Mechanisms of ketamine and its metabolites as antidepressants

The lanicemine 100 mg study did not find rapid antidepressant effects.

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

• cites Sanacora et al., 2014 sourceDisputed

  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.

  Experimental — accuracy not yet measured

Sub-anesthetic doses of racemic ketamine produce rapid antidepressant responses, sometimes within hours, in people whose depression has not responded to monoaminergic drugs.

“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.”

• cites Daly et al., 2018 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Zarate, Singh, Carlson, et al., 2006Not matched

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

A phase III study of 15 lanicemine treatments over 12 weeks did not improve MADRS scores compared with placebo in patients with major depression.

“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”

• cites Sanacora et al., 2017 sourcePartly 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)

  Experimental — accuracy not yet measured

The extent of Mg2+ block and Ca2+ permeability depends on NMDAR subunit composition.

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

• cites Kuner & Schoepfer, 1996 sourceSupported
• cites Matsuda et al., 2003 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Monyer et al., 1992 sourceNot checked — no full text of the source

Lanicemine 150 mg IV transiently improved MADRS scores at 80 and 110 minutes after treatment in unmedicated patients with major depression.

“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”

• cites Zarate et al., 2013 sourceSupported

Evidence indicates that NMDAR antagonism causes ketamine's dissociative and psychotomimetic effects.

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

• cites Krystal et al., 1994 sourceNot checked — no full text of the source
• cites Zorumski et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

Lanicemine 100 mg IV every other day for three weeks as an adjunct improved MADRS scores from the second week through two weeks after treatment in patients with major depression.

“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”

• cites Sanacora et al., 2014 sourceSupported

Ketamine is rapidly metabolized into neuroactive products that likely contribute to its therapeutic effects.

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

• cites Highland et al., 2021 sourceSupported
• cites Zanos et al., 2018Not matched

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

Patients in remission were more likely to relapse when switched to placebo nasal spray plus an oral antidepressant.

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

• cites Daly et al., 2019 sourceSupported

NMDAR antagonism may not fully account for ketamine's antidepressant effects.

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

• cites Autry et al., 2011 sourceSupported
• cites Gould et al., 2019 sourceSupported
• cites Hillhouse & Porter, 2014 sourceSupported

Ketamine was first characterized as an NMDAR antagonist.

“Ketamine was initially characterized as an NMDAR antagonist”

• cites Anis et al., 1983 sourceSupported
• cites Zorumski et al., 2016 sourceSupported

Memantine, which blocks the NMDAR ion channel at the same site as ketamine, did not produce antidepressant effects in patients with depression.

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

• cites Omranifard et al., 2014Not checked — no full text of the source
• cites Smith et al., 2013 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Zarate, Singh, Quiroz, et al., 2006 sourceNot checked — no full text of the source

Knockdown of GluN2B in SST interneurons mimicked ketamine's effects on SST Ca2+ dynamics and pyramidal neuron dendrites.

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

• cites Ali et al., 2020 sourceSupported

Loss of GluN2B in medial prefrontal cortex GABAergic interneurons, specifically those expressing somatostatin and parvalbumin, occluded ketamine's antidepressant-like effects in the mouse forced swim test.

“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).”

• cites Gerhard et al., 2020 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

The genetic manipulation alone reduced immobility relative to controls to a point where ketamine could not elicit a further reduction.

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

• cites Gerhard et al., 2020 sourcePartly 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)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Without Mg2+, ketamine IC50 values are lower for GluN2A/B/C/D receptors (0.33, 0.31, 0.51, and 0.83 μM).

“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).”

• cites Kotermanski & Johnson, 2009 sourcePartly 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)

  Experimental — accuracy not yet measured

Phosphorylation at S845 selectively increases extrasynaptic AMPAR insertion, allowing receptors to diffuse to synapses and promote long-term potentiation.

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

• cites Derkach et al., 2007 sourceNot checked — no full text of the source
• cites Oh et al., 2006Not matched

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

• cites Sun et al., 2005 sourcePartly 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)

  Experimental — accuracy not yet measured

Under physiological Mg2+, glutamate, glycine, and pH 7.2, GluN2C/D-containing NMDARs in HEK293T cells are more sensitive to ketamine block (IC50 1.18 and 2.95 μM) than GluN2A/B-containing receptors (5.35 and 5.08 μM).

“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”

• cites Kotermanski & Johnson, 2009 sourcePartly 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)

  Experimental — accuracy not yet measured

Ketamine 20 μM for 30 minutes potentiates AMPAR-mediated evoked neurotransmission in mouse CA1 independently of changes in presynaptic release probability.

“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”

• cites Autry et al., 2011 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Nosyreva et al., 2013 sourceSupported

Lowering pH from 7.6 to 6.9 decreased ketamine IC50 values at all NMDAR subunits.

“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).”

• cites Dravid et al., 2007 sourceSupported

In rat hippocampal slices, ketamine 1 μM for 20 minutes increased CA1 action potential probability through disinhibition of pyramidal neurons.

“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”

• cites Widman & McMahon, 2018 sourceSupported

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

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

• cites Abbott & Popescu, 2020 sourcePartly 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)

  Experimental — accuracy not yet measured

Production of 6-HNKs is important for the full antidepressant-like behavioral effects of ketamine.

“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).”

• cites Zanos, Highland, Liu, et al., 2019 sourceSupported
• cites Zanos et al., 2016 sourceSupported
• cites Zheng et al., 2021 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

(2R,6R)-HNK does not displace MK-801 binding to NMDARs at 10 μM.

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

• cites Moaddel et al., 2013 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Morris et al., 2017 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Zanos et al., 2016 sourceSupported

GluN2A-containing NMDARs in PV interneurons are necessary for ketamine's rapid actions on evoked firing of visual cortex pyramidal neurons and gamma-band oscillations in mice.

“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).”

• cites Picard et al., 2019 sourceSupported

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

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

• cites Abbott & Popescu, 2020 sourceSupported

Inhibitory effects of (2R,6R)-HNK at 500 μM at GluN2A-containing NMDARs in HEK-293 cells with glutamate and glycine were enhanced by 84% at pH 6.8 and 87% at pH 7.2.

