Next Article in Journal
Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3
Next Article in Special Issue
Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling
Previous Article in Journal
Antitumor Activity of the Cardiac Glycoside αlDiginoside by Modulating Mcl-1 in Human Oral Squamous Cell Carcinoma Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 21
10.3390/ijms21217951
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions

by
Motohiro Okada
*,
Yasuhiro Kawano
,
Kouji Fukuyama
,
Eishi Motomura
and
Takashi Shiroyama
Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 7951; https://doi.org/10.3390/ijms21217951
Submission received: 25 September 2020 / Revised: 19 October 2020 / Accepted: 23 October 2020 / Published: 26 October 2020
(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)
Browse Figures
Versions Notes

Abstract

:
Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.

1. Introduction

Using N-methyl-D-aspartate/glutamate receptor (NMDAR) inhibiting treatment for mood disorders has been a fundamental discussion in psychiatry and psychopharmacology, since esketamine (a racemic enantiomer of ketamine), a noncompetitive NMDAR antagonist, was approved, although with rigorous restrictions, by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2019 for the treatment of antidepressant-resistant depressive disorders [1,2]. It is well known that approximately two-thirds of depressed patients fail to achieve an adequate response to first-line pharmacotherapy using conventional monoaminergic antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI), and ultimately as many as one-third of patients remain unwell even after several adequate trials of antidepressants [3]. Furthermore, available medications, such as monoaminergic antidepressants and psycho-behavioural therapies, require more than several weeks for beneficial effects to occur [3]. The delay of conventional monoaminergic antidepressants and psycho-behavioural therapies is one of the major drawbacks to current therapies for major depressive disorder, and faster-acting antidepressants are needed for patients at risk of suicide [4]. Numerous clinical trials have demonstrated that ketamine, a non-competitive NMDAR antagonist, could evoke a rapid onset (within several hours) and shorter sustained (lasting up to 7 days) antidepressive action [5,6,7,8]. Additionally, although monoaminergic antidepressants exhibit limited effectiveness against anhedonia and suicidal ideation of mood disorders, ketamine has also been shown to have distinct and independent anti-suicidal effects in patients with mood disorders [9,10]. Therefore, ketamine holds potential to improve monoaminergic antidepressant-resistant dysfunction of emotional perception/cognition in mood disorders with rapid action. Ketamine comprises two racemic enantiomers, arketamine and esketamine [11,12]. Esketamine (Ki = 0.3~0.7 μM) is a potent antagonist of NMDAR, more so than arketamine (Ki = 1.4~2.6 μM) [11,12]. Similar to the binding affinity, the anaesthetic effect of esketamine is more potent than racemic-ketamine and arketamine [13].
In spite of these clinical advantages of ketamine, both clinical and preclinical studies have established that non-competitive NMDAR antagonists, such as phencyclidine, ketamine, and dizocilpine (MK801), contribute to the pathophysiology of schizophrenia, as they produce schizophrenia-like positive/negative symptoms and cognitive impairments in healthy individuals and experimental animal models, as well as exacerbating the psychotic symptoms of patients with schizophrenia [14,15,16,17,18,19,20,21,22,23,24]. Notably, the ketamine dosage for antidepressant action (0.5 mg/kg) is comparable to that for the generation of psychotic symptoms in healthy volunteers [24]. These findings suggest that ketamine probably both improves emotional/mood states in depression and aggravates perception/cognition in healthy individuals. Therefore, to develop a novel strategy for the treatment of antidepressant-resistant depression without neuropsychiatric adverse effects, the present review is focused on the complicated links between NMDAR and the pathophysiology of schizophrenia and depression.

