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Antidepressant mechanism of ketamine: perspective from preclinical studies.

Scheuing L, Chiu CT, Liao HM, Chuang DM - Front Neurosci (2015)

Bottom Line: However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use.To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action.Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health Bethesda, MD, USA.

ABSTRACT
A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.

No MeSH data available.


Related in: MedlinePlus

Putative signaling pathways involved in ketamine's antidepressant effects and the potentiation by lithium. Ketamine blocks pre-synaptic NMDAR signaling, resulting in increased glutamate release. Enhanced glutamate signaling activates post-synaptic AMPA receptors, and the resultant cell depolarization stimulates voltage-dependent calcium channels (VDCC), leading to calcium influx and BDNF exocytosis. BDNF release activates TrkB receptors and downstream signaling pathways, PI3K-Akt and MEK-Erk1/2. Both pathways activate mTOR complex 1 through phosphorylation. The activity of mTOR can be potentiated by lithium through Akt activation and GSK-3 inhibition. mTOR then phosphorylates and activates p70S6K, which inhibits eEF2K, halting the phosphorylation of eEF2, effectively inhibiting eEF2. In parallel, mTOR hyperphosphorylates 4E-BP1, reducing its interaction with eIF4E. Together, decreased eEF2 phosphorylation and the release of eIF4E from 4E-BP1 disinhibit protein translation, producing more synaptic proteins such as GluR1, PSD95, Arc, and synapsin I, as well as BDNF. This facilitates increased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus, and leads to antidepressant-like behavior in rodents. Lines with arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result of ketamine or lithium treatment.
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Figure 1: Putative signaling pathways involved in ketamine's antidepressant effects and the potentiation by lithium. Ketamine blocks pre-synaptic NMDAR signaling, resulting in increased glutamate release. Enhanced glutamate signaling activates post-synaptic AMPA receptors, and the resultant cell depolarization stimulates voltage-dependent calcium channels (VDCC), leading to calcium influx and BDNF exocytosis. BDNF release activates TrkB receptors and downstream signaling pathways, PI3K-Akt and MEK-Erk1/2. Both pathways activate mTOR complex 1 through phosphorylation. The activity of mTOR can be potentiated by lithium through Akt activation and GSK-3 inhibition. mTOR then phosphorylates and activates p70S6K, which inhibits eEF2K, halting the phosphorylation of eEF2, effectively inhibiting eEF2. In parallel, mTOR hyperphosphorylates 4E-BP1, reducing its interaction with eIF4E. Together, decreased eEF2 phosphorylation and the release of eIF4E from 4E-BP1 disinhibit protein translation, producing more synaptic proteins such as GluR1, PSD95, Arc, and synapsin I, as well as BDNF. This facilitates increased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus, and leads to antidepressant-like behavior in rodents. Lines with arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result of ketamine or lithium treatment.

Mentions: Another significant protein called glycogen synthase kinase-3 (GSK-3), a master switch serine-threonine kinase implicated in psychiatric disorders such as MDD and bipolar disorder (Beurel et al., 2015), undergoes necessary inhibition for ketamine's rapid antidepressant effects. Researchers used a knock-in mouse model rendering both the alpha and beta isoforms of GSK-3 maximally active, by eliminating the inhibitory phosphorylation sites of serine-21 and -9 for GSK-3α and GSK-3β, respectively (Beurel et al., 2011). When GSK-3 could not be inhibited, the antidepressant-like effects of ketamine were not observed in the learned helplessness paradigm. Thus, GSK-3 inhibition is also necessary for ketamine's rapid antidepressant-like effects. Building upon the requirement of decreased GSK-3 activity, two separate preclinical studies have demonstrated that lithium, a GSK-3 inhibitor, combined with low-dose ketamine potentiated and prolonged the molecular and behavioral effects of ketamine (Liu et al., 2013; Chiu et al., 2014), see Figure 1 for a schematic. These two studies will be discussed in depth in the following section.


