Val group versus 24% for Met carriers. Scores were measured 210 or 230 minutes after infusion, consistent with the citing sentence’s approximate “4 hours.” (LLM, conf=0.93)

  cites Laje et al., 2012 source

In the paper

“morphine (10 mg/kg s.c.) was administered prior to the forced swim test but did not produce the same reduction in immobility as ketamine.”

What the sources say

• Supported

  The section “A Hedonic Dose of Morphine Does Not Mimic Behavioral or Cellular Effects of Ketamine” reports that morphine at 10 mg/kg subcutaneously had no effect on forced-swim-test performance, unlike ketamine. The supplied passages do not give a page number. (LLM, conf=0.94)

  cites Klein et al., 2020 source

In the paper

“The effect of (2R,6R)-HNK was blocked by pretreatment with the opioid receptor antagonist naltrexone”

What the sources say

• Partly supported

  In Results and Discussion, naltrexone pretreatment abolished HNK’s inverse-agonist effect at the μ opioid receptor, but at the κ receptor it increased the IC50 rather than eliminating the effect. The paper therefore supports inhibition of HNK’s measured receptor effect, not an unqualified claim that pretreatment prevented it. (LLM, conf=0.87)

  cites Joseph et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“Likewise, similar range of affinity values at μ and κ opioid receptors were recently reported for (S)-ketamine (μ: Ki = 7 μM and κ: Ki = 19 μM) and (R)-ketamine (μ: Ki = 14 μM and κ: Ki = 40 μM) (Bonaventura et al.,”

What the sources say

• Partly supported

  The Results section on in vitro target engagement reports micromolar affinities for both enantiomers at μ and κ opioid receptors, supporting the claim that they fall in similar ranges. However, the citing sentence swaps two values: the paper gives (R)-ketamine μ Ki = 19 ± 5 μM and (S)-ketamine κ Ki = 14 ± 7 μM, not 14 and 19 μM respectively. (LLM, conf=0.92)

  cites Bonaventura et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“(2R,6R;2S,6S)-HNK (20 mg/kg) did not result in a change in dopamine.”

What the sources say

• Partly supported

  The Results section reports that neither (2R,6R)-HNK nor (2S,6S)-HNK, each administered separately at 20 mg/kg, affected prefrontal dopamine release in normal mice. It does not report testing the combined (2R,6R;2S,6S)-HNK preparation named in the claim. (LLM, conf=0.84)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Reduced SERT occupancy was also observed using the radioligand [11C]DASB in these brain regions in addition to the occipital cortex and lateral geniculate nucleus.”

What the sources say

• Supported

  The section “Effect of ketamine on [11C]DASB binding to the SERT” reports significantly decreased [11C]DASB binding in the nucleus accumbens, ventral globus pallidus, nucleus reuniens, occipital cortex and lateral geniculate nucleus. This supports the cited observation, although the paper describes the measured outcome as radioligand binding rather than SERT occupancy. (LLM, conf=0.91)

  cites Yamanaka et al., 2014 source

In the paper

“a study in rats observed that the acute and sustained antidepressant-like effects of (S)-ketamine (15 mg/kg) in the forced swim test one and 48-hours post-treatment are prevented by serotonin depletion via pretreatment with an irreversible tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) (du Jardin et al., 2017).”

What the sources say

• Supported

  The Results (Forced Swim Test; page not provided) report that S-ketamine at 15 mg/kg reduced immobility and increased swimming in FSL rats at 1 and 48 hours, and that pCPA pretreatment prevented both effects. The Results (Frontal Cortical 5-HT Levels and Turnover; page not provided) also confirm that pCPA substantially depleted serotonin. (LLM, conf=0.94)

  cites du Jardin et al., 2017 source

In the paper

“For serotonin, (R)-ketamine (10 and 20 mg/kg i.p.) produced an increase at 20-, 40-, and 60-minutes post-treatment with a peak effect size at ~275% of baseline following a 20 mg/kg dose at 20 minutes.”

What the sources say

• Partly supported

  The Results section on normal mice reports that 10 and 20 mg/kg (R)-ketamine increased extracellular 5-HT in the PFC, and the Figure 1 caption confirms i.p. injection at 0 minutes. Our text copy does not give the claimed increases specifically at 20, 40, and 60 minutes or a peak of approximately 275% of baseline; those details are not verifiable from its figure caption. Page numbers are unavailable. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“(R) and (S)-norketamine (20 mg/kg) shared a ~150% peak increase at 60 minutes that was largely maintained following 120 minutes.”