2. Overview of NMDAR

Although NMDAR is characterised as a cation channel-containing receptor, it possesses unique voltage-dependent and substance-sensitive characteristics. Interestingly, activation of NMDAR requires binding of not only glutamate but also D-serine/glycine [25,26,27,28,29]. Furthermore, during the resting stage, glutamate binding to NMDAR cannot induce cation inflow through its cation channel, because the cation channel in NMDAR is blocked by Mg2+ and Zn2+ caps via specific binding sites [28]. Depolarisation (higher than −20 mV) of the plasma membrane repels Mg2+ and Zn2+ from the cation channel pore, resulting in the voltage-dependent inflow of Na+ and Ca2+, and outflow of K+, through the cation channel in NMDAR [28]. Notably, the resting membrane potential of GABAergic interneurons is more positive (−50~−60 mV) than those of monoaminergic and glutamatergic neurons (−65~−75 mV) [30,31]. Therefore, at the resting stage, the major targets of NMDAR are GABAergic transmissions rather than monoaminergic or glutamatergic transmissions [29,32,33,34,35,36,37,38,39,40,41,42].
It is well known that NMDAR is a hetero-tetramer receptor comprising three distinct subunits, GluN1, GluN2 and GluN3. The GluN1 subunit exhibits eight splicing variants; GluN1-1a,b, GluN1-2a,b, GluN1-3a,b and GluN1-4a,b (GluN1-1a is the predominant expression in the brain) [43]. The GluN2 subunits subfamily is subdivided into GluN2A, GluN2B, GluN2C and GluN2D subunits, but the GluN3 subunit subfamily is subdivided into GluN3A and GluN3B subunits [25,26,27,28]. The NMDAR cation channel is formed by two GluN1 subunits, and either two GluN2 subunits or a combination of GluN2 and GluN3 subunits [25,26,27,28]. The cation channel pore of predominant functional NMDAR (classical NMDAR) is formed by a combination of the GluN1 dimer and the GluN2 dimer [44]. Mg2+, Zn2+ and the non-competitive NMDAR antagonists, ketamine, MK801, amantadine and memantine, bind the pore region [27]. Activation of NMDAR requires binding of glutamate to GluN2 together with binding of D-serine/glycine to GluN1. They assemble with GluN1 and GluN2 (A–D) subunits to form tri-heteromeric NMDARs. GluN3 subunits are the newest members of the ionotropic glutamate receptor subunit family, and their detailed functional role remains elusive [45,46]. NMDAR-containing GluN3A seems to counteract some of the well-known functions of classical NMDARs (GluN1–GluN2 di-heteromers) in long-term plasticity and synapse development [45,46].

3. Clinical Findings

3.1. NMDAR Expression in the Central Nervus System of Patients with Depression and Schizophrenia

It has been established that the expression level of the mRNA of GluN2B is one of the biomarkers of suicide [47]. Additionally, polymorphisms of the GluN2B gene (GRIN2B) have been considered to be prediction factors of antidepressant-resistant depression [48,49]. Epigenetic studies found hypermethylation of gene bodies of GluN1 and GluN2A in depression [50,51]. Methylation of the promotor generally downregulates expression of mRNA production, whereas methylation of the gene body increases expression of gene production [52]. Therefore, the hypermethylation of the gene body of GluN1 and GluN2A is possibly due to increased expression of these subunits [53]. Several post-mortem studies of patients with major depression provided fundamental evidence of the pathophysiology of depressive disorders in the cortex and locus coeruleus (LC). Two post-mortem studies reported increased expression of GluN2B and GluN2C in the LC of depressed patients [54,55]. Contrary to the LC, great variability in NMDAR expression in the frontal cortex has been found. In the dorsolateral prefrontal cortex, GluN2B expression was higher in patients with depression who committed suicide when compared to those who did not [47]. GluN1 expression in the prefrontal cortex of patients with depression was almost equal to healthy individuals [56,57], whereas the expression of GluN1 carrying the C1 cytosolic segment was increased [56]. In contrast, reduced expression of GluN2A and GluN2B was seen in the prefrontal and perirhinal cortices [57,58], whereas increased expression of GluN2A was found in the amygdala [59]. Therefore, the results obtained from post-mortem studies suggest consistent increased NMDAR expression in the LC of depressed individuals; however, the expression abnormalities of NMDAR in the frontal cortex are far from consistent, which is possibly due to variations in the target brain regions examined or the methodological procedures.
Reduced GluN2C expression in the cortex of schizophrenics seemed to be consistent evidence; however, meta-analyses could not detect the statistically significant differences in cortical expressions of GluN2A, GluN2B or GluN2D in schizophrenics [60,61,62]. Expression of GluN1 mRNA was also reduced in the prefrontal cortex and hippocampus of schizophrenics [62,63,64,65]. Interestingly, reduction in the density of both postsynaptic protein PSD-95 and downstream signalling associated with NMDAR was displayed in schizophrenia [62,66]. A selective single-photon emission tomography study demonstrated that intravenous administration of ketamine reduced NMDAR in the human brain, including the thalamus and middle inferior frontal cortex of healthy individuals [67]. In particular, reduced NMDAR binding density in the middle inferior frontal cortex significantly correlated with a negative Brief Psychiatric Rating Scale score [67]; however, ketamine-induced reduction in NMDAR expression was not observed in the hippocampus [67].
These findings suggest that enhanced and reduced transmission associated with NMDAR possibly occurs in the brain of individuals with depression and schizophrenia, respectively. However, as aforementioned, care must be taken, since at least some of these changes are observed in different psychiatric conditions and/or possibly induced by medications, and, by no means, are compelling, as long as discrepant results have been observed.