Antidepressant mechanism of ketamine: perspective from preclinical studies.

Scheuing L, Chiu CT, Liao HM, Chuang DM - Front Neurosci (2015)

Putative signaling pathways involved in ketamine's antidepressant effects and the potentiation by lithium. Ketamine blocks pre-synaptic NMDAR signaling, resulting in increased glutamate release. Enhanced glutamate signaling activates post-synaptic AMPA receptors, and the resultant cell depolarization stimulates voltage-dependent calcium channels (VDCC), leading to calcium influx and BDNF exocytosis. BDNF release activates TrkB receptors and downstream signaling pathways, PI3K-Akt and MEK-Erk1/2. Both pathways activate mTOR complex 1 through phosphorylation. The activity of mTOR can be potentiated by lithium through Akt activation and GSK-3 inhibition. mTOR then phosphorylates and activates p70S6K, which inhibits eEF2K, halting the phosphorylation of eEF2, effectively inhibiting eEF2. In parallel, mTOR hyperphosphorylates 4E-BP1, reducing its interaction with eIF4E. Together, decreased eEF2 phosphorylation and the release of eIF4E from 4E-BP1 disinhibit protein translation, producing more synaptic proteins such as GluR1, PSD95, Arc, and synapsin I, as well as BDNF. This facilitates increased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus, and leads to antidepressant-like behavior in rodents. Lines with arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result of ketamine or lithium treatment.
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Figure 1: Putative signaling pathways involved in ketamine's antidepressant effects and the potentiation by lithium. Ketamine blocks pre-synaptic NMDAR signaling, resulting in increased glutamate release. Enhanced glutamate signaling activates post-synaptic AMPA receptors, and the resultant cell depolarization stimulates voltage-dependent calcium channels (VDCC), leading to calcium influx and BDNF exocytosis. BDNF release activates TrkB receptors and downstream signaling pathways, PI3K-Akt and MEK-Erk1/2. Both pathways activate mTOR complex 1 through phosphorylation. The activity of mTOR can be potentiated by lithium through Akt activation and GSK-3 inhibition. mTOR then phosphorylates and activates p70S6K, which inhibits eEF2K, halting the phosphorylation of eEF2, effectively inhibiting eEF2. In parallel, mTOR hyperphosphorylates 4E-BP1, reducing its interaction with eIF4E. Together, decreased eEF2 phosphorylation and the release of eIF4E from 4E-BP1 disinhibit protein translation, producing more synaptic proteins such as GluR1, PSD95, Arc, and synapsin I, as well as BDNF. This facilitates increased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus, and leads to antidepressant-like behavior in rodents. Lines with arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result of ketamine or lithium treatment.
Mentions: Another significant protein called glycogen synthase kinase-3 (GSK-3), a master switch serine-threonine kinase implicated in psychiatric disorders such as MDD and bipolar disorder (Beurel et al., 2015), undergoes necessary inhibition for ketamine's rapid antidepressant effects. Researchers used a knock-in mouse model rendering both the alpha and beta isoforms of GSK-3 maximally active, by eliminating the inhibitory phosphorylation sites of serine-21 and -9 for GSK-3α and GSK-3β, respectively (Beurel et al., 2011). When GSK-3 could not be inhibited, the antidepressant-like effects of ketamine were not observed in the learned helplessness paradigm. Thus, GSK-3 inhibition is also necessary for ketamine's rapid antidepressant-like effects. Building upon the requirement of decreased GSK-3 activity, two separate preclinical studies have demonstrated that lithium, a GSK-3 inhibitor, combined with low-dose ketamine potentiated and prolonged the molecular and behavioral effects of ketamine (Liu et al., 2013; Chiu et al., 2014), see Figure 1 for a schematic. These two studies will be discussed in depth in the following section.

Bottom Line: However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use.To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action.Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health Bethesda, MD, USA.

ABSTRACT
A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.

No MeSH data available.


Related in: MedlinePlus