What the sources say

• Partly supported

  The Results section (page not provided) reports that both norketamine enantiomers at 20 mg/kg increased prefrontal dopamine release in mice. Neither the Results text nor the Figure 1 caption in our copy gives a ~150% peak at 60 minutes or says the increase was largely maintained at 120 minutes. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“The peak increases in dopamine by (R)-ketamine and peak increases in serotonin and dopamine by (S)-ketamine are prevented by the AMPAR antagonist NBQX pretreatment 20 minutes prior.”

What the sources say

• Partly supported

  The Results section reports that NBQX blocked dopamine release induced by both ketamine enantiomers, and the Figure 3 caption confirms pretreatment 20 minutes before ketamine. But the Results and Discussion describe (S)-ketamine-induced serotonin release as attenuated or partially blocked, not prevented. Page numbers are not supplied in the passages. (LLM, conf=0.90)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“The current predominant theory according to these studies is that ketamine, and possibly the placebo effect, require a functional opioid system to achieve their antidepressant effects (Krimmel et al., 2020).”

What the sources say

• ?Could not verify

  The Introduction and Discussion report antidepressant-like effects of ketamine and conditioned placebo responses, but do not say that either requires a functional opioid system. A search for “opioid” found only a reference concerning placebo analgesia, not this proposed requirement for antidepressant effects. Page numbers were not available in our copy. (LLM, conf=0.76)

  cites Krimmel et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“A significant increase in 5-HT1B receptor binding (16.7%) was observed in the hippocampus following a single ketamine treatment.”

What the sources say

• Supported

  The Abstract reports a 16.7% increase in hippocampal 5-HT1B receptor binding after one ketamine treatment (p = 0.036) in patients with SSRI-resistant MDD. The Results table also shows a significant increase from baseline within the ketamine group; the paper does not report a significant difference in binding change versus placebo. (LLM, conf=0.94)

  cites Tiger et al., 2020 source

In the paper

“The acute and sustained effects of (S)-ketamine were rescued by a 5-HT1B receptor agonist CP94253 administered two hours prior to the forced swim test.”

What the sources say

• Supported

  The Results (Forced Swim Test) report that CP94253 given two hours before testing rescued both the acute and 48-hour effects of S-ketamine. The Conclusion specifies that this was an antidepressant-like effect in 5-HT-depleted FSL rats. (LLM, conf=0.95)

  cites du Jardin et al., 2017 source

In the paper

“the antidepressant-like effects of ketamine (32 mg/kg i.p.) were absent in mice lacking SERT or plasma membrane monoamine transporter (PMAT) (Bowman et al., 2020).”

What the sources say

• Supported

  Results §2.4 reports that 32 mg/kg ketamine had no antidepressant-like effect in either SERT−/− or PMAT−/− mice in the forced swim test. Materials and Methods §4.5 specifies that ketamine was given i.p.; page numbers were not available in our copy. (LLM, conf=0.95)

  cites Bowman et al., 2020 source

In the paper

“This study did not observe significant occupancy of ketamine at SERT in the caudate, putamen, thalamus, and whole brain ROIs.”

What the sources say

• Supported

  The Discussion reports occupancy values within PET test-retest variability in the caudate, putamen, thalamus, and whole-brain ROI, and concludes that no measurable SERT occupancy was detected after an antidepressant ketamine dose. The paper also identifies the participants as healthy subjects and the dose as 0.50 mg/kg. (LLM, conf=0.94)

  cites Spies et al., 2018 source

In the paper

“For dopamine, (R)-ketamine (20 mg/kg) resulted in only modest changes, with a modest increase 40 minutes post-injection.”

What the sources say

• Partly supported

  The Results section (page unavailable) reports that 20 mg/kg (R)-ketamine increased prefrontal dopamine release, and the Discussion describes its effect as small. Neither passage specifies an increase at 40 minutes post-injection, so that timing is not supported by our copy. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Systemic (10 mg/kg s.c.) or direct infusion (0.03 nmol/side) of the AMPAR antagonist NBQX into the mPFC blocked the antidepressant-like effects in the forced swim test.”