3.2. Clinical Pharmacological Findings of NMDAR in Depression and Schizophrenia

Both of the non-competitive NMDAR antagonists, phencyclidine and ketamine, were synthesized as intravenous anaesthetics with minimal impact on the cardiovascular or pulmonary system in 1956 and 1970, respectively. Initially, these agents were considered to be safe anaesthetics; however, those administrated with phencyclidine and ketamine exhibited psychotic side-effects, i.e., severe/prolonged delirium and schizophrenia-like psychosis [68,69]. Indeed, phencyclidine and ketamine generated schizophrenia-like psychosis in healthy individuals and aggravated symptoms of schizophrenics [15,16,17,24,68]. In contrast to NMDAR antagonists, two recent randomized, double-blind, placebo-controlled trials demonstrated that adjunctive therapy with benzoate, a D-amino acid oxidase inhibitor, improved cognitive function and the negative symptoms of patients with schizophrenia [70,71]. Inhibition of D-amino acid oxidase, which is a major degradation enzyme of D-serine in the central nervous system, increases D-serine levels [72,73]. Therefore, suppression of NMDAR function plays important roles in the pathophysiology of schizophrenia.
Contrary to these disadvantages of ketamine, the rapid acting antidepressant effects of ketamine in patients with major depression were demonstrated by placebo-controlled double-blind clinical trial in 2000 [8]. Other double-blind clinical studies also demonstrated that ketamine rapidly improved suicidal ideation compared with midazolam (active control) [74,75]. The responder ratio of ketamine was 25~85% within a day post-injection, and 14~70% at 3 days post-ketamine injection [21] (Table 1). In particular, 70.8% of antidepressant-resistant patients with depression improved by repetitive intravenous administration of ketamine (six times over 12 days) [76]. Therefore, compared to conventional monoaminergic antidepressants, in spite of severe psychotic side-effects, the surprisingly rapid action and efficacy of ketamine for the treatment of conventional antidepressant-resistant depression were demonstrated (Table 1).
Ketamine acutely produces various dose-dependent neuropsychiatric adverse effects [97]. Single intravenous administration commonly produces dissociation (distortions in visual, auditory, somatosensory stimuli and alterations in the perception of self or time), cognition (mental sharpness, concentration, recall, recognition, explicit and implicit), memory (vigilance, verbal fluency and delayed recalls), and positive (conceptual disorganization, hallucinations, suspiciousness, unusual thought content) and negative psychotomimetic effects (blunted affect, emotional withdrawal, motor retardation) [97]. Schizophrenia-like positive symptoms are considered to be due to the actions of esketamine rather than arketamine, since, using equimolar doses of esketamine and arketamine, esketamine was associated with acute psychotic reactions, but arketamine was not [98]. In contrast, arketamine contributes to relaxation and euphoric feelings [98]. Unfortunately, it has been speculated that repeated/sustained ketamine intake has been consistently associated with long-lasting memory deficits, and arketamine-induced euphoria is involved in the recreational feature of “kai-jai” [99].
It is well established that ketamine is a non-competitive NMDAR antagonist (Ki = 0.3~0.7 μM), but it is also a high affinity dopamine D2 receptor partial agonist (Ki = 0.05~0.5 μM) [100]. Although a recent meta-analysis reported that ketamine does not directly affect dopaminergic signalling [101], both clinical and preclinical findings show that the psychotomimetic effects of ketamine are mediated by its dopamine D2 receptor agonism [97,102,103,104]. Indeed, pre-administration of haloperidol prevented ketamine-induced agitation [104].
Contrary to the non-selective NMDAR antagonist ketamine, clinical trials reported the efficacy of the selective GluN2B antagonists CP-101,606 [95] and MK0657 [96] in the treatment of depressive states; however, the antidepressive effects of these selective GluN2B antagonists were comparatively modest and short-lived compared with that of ketamine (Table 1). In contrast, adverse psychiatric effects, including schizophrenia-like psychotic symptoms and dissociative responses, induced by CP-101,606 and MK0657 were lower than those induced by ketamine [95,96]. Until recently, in spite of the initial promising antidepressant potential of selective GluN2B antagonists, development of these compounds has been discontinued.
As shown Table 1, the clinical studies indicated consistent demonstrations that the noncompetitive NMDAR antagonists improved depression but aggravated schizophrenia or cognitive function; however, contrary to non-competitive NMDAR antagonists, several clinical studies reported that the enhancement of an endogenous NMDAR partial co-agonist, D-seine, improved both depression and schizophrenia (see details in review [105]). Traditionally, the efficacies of D-serine adjunctive therapy for schizophrenia had been studied by numerous clinical trials. Indeed, meta-analysis demonstrated that adjunctive D-serine modulation improved negative total symptoms of chronic schizophrenia [106]. Furthermore, inhibition of D-amino acid oxidase (major degradation enzyme of D-serine in the central nervous system [72,73]) improved cognitive function and the negative symptoms of patients with schizophrenia [70,71]. Contrary to schizophrenia, a randomized, double-blind, placebo-controlled trial reported that D-serine improved depressive mood in healthy volunteers [107]. This clinical evidence was supported by preclinical study using D-amino acid oxidase inhibitor [108]. These discrepancies between noncompetitive NMDAR antagonists and NMDAR co-agonists on schizophrenia and depressive disorders suggest that direct inhibition of cation channels in NMDAR and enhancement of GluN1 function are not clinically homologous. Elucidation of the underlying mechanism by which the GluN1 functional regulation affects mood and cognition possibly provides novel strategies for the development of novel therapeutic agents for treatment-resistant depression.