“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).”

• cites Abbott & Popescu, 2020 sourcePartly 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)

  Experimental — accuracy not yet measured

HNKs, which have antidepressant-like effects in preclinical models, may not require NMDARs for their long-lasting effects on behavior or synaptic plasticity in hippocampus.

“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).”

• cites Gould et al., 2017 sourceNot checked — no full text of the source
• cites Riggs et al., 2020 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Zanos et al., 2016 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

When (2R,6R)-HNK was applied before glutamate, its inhibitory effects on whole-cell NMDAR currents increased relative to co-application, suggesting preferential binding to inactive receptors.

“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.”

• cites Abbott & Popescu, 2020 sourceSupported

The disinhibition theory posits that ketamine blocks NMDARs on GABAergic interneurons, reducing their firing rate and removing the brakes on glutamatergic neurons.

“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).”

• cites Grunze et al., 1996 sourcePartly 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)

  Experimental — accuracy not yet measured

Ketamine at 0.5 μM facilitated BDNF release from primary cortical neurons at 15, 60, and 360 minutes after treatment.

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

• cites Lepack et al., 2014 sourceSupported

Long-term treatment for 21 days with SSRIs or SNRIs increases BDNF mRNA expression in rat hippocampus.

“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).”

• cites Nibuya et al., 1996 sourcePartly 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)

  Experimental — accuracy not yet measured

Chronic electroconvulsive seizure treatment increases BDNF mRNA expression in hippocampus.

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

• cites Nibuya et al., 1995 sourceSupported

The effects of (2R,6R)-HNK in the forced swim test and novelty suppressed feeding test were blocked in mice carrying the BDNF Val66Met allele, including heterozygous Val/Met and homozygous Met/Met mice.

“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).”

• cites Fukumoto et al., 2019 sourceSupported

Ketamine restored dendritic spines specifically lost during corticosterone exposure.

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

• cites Moda-Sava et al., 2019 sourceSupported

LY341495 at 3 mg/kg i.p. in rats reversed anhedonia produced by chronic unpredictable stress measured by sucrose preference at 48 hours post-treatment.

“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).”

• cites Dwyer et al., 2013 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

(2R,6R)-HNK at 30 mg/kg intraperitoneally produced antidepressant-like effects in mice in the forced swim test and female urine sniffing test 24 hours after treatment.

“(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”

• cites Fukumoto et al., 2019 sourceSupported

Ketamine rescued the increase in immobility produced by corticosterone exposure in the tail suspension test from three hours to one week post-treatment.

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

• cites Moda-Sava et al., 2019 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Serotonin receptor agonists have differential effects on BDNF expression by brain region, with decreases in dentate gyrus and increases in parietal, frontal, and temporal cortex of rats.

“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).”

• cites Vaidya et al., 1997 sourceSupported

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.

“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).”

• cites Singh et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

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

“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.”

• cites Moda-Sava et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

The neurotrophic factor theory of depression emerged in part from clinical and preclinical studies showing significant gross structural changes in hippocampus and PFC linked to neuronal atrophy.

“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).”

• cites Deyama & Duman, 2020 sourceSupported

Specific deletion of newly formed spines 24 hours post-treatment via AS-PaRac1 reversed ketamine's effects in the tail suspension test 48 hours post-treatment.

“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.”

• cites Moda-Sava et al., 2019 sourceSupported

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

A lack of D-serine might preferentially impact GluN2B-containing NMDARs because D-serine restricts their diffusion within membranes and reduces synaptic expression.

“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).”

• cites Ferreira et al., 2017 sourceSupported

In mice, ketamine at 3 mg/kg intraperitoneally raised hippocampal BDNF protein levels 30 minutes after administration.

“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).”

• cites Autry et al., 2011 sourceSupported

In rats, infusing an anti-BDNF antibody into the medial prefrontal cortex blocked the antidepressant-like effects of ketamine at 10 mg/kg intraperitoneally in the forced swim test.

“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”

• cites Lepack et al., 2014 sourceSupported

Severity of depressive symptoms measured by HAMD-17 inversely correlated with synaptic density marker SV2A labeled with [11C]UCB-J and measured via PET.

“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).”

• cites Holmes et al., 2019 sourceSupported

The antidepressant-like effects of ketamine in the mouse forced swim test were absent in BDNF knockout mice.

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

• cites Autry et al., 2011 sourceSupported

Neither ketamine enantiomer activated β-arrestin.

“Interestingly, neither enantiomer activated ß-arrestin.”

• cites Bonaventura et al., 2021 sourceSupported

Mutation of the putative transmembrane binding site of TrkB at residue Y433 prevented ketamine's effects at 10 mg/kg in the forced swim test and in extinction of conditioned fear.

“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).”

• cites Casarotto et al., 2021 sourceSupported

At both μ and κ opioid receptors, (R)-ketamine behaved as a weak partial agonist.

“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%).”

• cites Bonaventura et al., 2021 sourceSupported

Fluoxetine at 30 mg/kg intraperitoneally also increased TrkB phosphorylation one hour after treatment in the hippocampus of wild-type and serotonin transporter knockout mice.

“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”

• cites Rantamäki et al., 2011 sourceSupported

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

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

• cites Fred et al., 2019 sourceSupported

In congenitally learned helpless (cLH) rats, Ca2+ signaling was increased in the lateral habenula (LHb) relative to wild-type rats.

“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).”

• cites Klein et al., 2020 sourceSupported

(S)-ketamine given as a 0.11 mg/kg bolus with 0.12 mg/kg maintenance intravenous infusion over 20 minutes significantly increased overall hippocampal subfield volumes in healthy volunteers 65 minutes after treatment initiation, regardless of Met allele carrier status.

“(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).”

• cites Höflich et al., 2021 sourceSupported

Buprenorphine, 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.

“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).”

• cites Falcon et al., 2016 sourceSupported

In patients with treatment-resistant depression (n=12), the opioid receptor antagonist naltrexone at 50 mg attenuated the antidepressant effects of ketamine at 0.5 mg/kg intravenously over 40 minutes one to three days after treatment, as measured by the Hamilton Depression Rating Scale 6-item and 17-item.

“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.”