What the sources say

• Supported

  The Results section reports that systemic NBQX (10 mg/kg s.c.) blocked the reductions in forced-swim-test immobility induced by LY341495 and ketamine (Figure 3a–b). It also reports that NBQX microinjected into the mPFC (0.03 nmol/0.1 μl/side) blocked both effects (Figure 3d–e). (LLM, conf=0.95)

  cites Fukumoto et al., 2016 source

In the paper

“there is evidence that (2R,6R)-HNK does not elicit the same desire to self-administer or hyperlocomotion effects as ketamine”

What the sources say

• Partly supported

  The Results section, “Lack of adverse effects of (2R,6R)-HNK in mice” (page unavailable), reports no change in locomotor activity after oral HNK. The Discussion says this is consistent with prior findings of no ketamine-associated hyperlocomotion, and also reports a prior finding of lower abuse potential. Our copy does not report a self-administration test or specifically establish a lack of desire to self-administer HNK. (LLM, conf=0.82)

  cites Highland et al., 2019 sourceExperimental — accuracy not yet measured
• Supported

  In “(2R,6R)-HNK lacks ketamine’s side effects” (page not supplied), the paper reports that mice self-administered ketamine but not pharmacologically relevant doses of (2R,6R)-HNK under the same conditions. The same section reports increased locomotor activity with ketamine but no significant change in locomotion with (2R,6R)-HNK. The citing sentence appropriately frames this as evidence rather than a claim about human behavior. (LLM, conf=0.94)

  cites Zanos et al., 2016 source

In the paper

“conditioned lever responding for (S)-ketamine is rapidly extinguished with fewer than 10 responses over three hours on the first extinction training day”

What the sources say

• Partly supported

  The Results (page not supplied) say that rats trained to respond for (S)-ketamine showed rapid extinction of drug seeking. The Methods (page not supplied) specify three-hour extinction sessions. Neither passage establishes fewer than 10 responses on the first extinction day. (LLM, conf=0.84)

  cites Bonaventura et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“Another study in mice observed antidepressant-like effects of ketamine in the forced swim test which mimicked the effects of the mGluR2/3 antagonist LY341495 (Fukumoto et al., 2016).”

What the sources say

• Supported

  The Abstract identifies the study as a forced swimming test in C57BL/6J male mice and reports antidepressant effects of both ketamine and LY341495. The Results report reduced immobility for each drug, supporting the comparison in the citing sentence. (LLM, conf=0.94)

  cites Fukumoto et al., 2016 source

In the paper

“norepinephrine levels were significantly impacted by (R)-ketamine (20 mg/kg) with a peak effect size of ~160% of baseline 40 minutes post-treatment and remained heightened following 120 minutes”

What the sources say

• Partly supported

  The Results section (page unavailable) reports that (R)-ketamine at 20 mg/kg significantly increased extracellular noradrenaline in the prefrontal cortex of mice. Our text does not give a peak of approximately 160% of baseline at 40 minutes or establish that levels remained elevated at 120 minutes; the Figure 1 caption describes time-point comparisons but provides no plotted values. (LLM, conf=0.87)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Likewise, for SERT, DAT, and NET, no inhibitory effects of ketamine or its metabolites were observed in binding or functional assays.”

What the sources say

• Supported

  The Results section reports no inhibition of binding at DAT, NET, or SERT by ketamine enantiomers or their metabolites, and no inhibition of transporter activity in functional assays. Both findings apply to concentrations tested up to 10 mM. (LLM, conf=0.94)

  cites Can et al., 2016 source

In the paper

“ketamine and (2R,6R)-HNK may be capable of binding TrkB to facilitate BDNF signaling which drives the mechanisms necessary for structural potentiation of synapses (Casarotto et al., 2021).”

What the sources say

• Supported

  The Results section on TRKB binding reports that (2R,6R)-HNK binds TRKB and that ketamine competes for antidepressant binding to TRKB. The Introduction links both drugs to increased BDNF–TRKB signaling, while the Results sections on membrane trafficking and antidepressant-induced plasticity connect TRKB signaling to dendritic spines and synaptic potentiation. Together, these support the citing sentence’s hedged mechanistic claim. (LLM, conf=0.87)

  cites Casarotto et al., 2021 source

In the paper

“ketamine restored LTP induction which was otherwise impaired in helpless rats in the hippocampus to nucleus accumbens core (NAcc) pathway when administered 20 minutes prior to induction.”