4. Preclinical Findings

4.1. Behavioural Study

Acute systemic administration of a non-competitive NMDAR antagonist increased locomotor activity and stereotypical behaviours in rodents [109,110,111,112]. NMDAR antagonism increases monoaminergic transmission, resulting in behavioural abnormalities [113,114], which are considered to be compatible with the positive symptoms of schizophrenia (Table 2) [115]. The stimulatory effect of non-competitive NMDAR antagonists on locomotor activity is enhanced by their long-term administration [110,111,112,116]. Non-competitive NMDAR antagonists generated severe disruptions in prepulse inhibition (PPI), and deficits in several domains of cognition, in rats (Table 2) [117,118]. Based on these functional changes following short- or long-term administration of NMDAR antagonists, it has been estimated that acute changes induced by NMDAR antagonists are comparable with those occurring in early stages of schizophrenia, but the duration of such changes induced by long-term administration appears to be more related to the persistence of clinical symptoms of schizophrenia [119,120,121,122,123].
Behavioural screening tests have provided important validation in the development of antidepressants [133]. Therefore, a novel screening framework is required for the development of novel effective antidepressants against conventional monoaminergic antidepressant-resistant depression. Paradoxically, utilizing animal models that do not respond to conventional monoaminergic antidepressants but are responsive to target agents that have shown efficacy in monoaminergic antidepressant-resistant patients with depression in the clinic can provide an improved framework to develop novel pharmacological screening for monoaminergic antidepressant-resistant depression (Table 2) [133]. Ideally, several animal models of monoaminergic antidepressant-resistant depression must be validated by demonstration that populations resistant to conventional monoaminergic antidepressants respond to medication that is effective in patients with depression [134]. Currently, some studies have focused on the understanding of which antidepressant responsiveness and resistance mechanisms are present in animal models [135]. According to these concepts, three basic approaches for the animal models of monoaminergic antidepressant-resistant depression have been proposed.
(1)
Separation of rodents into bimodal subpopulations that respond or are resistant to traditional antidepressant treatments, which are often used following a behavioural stressor such as chronic mild stress [136] or chronic social defeat (Table 2) [137].
(2)
Treatments that render rodents resistant to antidepressants (e.g., adrenocorticotropic hormone) [138] or inflammation [139] (Table 2).
(3)
Genetic models that show resistance to conventional monoaminergic antidepressant treatments (e.g., use of genetically modified mice) (Table 2) [4,125].
Behavioural studies have demonstrated that non-competitive NMDAR antagonists exhibit antidepressant-like effects in forced swimming and tail suspension tests, in learned helplessness paradigms, and in animals exposed to chronic stressors [4,140,141,142,143]. Several studies reported that ketamine displayed rapid-acting antidepressant-like features in mice exposed to a learned helplessness paradigm and forced swimming test (Table 2) [4,124,125]. Several studies also demonstrated that ketamine produced antidepressant-like behaviour in animals exposed to various distinct stressors [127,144]. Furthermore, in the maternal deprivation protocol, ketamine could produce antidepressant-like effects in the forced swimming test (Table 2) [128,129,130].
The approval of esketamine has come with serious restrictions, since the doses of esketamine required for depression may cause dissociation and delirium, which probably presents shortly after onset of the drug but rapidly disappears just before the antidepressant response [8]. To overcome the adverse side effects, other NMDAR antagonism alternatives have been pursued. Selective antagonists to both GluN2A (NVP-AAM077) and GluN2B (Ro25–6981) have shown antidepressant-like effects without psychotomimetic-like activities preclinically [124,133,145]; however, combination administration of these two agents was sufficient to generate schizophrenia-like stereotypical behaviour [145].
Behavioural studies indicated that NMDAR inhibition probably contributed to the rapid-acting antidepressant effect but could not be involved in the long-lasting antidepressant effect. Indeed, the correlation between NMDAR binding affinity and antidepressant duration was not observed, since duration of the antidepressant effect of arketamine was longer than that of MK801 and esketamine, which show more potent affinity than arketamine (Table 2).