• cites Williams et al., 2018 sourceSupported

The effects of ketamine at 10 mg/kg intraperitoneally on spine morphology 24 hours after treatment-increased spine number, increased diameter, and reduced length-were significantly blunted but not completely abolished in Met/Met mice.

“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.”

• cites Liu et al., 2012 sourcePartly 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)

  Experimental — accuracy not yet measured

A computational study predicted that (2R,6R)-HNK binds the orthosteric sites of μ and κ opioid receptors with high affinity.

“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).”

• cites Joseph et al., 2021 sourceSupported

The antidepressant-like effect of ketamine in the forced swim test, measured as reduced immobility, was absent in Met/Met mice.

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

• cites Liu et al., 2012 sourceSupported

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

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

• cites Casarotto et al., 2021 sourceSupported

In mice, imipramine at 30 mg/kg intraperitoneally increased phosphorylation of TrkB at residue Y816 in the prefrontal cortex 30 minutes after treatment.

“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).”

• cites Rantamäki et al., 2011 sourceSupported

In patients, Val/Val individuals showed greater response to ketamine therapy 4 hours after treatment, with a 41% reduction in HAM-D score, compared with Met allele carriers, who had a 24% reduction.

“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).”

• cites Laje et al., 2012 sourceSupported

Morphine at 10 mg/kg subcutaneously did not produce the same reduction in immobility as ketamine in the forced swim test.

“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.”

• cites Klein et al., 2020 sourceSupported

Naltrexone pretreatment prevented the effect of (2R,6R)-HNK.

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

• cites Joseph et al., 2021 sourcePartly 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)

  Experimental — accuracy not yet measured

Reported μ and κ opioid receptor affinities for (S)- and (R)-ketamine fell in similar ranges.

“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.,”

• cites Bonaventura et al., 2021 sourcePartly 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)

  Experimental — accuracy not yet measured

(2R,6R;2S,6S)-HNK at 20 mg/kg did not change dopamine.

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

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

SERT occupancy also decreased in those regions and in the occipital cortex and lateral geniculate nucleus.

“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.”

• cites Yamanaka et al., 2014 sourceSupported

In rats, depleting serotonin with pCPA pretreatment prevented both the acute and 48-hour antidepressant-like effects of (S)-ketamine (15 mg/kg) in the forced swim test.

“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).”

• cites du Jardin et al., 2017 sourceSupported

In mouse PFC, (R)-ketamine (10 and 20 mg/kg i.p.) raised extracellular serotonin at 20, 40, and 60 minutes, peaking at about 275% of baseline after 20 mg/kg at 20 minutes.

“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.”

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

Both norketamine enantiomers (20 mg/kg) increased dopamine to about 150% of baseline at 60 minutes, largely sustained at 120 minutes.

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

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

Pretreatment with the AMPAR antagonist NBQX 20 minutes earlier blocked the dopamine peak from (R)-ketamine and the serotonin and dopamine peaks from (S)-ketamine.

“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.”

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

The leading theory holds that an intact opioid system is needed for ketamine-and perhaps placebo-to produce antidepressant effects.

“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).”

• cites Krimmel et al., 2020 sourceCould 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)

  Experimental — accuracy not yet measured

In SSRI-resistant major depression, one ketamine treatment raised hippocampal 5-HT1B receptor binding by 16.7%.

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

• cites Tiger et al., 2020 sourceSupported

A 5-HT1B agonist, CP94253, given two hours before the forced swim test restored both the acute and sustained effects of (S)-ketamine.

“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.”

• cites du Jardin et al., 2017 sourceSupported

In mice without SERT or PMAT, ketamine (32 mg/kg i.p.) did not produce antidepressant-like effects.

“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).”

• cites Bowman et al., 2020 sourceSupported

A PET study in healthy volunteers found no significant SERT occupancy from ketamine (0.5 mg/kg i.v. over 40 minutes) in caudate, putamen, thalamus, or whole-brain regions.

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

• cites Spies et al., 2018 sourceSupported

For dopamine, (R)-ketamine (20 mg/kg) caused only a small rise at 40 minutes.

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

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

Giving NBQX systemically or infusing it into the mPFC blocked the antidepressant-like effects in the forced swim test.

“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.”

• cites Fukumoto et al., 2016 sourceSupported

Unlike ketamine, (2R,6R)-HNK does not appear to drive self-administration or hyperlocomotion.

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

• cites Highland et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Zanos et al., 2016 sourceSupported

Lever responding for (S)-ketamine extinguished quickly, with under 10 responses in three hours on the first extinction day.

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

• cites Bonaventura et al., 2021 sourcePartly 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)

  Experimental — accuracy not yet measured

In mice, ketamine's antidepressant-like effect in the forced swim test resembled that of the mGluR2/3 antagonist LY341495.

“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).”

• cites Fukumoto et al., 2016 sourceSupported

Norepinephrine was significantly affected by (R)-ketamine (20 mg/kg), peaking near 160% of baseline at 40 minutes and staying elevated at 120 minutes.

“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”

• cites Ago et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured

Binding and functional assays found no inhibition of SERT, DAT, or NET by ketamine or its metabolites.

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

• cites Can et al., 2016 sourceSupported

Ketamine and (2R,6R)-HNK might bind TrkB, promoting BDNF signaling that supports synaptic structural potentiation.

“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).”

• cites Casarotto et al., 2021 sourceSupported

Ketamine, given 20 minutes before induction, restored LTP in the hippocampus-to-NAcc pathway of helpless rats.

“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.”

• cites Belujon & Grace, 2014 sourceSupported

Ketamine might also block specific postsynaptic NMDARs, including GluN2B-containing ones, that normally suppress AMPAR signaling.

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

• cites Ferreira et al., 2015 sourcePartly 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)

  Experimental — accuracy not yet measured

NMDAR blockade cannot account for (2R,6R)-HNK's action, since its NMDAR affinity and effects occur only above therapeutic concentrations.

“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).”

• cites Lumsden et al., 2019 sourceSupported

At high concentrations, ketamine inhibited NET, DAT, and SERT with Ki values of 66.8, 62.9, and 162 μM, respectively.

“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).”