What the sources say

• Supported

  The Results section reports that ketamine injected 20 minutes before high-frequency stimulation restored LTP in the hippocampus–NAc pathway of helpless rats. The Discussion explicitly says it restored normal plasticity in both the NAc core and shell, supporting the claim about the core. (LLM, conf=0.93)

  cites Belujon & Grace, 2014 source

In the paper

“Alternatively, ketamine may block discrete postsynaptic NMDARs, such as those containing GluN2B which otherwise inhibit AMPAR signaling (Ferreira et al., 2015).”

What the sources say

• Partly supported

  The Discussion reports increased synaptic AMPAR expression in GluN2B-knockout neurons and concludes that GluN2B-containing NMDARs limit synaptic AMPAR content under basal conditions. The paper does not address whether ketamine blocks those receptors, so it supports the proposed target’s inhibitory role but not the ketamine-specific part of the sentence. (LLM, conf=0.85)

  cites Ferreira et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“NMDAR blockade does not explain the mechanism of action of (2R,6R)-HNK as its affinity for and functional effects at NMDARs are beyond therapeutically relevant concentrations (Lumsden et al., 2019).”

What the sources say

• Supported

  The Discussion reports that an antidepressant-relevant (2R,6R)-HNK concentration of 8 µM left all tested NMDAR subtypes unaffected; blocking them required roughly 30–60 times higher concentrations. The paper concludes that direct NMDAR inhibition does not contribute to its antidepressant-relevant effects. Its measurements establish inhibitory potency and function rather than a separate binding-affinity estimate. (LLM, conf=0.92)

  cites Lumsden et al., 2019 source

In the paper

“it was found that high concentrations of ketamine (Ki = 66.8, 62.9, and 162 μM) can functionally inhibit NET, DAT, and SERT respectively (Nishimura et al., 1998).”

What the sources say

• Supported

  The Competition Experiments section (p. 5) reports that ketamine competitively inhibited NET, DAT, and SERT, with Ki values of 66.8, 62.9, and 161.7 μM, respectively. Table 1 (p. 5) confirms those values; 162 μM is the rounded SERT value. (LLM, conf=0.95)

  cites Nishimura et al., 1998 source

In the paper

“Enhancement in synaptic plasticity is one of the key phenomena that contributes to the antidepressant effects of ketamine (Duman et al., 2016; Riggs & Gould, 2021).”

What the sources say

• Supported

  The ‘Rapid acting antidepressants: mechanism of action’ section says ketamine increases synaptic number and function, and that the resulting long-lasting synaptic changes correlate with its persistent antidepressant behavioral effects. It also describes ketamine-induced synaptogenesis as a possible way to reverse depression-related loss of connections, supporting the paraphrase’s proposed contribution rather than establishing it as the sole mechanism. (LLM, conf=0.91)

  cites Duman et al., 2016 source
• Supported

  The “Ketamine Enhances Glutamatergic Transmission and Promotes Synaptogenesis” section (page not provided) states that ketamine initiates synaptogenesis as part of its antidepressant-like effects and may produce a lasting increase in synaptic transmission. This supports the claim that enhanced synaptic plasticity contributes to those effects. (LLM, conf=0.92)

  cites Riggs & Gould, 2021 source

In the paper

“had little to no ability to bind or functionally agonize or antagonize D1-5 receptors (Can et al., 2016).”

What the sources say

• Supported

  The Results section’s “Dopamine Receptor Binding Affinity and Functional Activity” reports that, at 10 μM, neither ketamine enantiomer nor the tested metabolites produced more than 50% inhibition at any D1–D5 receptor. It also reports no agonist or antagonist action in the in vitro functional assays. (LLM, conf=0.94)

  cites Can et al., 2016 source

In the paper

“It appears that increased strength of excitatory neurotransmission, in particular involving AMPARs, represents a common downstream target that is necessary for antidepressant efficacy among classical and rapid-acting antidepressants (Alt et al., 2006; Gould et al., 2019; Thompson et al., 2015).”