4.2. Signal Transduction Associated with NMDAR

Numerous investigations using depression rodent models have demonstrated that exposure to various stresses leads to enhancement of glutamatergic transmission and upregulation of NMDAR [53,146,147,148]. Chronic restraint stress increased the mRNA of GluN1, GluN2A and GluN2B in the hippocampus [149,150]. Maternal separation also increased the mRNA expression of GluN2A but not GluN2B in the hippocampus of adult rats [151]. Long-term administration of corticosterone, which mimics the endocrine response to stress, increased mRNA expression of GluN2A and GluN2B in the hippocampus [152]. Similar to the hippocampal response, a deficit of brain-derived neurotrophic factor (BDNF), which emulates the response to chronic stress and is considered to be a candidate mechanism of depression, also led to increased expression of GluN1, GluN2A and GluN2B mRNA in the frontal cortex during the early stage of development [153]. These findings suggest that upregulation of NMDAR induced by stress exposure and genetic abnormalities plays important roles in the pathomechanism of monoaminergic antidepressant-resistant depression, leading to the reasonable hypothesis that inhibition of NMDAR signalling contributes to robust antidepressant-like action.
Neither acute nor chronic administration of ketamine affected serum levels of corticosterone and adrenocorticotropic hormone (ACTH), whereas administration of both prevented elevation of corticosterone and ACTH levels induced by chronic mild stress [127]. In contrast, BDNF expression in the hippocampus was not affected by mild chronic stress or ketamine [127]. Both ketamine and MK801 increased BDNF expression in the frontal cortex but not the nucleus accumbens [4].
Acute MK801 administration downregulated hippocampal GluN1 and GluN2B [154], whereas contrary to NMDAR, the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor (AMPAR) was increased by ketamine [133,155,156,157]. The mechanisms of ketamine-induced upregulation of GluA1 are speculated to activate mammalian target of rapamycin (mTOR) [133,158] and/or extracellular signal-regulated kinase (Erk) signalling [159], which regulates the initiation of protein translation, and protein synthesis, for synaptogenesis [160,161]. mTOR signalling plays a responsible role in the antidepressant effects of ketamine, since local administration of rapamycin (mTOR inhibitor) into the medial prefrontal cortex prevented the antidepressant effects of ketamine [133]. In spite of these efforts, enhanced mTOR and Erk signalling can explain the increased AMPAR expression, but contradicts the decreased NMDAR expression.