• cites Nishimura et al., 1998 sourceSupported

Increased synaptic plasticity is a key contributor to ketamine's antidepressant effects.

“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).”

• cites Duman et al., 2016 sourceSupported
• cites Riggs & Gould, 2021 sourceSupported

In an in vitro screen, (S)- and (R)-ketamine and their metabolites at 10 μM showed little or no binding or functional activity at D1-5 receptors.

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

• cites Can et al., 2016 sourceSupported

Stronger excitatory neurotransmission, especially via AMPARs, appears to be a shared requirement for antidepressant efficacy across classical and rapid-acting drugs.

“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).”

• cites Alt et al., 2006 sourceNot checked — no full text of the source
• cites Gould et al., 2019 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Thompson et al., 2015 sourcePartly 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)

  Experimental — accuracy not yet measured

In Wistar-Kyoto rats susceptible to learned helplessness, ketamine (5 mg/kg i.p.) reduced escape failures and latency when given 20 minutes or 24 hours before an active avoidance task.

“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).”

• cites Belujon & Grace, 2014 sourceSupported

Ketamine acts as an open-channel blocker of NMDARs.

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

• cites Zorumski et al., 2016 sourceSupported

In anesthetized mice, ketamine (2, 10, or 50 mg/kg i.p.) did not change the rise time, decay, or peak amplitude of evoked dopamine release from VTA inputs to the NAcc.

“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.”

• cites Can et al., 2016 sourceSupported

Blocking NMDARs can lower GABA release, which disinhibits other neurotransmitter release.

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

• cites Grunze et al., 1996 sourcePartly 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)

  Experimental — accuracy not yet measured

A seminal study found that ketamine 0.5 mg/kg IV over 40 minutes reduced HDRS depression scores within four hours compared with placebo in adults with depression.

“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”

• cites Berman et al., 2000 sourceNot checked — no full text of the source

Twelve HNKs have been detected in human plasma after ketamine, classified by hydroxyl position and stereochemistry.

“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).”

Ketamine's rapid behavioral effects may result from a strong influence on glutamatergic signaling.

“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.”

Ketamine metabolism may be an important part of how ketamine exerts its antidepressant action.

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

AP-7 and MK-801, other NMDAR antagonists, produced antidepressant-like effects in mice before ketamine was clinically used for depression.

“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”

• cites Trullas & Skolnick, 1990 sourceNot checked — no full text of the source

After a single ketamine treatment, some patients had antidepressant effects lasting a week or longer.

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

• cites Zarate et al., 2006Not matched

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

Ketamine is first metabolized in the liver to norketamine.

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

AGN-241751 at 50 μg/kg p.o. produced antidepressant-like effects in mouse forced swim and novelty suppressed feeding tests when given 24 hours before testing.

“AGN-241751 (50 μg/kg p.o.) was found to produce antidepressant-like effects in the forced swim and novelty suppressed feeding tests when administered 24 hours prior to testing (Pothula et al., 2021).”

• cites Pothula et al., 2021Not matched

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

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

In that study, ketamine 20 μM for 30 minutes was correlated with enhanced excitatory signaling in CA1 slices.

“The effects of ketamine (20 μM, 30-minute bath application) in this study were correlated to an enhancement in excitatory signaling in CA1 slices.”

• cites Aguilar-Valles et al., 2021 sourceNot checked — no full text of the source

The rapid antidepressant-like effects of ketamine 2.5 mg/kg i.p. and Ro25-6981 3 mg/kg i.p. in mice, measured by forced swim immobility, are blocked by the AMPAR antagonist NBQX.

“a seminal study observed that the rapid (within 30 minutes) antidepressant-like effects, as measured by immobility time in the forced swim test, of ketamine (2.5 mg/kg i.p.) and the GluN2B specific antagonist Ro25-6981 (3 mg/kg i.p.) in mice are blocked by the AMPAR antagonist NBQX”

• cites Maeng et al., 2008 sourceNot checked — no full text of the source

In mice, mTOR effectors 4E-BP1 and 4E-BP2 are required for the antidepressant-like effects of ketamine 10 mg/kg i.p. and (2R,6R)-HNK 20 mg/kg i.p. in forced swim and novelty suppressed feeding tests.

“another study in mice found that the mTOR effectors 4E-BP1 and 4E-BP2 are necessary for the antidepressant-like effects of ketamine (10 mg/kg i.p.) and (2R,6R)-HNK (20 mg/kg i.p.) in the forced swim and novelty suppressed feeding tests when administered one hour prior to testing”

• cites Aguilar-Valles et al., 2021 sourceNot checked — no full text of the source

For native hippocampal NMDARs, ketamine IC50 is 0.43 μM without Mg2+ at pH 7.4.

“Regarding native NMDARs in hippocampal neurons, the IC50 value for ketamine is 0.43 μM in the absence of Mg2+ and at a pH of 7.4.”

• cites Parsons et al., 1996 sourceNot checked — no full text of the source

In rat prefrontal cortex, ketamine 10 mg/kg i.p. induced phosphorylation of 4E-PB1, p70S6K, mTOR, ERK, and Akt one hour after treatment.

“Another study in the rat prefrontal cortex (PFC) observed that ketamine (10 mg/kg i.p.) induces the phosphorylation of the key intracellular messengers 4E-PB1, p70S6K, mTOR, ERK, and Akt one hour post-treatment”

• cites Li et al., 2010Not matched

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

No evidence supports ketamine or its metabolites binding to or functionally acting on AMPARs directly.

“Importantly, there is no evidence that supports ketamine nor its metabolites binding or functionally acting on AMPARs directly”

• cites Shaffer et al., 2019 sourceNot checked — no full text of the source

In rats, ketamine 20 μM increased GluA1 expression and S845 phosphorylation at 30 minutes, maintained for 4 hours.

“Likewise, another study in rats found that ketamine (20 μM bath application) increased GluA1 expression and S845 phosphorylation 30 minutes post-treatment and was maintained for 4 hours”

• cites Zhang et al., 2017 sourceNot checked — no full text of the source

Ketamine increases phosphorylation of GluA1 at serine 845.

“At the molecular level, ketamine increases phosphorylation of GluA1 at serine residue 845 (S845).”