What the sources say

• ?Not checked — no full text of the sourcecites Alt et al., 2006 source
• Partly supported

  The 'Antidepressant Expression Mechanisms' section says AMPARs are required for rapid antidepressant actions and links sustained effects to stronger synapses. But 'Future Medication Development for the Rapid Treatment of Depression' says classical monoamine-acting antidepressants appear insensitive to acute AMPAR blockade. The paper therefore does not support an AMPAR requirement shared across classical and rapid-acting drugs; page numbers were not available in our copy. (LLM, conf=0.88)

  cites Gould et al., 2019 sourceExperimental — accuracy not yet measured
• Partly supported

  The Formal statement of the excitatory synapse hypothesis (page unavailable) calls restoration of excitatory synaptic strength critical for both conventional antidepressants and ketamine. The Ketamine and NMDAR antagonists section says ketamine loses its antidepressant effect without functional AMPARs. The SSRIs section links their therapeutic effects to potentiated excitation, but does not establish that AMPAR involvement is necessary for classical antidepressants. (LLM, conf=0.86)

  cites Thompson et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“it was found that ketamine (5 mg/kg i.p.) rescued the learned helplessness phenotype, i.e. had fewer escape failures and reduced latency to escape, when administered 20 minutes or 24 hours prior to an active avoidance task (Belujon & Grace, 2014).”

What the sources say

• Supported

  The Abstract Methods identify Wistar-Kyoto rats, and the Learned Helplessness paradigm Methods specify ketamine at 5 mg/kg i.p. The Results report fewer escape failures and shorter escape latency after ketamine given 20 minutes or 24 hours before testing. The 24-hour treatment improved behavior but did not restore it to non-helpless levels; the claim says reduced, not normalized. (LLM, conf=0.93)

  cites Belujon & Grace, 2014 source

In the paper

“First, ketamine acts as an open-channel blocker of NMDARs (Zorumski et al., 2016).”

What the sources say

• Supported

  The Introduction states that ketamine antagonizes NMDARs through an open-channel block mechanism: the channels must open before ketamine can block them. No page number is provided in our copy. (LLM, conf=0.94)

  cites Zorumski et al., 2016 source

In the paper

“Ketamine (2, 10, or 50 mg/kg i.p.) failed to alter the rise time, decay constant, or peak amplitude of evoked dopamine release from VTA afferents into the NAcc.”

What the sources say

• Supported

  The Results report that mice received ketamine at 2, 10, or 50 mg/kg i.p. during recordings of VTA-stimulation-evoked dopamine in the NAc core. Figure 3 identifies peak amplitude, rise time, and decay constant as measured parameters; the Discussion reports no significant effect on the magnitude or kinetics of evoked dopamine concentrations in anesthetized mice. (LLM, conf=0.94)

  cites Can et al., 2016 source

In the paper

“NMDAR blockade can lead to reductions in GABA release which disinhibits (facilitates) release of other neurotransmitters (Grunze et al., 1996).”

What the sources say

• Partly supported

  The Results report that the NMDA receptor antagonist APV reduced evoked inhibitory postsynaptic potentials in CA1 neurons, and the Discussion says NMDA antagonists can reduce baseline inhibitory transmission. The paper does not establish that this reduction reflects lower GABA release or that it facilitates release of other neurotransmitters. No page number is available in our copy. (LLM, conf=0.87)

  cites Grunze et al., 1996 sourceExperimental — accuracy not yet measured

In the paper

“A decade later, a seminal study of ketamine for use in adults with depression observed a significant reduction in depression symptoms as measured by the Hamilton Depression Rating Scale (HDRS) within four hours post-ketamine treatment (0.5 mg/kg intravenously [i.v.] over 40 minutes) relative to placebo”

What the sources say

• ?Not checked — no full text of the sourcecites Berman et al., 2000 source

In the paper

“Notably, there are 12 HNKs that have been detected in human plasma following ketamine treatment which are categorized based on the positioning of a hydroxyl group on the cyclohexyl ring (in position 4, 5, or 6) and their stereochemistry at two stereocenters (R,R; S,S; R,S; or S,R).”

In the paper

“The ability for ketamine to elicit rapid behavioral effects may be due to its profound impact on glutamatergic signaling – the primary excitatory neurotransmitter system in the brain.”

In the paper

“An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action”

In the paper

“The clinical use of NMDAR antagonists, such as ketamine, for the treatment of depression was preceded by the finding that other NMDAR antagonists, including AP-7 and MK-801, produced antidepressant-like effects in mice”

What the sources say

• ?Not checked — no full text of the sourcecites Trullas & Skolnick, 1990 source

In the paper

“Remarkably, the effects of the single ketamine treatment persisted in some patients for a week or longer”

What the sources say

• ?Not matched

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

  cites Zarate et al., 2006

In the paper

“Ketamine undergoes its first metabolic transformation into (R,S)-norketamine in the liver”