Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review.
03 Nov 2016-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 71, pp 27-38
TL;DR: The current evidence for a serotonergic role in ketamine's antidepressant effects is reviewed, and it is suggested that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors.
Abstract: A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine's antidepressant effects. The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine's antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine's antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine's antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.
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TL;DR: The level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression, as there is a lack of data concerning ketamine with repeated administration at higher doses.
Abstract: Depression is the third leading cause of disability in the world. Depressive symptoms may be reduced within several weeks after the start of conventional antidepressants, but treatment resistance concerns one-third of patients who fail to achieve recovery. Over the last 20 years, ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been described to have antidepressant properties. A literature review was conducted through an exhaustive electronic search. It was restricted to Cochrane reviews, meta-analyses, and randomized controlled trials (RCTs) of ketamine for major depressive disorder and/or bipolar disorder. This review included two Cochrane reviews, 14 meta-analyses and 15 trials. Ketamine was studied versus placebo, versus other comparators and as an anesthetic adjuvant before electroconvulsive therapy. In 14 publications, ketamine provided a rapid antidepressant effect with a maximum efficacy reached at 24 hrs. Its effect lasted for 1-2 weeks after infusion, but a longer-term effect is little reported. Ketamine does not seem to improve depressive symptoms at the end of electroconvulsive sessions. Safety and tolerability profiles with ketamine at low single dose are generally good in depressed patients. However, there is a lack of data concerning ketamine with repeated administration at higher doses. The clinical use of ketamine is increasing. Intranasal (S)-ketamine has recently been approved for depression by the Food and Drug Administration. It could be a promising treatment in depressed patients with suicidal ideation. Collectively, the level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression.
126 citations
TL;DR: Evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN) are reviewed, with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance.
97 citations
TL;DR: Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressant effects of repeated ketamine administration.
Abstract: Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine’s antidepressant effects Six intravenous infusions of ketamine (05 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d) Blood samples from sixty healthy controls were collected for comparison with samples from the patients Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls Overall, fifty (595%) patients responded to ketamine at 13 d Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P
63 citations
TL;DR: A historical review of the development of monoaminergic antidepressant drugs and the role of ketamine as the introductory agent of a new era in the research of the neurobiology of depression and how it revealed itself as an exciting option towards obtaining pharmacological agents to treat depression, through the understanding of biological markers.
Abstract: ObjectiveAlthough monoaminergic-targeted drugs have prompted great advances in the development of treatments for depression, the need for new options persists, since these drugs still have a delayed clinical effect and most patients do not respond properly to them. Recently, the observation of the antidepressant effects of ketamine brought on a new wave of studies regarding the comprehension of the neurobiology of depression and the development of new and more effective antidepressant drugs.MethodsThus, in this paper, we present a historical review of the development of monoaminergic antidepressant drugs and the role of ketamine as the introductory agent of a new era in the research of the neurobiology of depression.ResultsFirstly, we review how the pharmacological treatment for major depression started, and we point out the main drugs discovered, the researchers involved, and how the studies developed have contributed to the understanding of the neurobiology of depression. Secondly, the major problems regarding the clinical efficacy and acceptance of these drugs are discussed, and the introduction of the glutamatergic system as a target for antidepressant drugs is presented. Finally, we review how ketamine revealed itself as an exciting option towards obtaining pharmacological agents to treat depression, through the understanding of biological markers.DiscussionKetamine contributed to confirm that different targets of the glutamatergic system and neurotrophic pathways are strictly related to the neurobiology of depression. There are several antidepressant drugs based on ketamine’s mechanism of action already in the pipeline, and glutamatergic-targeted antidepressants may be on the market in the near future.
53 citations
Cites background from "Potential involvement of serotonerg..."
...Several ongoing studies will help clarify the impact of the glutamatergic modulation per se or its interaction with monoaminergic, nitrergic and inflammatory systems, as the role of plasticity shifts into the complex grid of behavioural control (62,68,154)....
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Journal Article•
TL;DR: In vitro and in vivo studies suggest that 5-HT1A and5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC).
Abstract: The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by 1) modulating the activity of different neuronal types, and 2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6 and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.
49 citations
References
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TL;DR: A first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression suggests a potential role for NMDA receptor-modulating drugs in the treatment of depression.