The difference in ketamine IC50 values between two studies may be explained by agonist concentration, because higher agonist levels open more channels and allow non-competitive antagonists like ketamine to block more effectively.

“The discrepancy in ketamine IC50 values between these two studies might be explained by the concentration of agonist used (50 μM versus 1 mM glutamate), as higher agonist concentrations allow non-competitive antagonists, e.g. ketamine, to block more effectively due to a greater number of open channels”

• cites Lipton, 2006 sourceNot checked — no full text of the source

These properties allow GluN2B-containing NMDARs to strongly enhance Ca2+-dependent intracellular mechanisms such as Ca2+-sensitive protein kinases.

“These biophysical characteristics allow GluN2B-containing NMDARs to potently enhance Ca2+ dependent intracellular mechanisms such as the activation of Ca2+ sensitive protein kinases.”

Ketamine and its metabolites interact with compounds influencing group 2 metabotropic glutamate receptors mGluR2/3, which have been implicated in depression.

“Ketamine and its metabolites have also been shown to interact with compounds that influence the function of group 2 metabotropic glutamate receptors (mGluR2/3) which have been implicated in depression.”

Acute one-hour and sustained 24-hour antidepressant-like effects of (2R,6R)-HNK at 10 mg/kg i.p. in mouse forced swim test are blocked by AMPAR antagonist NBQX, similar to ketamine and Ro25-6981.

“the acute (one hour) and sustained (24 hour) antidepressant-like effects produced by (2R,6R)-HNK (10 mg/kg i.p.) in mice during the forced swim test are blocked by the AMPAR antagonist NBQX, akin to ketamine and Ro25-6981 as mentioned previously.”

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Knockdown of GluN2B in pyramidal neurons, but not GABAergic interneurons, prevented AGN-241751's behavioral effects in forced swim, novelty suppressed feeding, and sucrose splash tests.

“knockdown of GluN2B in pyramidal neurons, but not GABAergic interneurons, prevented the behavioral effects of AGN-241751 in the forced swim, novelty suppressed feeding, and sucrose splash tests.”

• cites Pothula et al., 2021Not matched

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

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

(2R,6R)-HNK concentration-dependently and rapidly within 10 minutes attenuated NMDAR-mediated mEPSCs in mouse hippocampal neuron cultures, with 10 μM having no effect and 50 μM producing about 40% reduction in charge transfer.

“NMDAR-mEPSCs were concentration-dependently and rapidly (within 10 minutes) attenuated by (2R,6R)-HNK with 10 μM having no effect and 50 μM producing an ~40% reduction in charge transfer.”

• cites Suzuki et al., 2017 sourceNot checked — no full text of the source

Glutamate release was not impacted by rapastinel.

“Notably, glutamate release was not impacted by rapastinel.”

• cites Pothula et al., 2020Not matched

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

A reduction in GABA and an increase in glutamate levels in PFC and hippocampus followed the forced swim test about 36 minutes post-treatment, consistent with disinhibition of synaptic glutamate signaling.

“another study observed a reduction in GABA and an increase in glutamate levels in the PFC and hippocampus following the forced swim test (about 36 minutes post-treatment), consistent with a disinhibition of synaptic glutamate signaling (Wang et al., 2014).”

• cites Wang et al., 2014 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Facilitation of AMPAR signaling by ketamine may be due to disinhibition of synaptic glutamate signaling through inhibition of GABAergic interneurons.

“The findings discussed above suggest that facilitation of AMPAR signaling by ketamine may be due to a disinhibition of synaptic glutamate signaling through inhibition of GABAergic interneurons.”

(2S,6S)-HNK was more potent than (2R,6R)-HNK at inhibiting NMDAR currents in Xenopus oocytes in a subunit-specific manner.

“(2S,6S)-HNK was markedly more potent at inhibiting NMDAR currents in the presence of glutamate and glycine in Xenopus oocytes in a subunit-specific manner relative to (2R,6R)-HNK.”

The IC50 of (2R,6R)-HNK to inhibit NMDAR-mediated mEPSC amplitude was 63.7 μM, about 10-fold higher than that of ketamine at 6.4 μM.

“the IC50 of (2R,6R)-HNK to inhibit NMDAR-mediated mEPSC amplitude (63.7 μM) was approximately 10-fold higher than that of ketamine (6.4 μM, Table 1).”

• cites Table 1Not matched

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

A single dose of ketamine 10 mg/kg i.p. in rats, which elicits rapid antidepressant-like effects in the forced swim test, coincided with reduced GAD67, PV, and GABA levels and increased glutamate 30 minutes post-administration in PFC.

“a single dose of ketamine (10 mg/kg i.p.), which elicits rapid antidepressant-like effects in the forced swim test, coincided with a reduction in GAD67, PV, and GABA levels and an increase in glutamate levels 30 minutes post-administration in the PFC (Zhou et al., 2015).”

• cites Zhou et al., 2015 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

MK-801 decreases firing of rapid spiking GABAergic interneurons, producing increased firing of pyramidal neurons in rat PFC.

“the NMDAR open channel blocker MK-801 decreases the firing of rapid spiking GABAergic interneurons which produces an increase in firing of pyramidal neurons in the rat PFC (Homayoun & Moghaddam, 2007).”

• cites Homayoun & Moghaddam, 2007 sourceNot checked — no full text of the source

Structural analyses of the ketamine-NMDAR interaction suggest HNKs have much lower potency in blocking NMDARs.

“structural analyses of the ketamine-NMDAR interaction are suggestive of HNKs having much lower potency in blocking NMDARs (Y. Zhang et al., 2021).”

• cites Y. Zhang et al., 2021Not matched

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

Clinical trials for rapastinel (NCT03560518) revealed a lack of therapeutic efficacy relative to placebo.

“clinical trials for rapastinel (ClinicalTrials.gov Identifier: NCT03560518) revealed a lack of therapeutic efficacy relative to placebo”

• cites NCT03560518Not matched

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

AMPAR currents were not altered by 100 nM AGN-241751.

“Notably, AMPAR currents were not altered in the presence of 100 nM AGN-241751.”

• cites Pothula et al., 2021Not matched

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

AGN-241751 increased NMDAR-mediated inward currents in layer 5 mPFC pyramidal neurons in a dose-dependent inverted U manner from 10 nM to 1 μM, with peak effect at 100 nM.

“AGN-241751 to increase NMDAR-mediated inward currents in layer 5 mPFC pyramidal neurons in a dose-dependent, inverted “U” shaped manner (10 nM to 1 μM range) with a peak effect at 100 nM.”

• cites Pothula et al., 2021Not matched

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

These data support the hypothesis that NMDAR blockade on GABAergic interneurons, especially PV-containing ones, may be involved in ketamine's mechanism of action.

“Collectively, these data lend support to the hypothesis that NMDAR blockade on GABAergic interneurons, especially those containing PV, may be involved in the mechanism of action of ketamine.”

Mg2+ was not present under the recording conditions, which would otherwise compete for binding to the ion pore with ketamine or (2R,6R)-HNK.

“Notably, Mg2+ was not present under these recording conditions which would otherwise compete for binding to the ion pore with ketamine or (2R,6R)-HNK.”

Systemic ketamine at 10 mg/kg i.p. increased expression of ARC, synapsin 1, PSD95, and GluA1 in rat PFC 2 hours post-treatment.

“systemic administration of ketamine (10 mg/kg i.p.) increased the expression of ARC, synapsin 1, PSD95, and GluA1, all key synaptic proteins, in the rat PFC 2 hours post-treatment.”

• cites Li et al., 2010Not matched

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

mGluR2/3 agonism via LY379268 at 3 mg/kg blocked the ability of ketamine and (2R,6R)-HNK at 10 mg/kg i.p. to reduce immobility.

“mGluR2/3 agonism via LY379268 (3 mg/kg) blocked the ability of ketamine and (2R,6R)-HNK (10 mg/kg i.p.) to reduce immobility.”

• cites Zanos, Highland, Stewart, et al., 2019Not matched

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

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Loss of brain volume in depressed patients coincides with loss of synapses.

“This supports the notion that the loss of volume coincides with a loss in synapses in depressed patients.”

Activation of serotonin or norepinephrine receptors facilitates intracellular signaling pathways that increase BDNF expression.

“activation of serotonin or norepinephrine receptors has been shown to facilitate intracellular signaling pathways that increases expression of BDNF.”

Preclinical studies have observed antidepressant-like effects of mGluR2/3 antagonists that align with ketamine's effects.

“Several preclinical studies have observed antidepressant-like effects of mGluR2/3 antagonists which align with the effects of ketamine (Chaki, 2017).”

• cites Chaki, 2017 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

A sub-effective dose of (2R,6R)-HNK at 1 mg/kg i.p. synergized with LY341495 at 0.1 mg/kg i.p. to significantly reduce immobility time 24 hours post-treatment, with a trend at one hour.

“a sub-effective dose of (2R,6R)-HNK (1 mg/kg i.p.) also synergized with LY341495 (0.1 mg/kg i.p.) to significantly reduce immobility time 24 hours post-treatment, with a trend towards a reduction at one-hour post-treatment.”

• cites Zanos, Highland, Stewart, et al., 2019Not matched

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

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Effects of ketamine on BDNF represent a key mechanism related to rapid induction and maintenance of an antidepressant state.

“The effects of ketamine on BDNF represents a key mechanism that appears to relate to the effects of ketamine and its metabolites which rapidly induce and maintain an antidepressant state.”

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

In the tail suspension test, MGS0039 and LY341495 both reduced immobility when administered one hour before the test.

“In a similar behavioral test, the tail suspension test, MGS0039 and LY341495 both reduced immobility when administered one hour before the test.”

• cites Chaki et al., 2004 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

A key change observed through NMDAR antagonism via ketamine, which largely targets GABAergic interneurons, is strengthening of glutamatergic/AMPAR signaling necessary for antidepressant-like effects.

“One of the key changes observed through NMDAR antagonism via ketamine, which largely targets GABAergic interneurons, is a strengthening of glutamatergic/AMPAR signaling which is necessary for antidepressant-like effects.”

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

Ketamine has a unique pharmacodynamic profile at NMDAR dependent on variables such as subunit composition, Mg2+, co-agonists, membrane potential, pH, phosphorylation status, and cellular localization.

“These data also demonstrate that ketamine has a unique pharmacodynamic profile at the NMDAR, which is dependent on numerous variables such as subunit composition, presence of Mg2+, presence of co-agonists, membrane potential, pH, phosphorylation status, and cellular localization.”

Ketamine at 10 mg/kg i.p. and (2R,6R)-HNK at 10 mg/kg i.p. mimicked the reduction in immobility time in forced swim test produced by LY341495 at 3 mg/kg 24 hours post-treatment.

“both ketamine (10 mg/kg i.p.) and (2R,6R)-HNK (10 mg/kg i.p.) mimicked the reduction in immobility time in the forced swim test produced by LY341495 (3 mg/kg) 24 hours post-treatment (Zanos, Highland, Stewart, et al., 2019).”

• cites Zanos, Highland, Stewart, et al., 2019Not matched

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

• AssumptionRests on an assumption: Rodent behavioral tests such as forced swim, tail suspension, novelty suppressed feeding, sucrose splash, female urine sniffing, and sucrose preference index antidepressant-like effects relevant to human depression.

MRI studies found that the left hippocampus of patients with remitted major depression had a 19% smaller volume.

“a series of magnetic resonance imaging (MRI) studies found that the left hippocampus of patients with remitted major depression had a 19% smaller volume (Bremner et al., 2000).”

• cites Bremner et al., 2000 sourceNot checked — no full text of the source

Twenty-four hours after ketamine, EPSC amplitude at thalamocortical and intracortical synapses was enhanced.

“24 hours later, EPSC amplitude at thalamocortical and intracortical synapses were enhanced.”

• cites Li et al., 2010Not matched

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

The mechanism of action of ketamine and its metabolite (2R,6R; 2S,6S)-HNK on the glutamate system, especially at NMDAR, is complex.

“Collectively, these findings demonstrate that the mechanism of action of ketamine and its metabolite (2R,6R; 2S,6S)-HNK on the glutamate system, especially at the NMDAR, is complex.”