3,039 citations
"Potential involvement of serotonerg..." refers background in this paper
...This focus was precipitated by the observation that an intravenous i.v. infusion of ketamine, classified as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, at sub-anesthetic doses produced an antidepressant effect within hours of administration (Berman et al., 2000)....
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TL;DR: The results demonstrate that the effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamines.
Abstract: The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.
2,345 citations
"Potential involvement of serotonerg..." refers background in this paper
...Furthermore, the association between rapamycin (selective mTOR inhibitor), antidepressantlike effects, and ketamine may be ambiguous (Autry et al., 2011; Cleary et al., 2008; Li et al., 2010)....
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...As demonstrated and proposed by the group of Duman (see table 2 and figure 1), activation of mTOR may be critical for an antidepressant-like effect in rodents (Li et al., 2010), and one can therefore speculate that the ketamine-enhanced 5-HT response is implicated in the antidepressant-like actions of this compound,...
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...…interneurons in rats (Homayoun and Moghaddam, 2007) - mTOR activation is essential for ketamine’s antidepressant-like activity and induction of synaptogenesis (Li et al., 2011, 2010) - Activation of AMPA receptors is required for the antidepressant-like effects of ketamine (Maeng et al., 2008) -...
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...…has concentrated on ketamine’s modifications of glutamatergic neurotransmission leading to neuroplastic changes (Kavalali and Monteggia, 2015; Li et al., 2010; Niciu et al., 2014) and, until recently, mostly disregarded any implication of other neurotransmitter systems in ketamine’s…...
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...Although the effect on 5-HT release may be temporary, one study has reported more protracted ketamine-evoked modifications of serotonergic neurotransmission in the prefrontal cortex of rats (Li et al., 2010)....
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TL;DR: The findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.
Abstract: Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.
1,697 citations
"Potential involvement of serotonerg..." refers background in this paper
...- Ketamine administration may cause a rapid but transient elevation of extracellular glutamate in the medial prefrontal cortex of rats (Chowdhury et al., 2012; Lorrain et al., 2003; Moghaddam et al., 1997; Sorce et al., 2010) - Ketamine blocks the tonic firing of GABAergic interneurons in rats (Homayoun and Moghaddam, 2007) - mTOR activation is essential for ketamine’s antidepressant-like activity and induction of synaptogenesis (Li et al....
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...…a rapid but transient elevation of extracellular glutamate in the medial prefrontal cortex of rats (Chowdhury et al., 2012; Lorrain et al., 2003; Moghaddam et al., 1997; Sorce et al., 2010) - Ketamine blocks the tonic firing of GABAergic interneurons in rats (Homayoun and Moghaddam, 2007) -…...
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TL;DR: These findings are consistent with smaller left hippocampal volume in depression, and were significant after brain size, alcohol exposure, age, and education were controlled for.
Abstract: OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.
1,640 citations
"Potential involvement of serotonerg..." refers background in this paper
...The prefrontal cortex and the hippocampus are two brain regions that are often affected in patients with MDD (Bell-McGinty et al., 2002; Bremner et al., 2000; Femenía et al., 2012; Rajkowska et al., 1999)....
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TL;DR: It is shown that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor, suggesting the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast- acting antidepressants.
Abstract: Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
1,551 citations
"Potential involvement of serotonerg..." refers background in this paper
...The antidepressant-like effect of ketamine is dependent on rapid synthesis of BDNF mediated by deactivation of eEF2 kinase and decreased phosphorylation of eEF2 (Autry et al., 2011) -...
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...No effect was found for pharmacological widespread induction or suppression of glutamate neuronal activity in mice (Autry et al., 2011) - Unlike memantine, ketamine blocks NMDA-receptors at rest and has antidepressant-like activity in mice (Gideons et al., 2014) Offsetting of inflammatory processes…...
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...In mice, ketamine-mediated blockade of NMDA receptors at rest deactivates eEF2 kinase, resulting in a reduction of eEF2 phosphorylation, and de-suppression of BDNF synthesis (Autry et al., 2011; Gideons et al., 2014; Nosyreva et al., 2013) -...
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...Furthermore, the association between rapamycin (selective mTOR inhibitor), antidepressantlike effects, and ketamine may be ambiguous (Autry et al., 2011; Cleary et al., 2008; Li et al., 2010)....
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