In mice, naltrexone at 2 mg/kg intraperitoneally 30 minutes before ketamine prevented the reduction in immobility produced by ketamine at 10 mg/kg intraperitoneally in the tail suspension test at both 30 minutes and 24 hours after treatment.

“naltrexone (2 mg/kg i.p. 30 minutes prior to ketamine) prevented the reduction in immobility produced by ketamine (10 mg/kg i.p.) in the tail suspension test both 30 minutes and 24 hours post-treatment (F. Zhang et al., 2021).”

• cites F. Zhang et al., 2021Not matched

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

Ketamine and its metabolites can enhance AMPAR signaling through a disinhibition mechanism involving either GABAergic interneuron NMDARs or inhibitory extrasynaptic NMDARs in pyramidal neurons.

“ketamine and its metabolites can enhance AMPAR signaling through a disinhibition mechanism involving either GABAergic interneuron NMDARs or inhibitory extrasynaptic NMDARs in pyramidal neurons.”

The rapid behavioral effects, occurring 30-60 minutes after either vlPAG microinjection of 1 pg/0.1 μL or systemic administration of 10 mg/kg of (2R,6R)-HNK, required intact BDNF signaling in the vlPAG.

“the rapid behavioral effects (30-60 minutes) of either vlPAG microinjection (1 pg/ 0.1 μL) or systemic administration (10 mg/kg) of (2R,6R)-HNK required intact BDNF signaling in the vlPAG.”

• cites Chou, 2020 sourceNot checked — no full text of the source

Agonism of κ-opioid receptors has been shown to produce depression-like symptoms in humans.

“agonism of κ-opioid receptors were shown to produce depression-like symptoms in humans (Pfeiffer et al., 1986).”

• cites Pfeiffer et al., 1986 sourceNot checked — no full text of the source

BDNF signaling is critical for the cellular, molecular, and behavioral effects of ketamine and its metabolites.

“Collectively, these studies demonstrate that BDNF signaling is critical for the cellular, molecular, and behavioral effects of ketamine and its metabolites.”

The analgesic effects of ketamine in mice are attenuated by antagonism of μ and δ opioid receptors via naloxone, clocinnamox, and naltrindole.

“the analgesic effects of ketamine in mice are attenuated by antagonism of μ and δ opioid receptors via naloxone, clocinnamox and naltrindole which suggests that ketamine and opioids likely overlap mechanistically in modulating pain perception (Pacheco Dda et al., 2014).”

• cites Pacheco Dda et al., 2014 sourceNot checked — no full text of the source

In guinea pig brain homogenate, (S)-ketamine bound μ, κ, and δ opioid receptors with greater affinity than (R)-ketamine, showing stereoselectivity.

“a study using guinea pig brain homogenate observed that the binding affinity of ketamine at opioid receptors is stereoselective (Table 2), with (S)-ketamine having a higher affinity for μ, κ, and δ opioid receptors (Ki = 11, 24, and 130 μM, respectively) over (R)-ketamine (Ki = 28, 100, and 130 μM, respectively) (Hustveit et al., 1995).”

• cites Hustveit et al., 1995 sourceNot checked — no full text of the source

In patients with comorbid major depression and alcohol use disorder (n=5), pretreatment with a single dose of naltrexone at 380 mg intramuscularly two to six days before the first ketamine infusion did not affect overall improvement in depression symptoms (MADRS score) across four ketamine infusions of 0.5 mg/kg over four weeks.

“pretreatment with a single dose of naltrexone (380 mg intramuscular [i.m.] two to six days prior to the first ketamine infusion) did not impact overall improvement of depression symptoms (MADRS score) over the course of four ketamine infusions (0.5 mg/kg) spread across four weeks (Yoon et al., 2019).”

• cites Yoon et al., 2019 sourceNot checked — no full text of the source

The opioid-related antidepressant actions of ketamine may involve its main metabolite, (2R,6R)-HNK.

“Given these data, it is possible that the antidepressant effects of ketamine that overlap with the opioid system involve its principal metabolite (2R,6R)-HNK.”

Ketamine and its metabolites interact with opioid receptors in a stereoselective manner that differs by receptor subtype.

“The strength of interaction between ketamine and its metabolites with opioid receptors are stereoselective and vary depending on the receptor (Zanos et al., 2018).”

• cites Zanos et al., 2018Not matched

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

Ketamine at 1 and 10 μM for 60 minutes increased structural features such as dendrite length, dendrite number, and soma area in mouse midbrain dopamine neurons 72 hours after treatment.

“ketamine (1 and 10 μM, 60-minute treatment) increased structural characteristics such as dendrite length, number, and soma area 72 hours post-treatment (Cavalleri et al., 2018).”

• cites Cavalleri et al., 2018 sourceNot checked — no full text of the source

The reduced abuse potential and psychotomimetic effects of (2R,6R)-HNK compared with ketamine in rodents may result from its direct TrkB mechanism, which maintains synaptic structural support while causing less NMDAR disruption.

“the lack of abuse potential and psychotomimetic effects observed with (2R,6R)-HNK relative to ketamine in rodents may be due to this mechanism”

In mice exposed to 10 days of social defeat stress, naltrexone at 10 mg/kg intraperitoneally 30 minutes before ketamine did not block the antidepressant-like effects of ketamine at 10 mg/kg intraperitoneally in the tail suspension test at 3 hours, forced swim test at 1 day, or sucrose preference test at 3 days after ketamine.

“naltrexone (10 mg/kg i.p. 30 minutes prior to ketamine) did not block the antidepressant-like effects of ketamine (10 mg/kg i.p.) in the tail suspension test (3 hours post-ketamine), forced swim test (1 day post-ketamine), or sucrose preference test (three days post-ketamine) (Zhang & Hashimoto, 2019).”

• cites Zhang & Hashimoto, 2019 sourceNot checked — no full text of the source

A genome-wide association study found no association between Met allele carriers and ketamine efficacy 4 weeks after treatment.

“a genome-wide association study that did not observe an association between Met allele carriers and ketamine efficacy 4 weeks post-treatment (Li et al., 2020).”

• cites Li et al., 2020Not matched

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

The addictive liability of (S)- and particularly (R)-ketamine seems lower than expected, especially relative to cocaine and morphine.

“the abuse potential of (S) and in particular (R)-ketamine appears to be much lower than anticipated, especially compared to stimulants and opioids like cocaine and morphine (Venniro et al., 2020).”

• cites Venniro et al., 2020 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Ketamine has rewarding properties.

Together, the microdialysis and behavioral pharmacology data support a ketamine antidepressant mechanism involving serotonin and norepinephrine release in the PFC.

“Collectively, these microdialysis and behavioral pharmacology experiments lend support to the antidepressant-like mechanism of action of ketamine involving serotonin and norepinephrine release into the PFC.”

Two hours after ketamine (25 mg/kg i.p.) in rats, extracellular serotonin and norepinephrine rose in the mPFC but not the DRN.

“Another microdialysis study observed increases in extracellular serotonin and norepinephrine in the mPFC but not in the DRN of rats two hours following treatment with ketamine (25 mg/kg, i.p.) (López-Gil et al., 2019).”

• cites López-Gil et al., 2019 sourceNot checked — no full text of the source

Such mechanisms might explain why preclinical animals self-administer (R,S)-ketamine more than (R)-ketamine or (2R,6R)-HNK.

“they may provide a mechanistic explanation for the differences in willingness to self-administer (R,S)-ketamine over (R)-ketamine and (2R,6R)-HNK in preclinical studies.”

Ketamine also raised extracellular glutamate in both the mPFC and DRN at two hours.

“Extracellular glutamate was also increased in the mPFC and the DRN two hours post-ketamine.”

• cites López-Gil et al., 2019 sourceNot checked — no full text of the source

With monoamine-targeting drugs, many patients need several treatment trials before depression remits.

“many patients require multiple treatment steps to achieve remission of their depression symptoms (Rush et al., 2006).”

• cites Rush et al., 2006 sourceNot checked — no full text of the source

Ketamine used clinically or recreationally may be unlikely to cause substance use disorder.

“Thus, the clinical or recreational/self-medicating use of ketamine is perhaps unlikely to result in substance abuse disorder.”

• AssumptionRests on an assumption: Ketamine has rewarding properties.

More swimming behavior correlated significantly with higher extracellular serotonin in the mPFC.

“The observed increase in swimming behavior was significantly correlated with an increase in extracellular serotonin in the mPFC.”

• cites Pham et al., 2017 sourceNot checked — no full text of the source

In mice, infusing ketamine directly into the mPFC was enough to produce antidepressant-like behavior in the forced swim test.

“Another study in mice found that direct infusion of ketamine (0.25 μg/side) into the mPFC was sufficient to produce antidepressant-like effects in the forced swim test (Pham et al., 2017).”

• cites Pham et al., 2017 sourceNot checked — no full text of the source

In mouse PFC, ketamine and its metabolites cause stereoselective and concentration-dependent changes in extracellular monoamines.

“These data demonstrate that the dynamic fluctuations in extracellular monoamines in the PFC of mice produced by ketamine and its metabolites are stereoselective and concentration dependent”

Ketamine probably does not produce its effects by directly binding monoamine receptors or transporters.

“it is unlikely that ketamine is directly binding monoamine receptors or transporters to produce its effects.”

Within 10 minutes, ketamine (10 mg/kg s.c.) raised mPFC extracellular dopamine by more than 300% over baseline.

“This effect corresponded to a peak increase of over 300% in extracellular dopamine in the mPFC within 10 minutes of ketamine treatment (10 mg/kg s.c.) relative to baseline.”

• cites Witkin et al., 2016 sourceNot checked — no full text of the source

This difference in monoamine modulation might explain why (2R,6R)-HNK lacks psychotomimetic and abuse-related effects.

“Because of this, the lack of psychotomimetic and abuse potential effects seen with (2R,6R)-HNK may be due to this difference.”

• AssumptionRests on an assumption: (2R,6R)-HNK lacks psychotomimetic and abuse potential effects.

In rats, ketamine (10 mg/kg i.v.) given 10 minutes before recording raised the count of spontaneously active VTA dopamine neurons.

“a study in rats observed that ketamine (10 mg/kg i.v.) increased the number of spontaneously firing dopamine neurons in the VTA when administered 10 minutes prior to recordings (Witkin et al., 2016).”

• cites Witkin et al., 2016 sourceNot checked — no full text of the source

Ketamine and (2R,6R)-HNK have different effects on the opioid system.

“Ketamine and (2R,6R)-HNK also differ in their ability to influence the opioid system.”

Ketamine, its stereoisomers, and its metabolites converge on AMPAR strengthening through their NMDAR, BDNF, and monoamine actions.

“the effects of ketamine and its stereoisomers and metabolites on NMDAR antagonism, BDNF signaling, and monoamine signaling all share a common downstream target; strengthening of AMPAR signaling”

The pharmacodynamic profile of (2R,6R)-HNK appears distinct from that of ketamine.

“Indeed, (2R,6R)-HNK does appear to differ in its pharmacodynamic effects relative to ketamine.”

NMDAR blockade probably alters release or sensitivity for glutamate, GABA, BDNF, opioids, and monoamines.

“this blockade likely contributes to changes in the release or receptor sensitivity to glutamate, GABA, BDNF, opioids, and monoamines.”

In the NAc, ketamine (25 mg/kg i.p.) caused a peak rise above 150% of baseline.

“A similar effect of ketamine (25 mg/kg i.p.) was observed in the NAc with a peak increase of over 150% of baseline.”

• cites Witkin et al., 2016 sourceNot checked — no full text of the source

Ketamine and its metabolites converge on AMPARs as a shared downstream target.

“Thus, AMPARs represent a common downstream target of ketamine and its metabolites.”

Ketamine's monoamine effects might account for adverse effects like acute psychosis via excessive 5-HT and D2 signaling.

“the effects of ketamine on the monoamine system may also explain how ketamine elicits its negative side effects such as acute psychosis presumably through overactivation of 5-HT and D2 receptor signaling”

• AssumptionRests on an assumption: The opioid system participates in reward processing and addiction.