4.3. Neurotransmitter Release Associated with NMDAR

Systemic administration of NMDAR antagonists acutely increased the release of glutamate [34,37,162], dopamine [34], norepinephrine [34,163] and serotonin (5-HT) [164] in the frontal cortex. Inhibition of NMDAR in the frontal cortex increased regional monoamine levels [39,40,41,42,165] (Figure 1). Inhibition of NMDAR in the ventral tegmental area (VTA), LC and dorsal raphe nucleus (DRN) also increased respective dopamine, norepinephrine and 5-HT releases in the frontal cortex [32,33,34,35,36,39,40,166,167] (Figure 1). This release of monoamines in the frontal cortex induced by systemic NMDAR antagonists is generated by cortical and sub-cortical GABAergic disinhibition, since GABAA receptor agonist prevented this monoamine release [32,33,34,35,36,39,40,166,167] (Figure 1). Contrary to monoamines, inhibition of NMDAR in the frontal cortex did not affect regional L-glutamate release, whereas inhibition of NMDAR in the mediodorsal (MDTN) and reticular thalamic nuclei (RTN) drastically increased L-glutamate release in the frontal cortex [29,32,34,36,37,38,166]. Activation of the GABAA receptor in MDTN or RTN suppressed L-glutamate release in the frontal cortex induced by NMDAR inhibition in the thalamus [32,34,36,37,162,166]. The L-glutamate release in the frontal cortex induced by systemic NMDAR antagonist administration is generated by thalamic GABAergic disinhibition, but not by frontal GABAergic disinhibition (Figure 1). Previous microdialysis studies suggest that a deficit of NMDAR in sub-cortical neural circuits increases neurotransmitter release in the frontal cortex via GABAergic disinhibition.
Taken together with the recent findings that enhanced GABAergic transmission is associated with parvalbumin-expressing interneurones [168,169,170] and upregulation of NMDAR [53,146,147,148], the compounds that can establish GABAergic disinhibition of parvalbumin-expressing GABAergic interneurones by targeting the microcircuit between glutamatergic and GABAergic transmission systems hold promise as rapid-acting antidepressants and represent a breakthrough strategy for the treatment of depression.

5. Candidate Pathophysiology of Depression and Schizophrenia Associated with NMDAR

5.1. Molecular Mechanism

The upregulation and downregulation of NMDAR expression in depression and schizophrenia, respectively, were observed in post-mortem studies [54,55,60,61,62,63,64,65]. Taken together with the clinical evidence that a non-competitive NMDAR antagonist, ketamine, generates schizophrenia-like psychotic symptoms and improves depression, the functional abnormalities of glutamatergic transmission associated with NMDAR probably contribute to the pathomechanisms of schizophrenia and depression. Other studies have reported that chronic exposure to stress enhanced parvalbumin-expressing GABAergic interneurones underlies depression-like behaviour [168,169,170]. Numerous microdialysis studies have also demonstrated that NMDAR antagonists exert a preferential suppression of NMDAR on GABAergic interneurones, resulting in enhanced neurotransmitter release in the frontal cortex via GABAergic disinhibition [29,34,35,36,37,39,41,42,162,165,166,171,172]. A recent study using the conditional knockdown technique clearly demonstrated that selective knockdown of GluN2B on somatostatin or parvalbumin expressing GABAergic interneurones blocked the antidepressant-like action of ketamine, whereas that on glutamatergic pyramidal neurones was not affected [173]. Therefore, the suppression of NMDAR function on the enhanced GABAergic interneurones plays fundamental roles in the improvement of several disturbances in the pathomechanisms associated with depression. Considered with the demonstrations of two clinical trials that GluN2B selective antagonists (CP-101,606 and MK0657) did not have rapid-acting antidepressant effects and exhibited fewer neuropsychiatric adverse effects [95,96], rapid-acting antidepressant effects probably require broad inhibition of NMDAR containing both GluN2A and GluN2B on GABAergic interneurones.

5.2. Pathophysiological Neural Circuits

Psychiatric disorders such as schizophrenia and depression are possible human-specific diseases in that they are diagnosed using various interview techniques with communication tools. In other words, it is not possible to verify the validity of animal models that reproduce the psychiatric dysfunction of schizophrenia or depression. Acute systemic administration of non-competitive NMDAR antagonists leads to hyperlocomotion and stereotypical behaviours in rodents that are potentially compatible with the positive symptoms of schizophrenia [109,115]. NMDAR antagonists also produce disruptions in PPI, and several deficits in several distinct domains of cognition in rodents [117,118]. The pathomechanisms of PPI deficit has yet to be clarified, whereas several studies using functional magnetic resonance imaging (fMRI) suggested that disturbance of the MDTN, including the cortico-pallido-thalamic pathway, plays a key role in the PPI disruption [174,175]. Another fMRI study reported that ketamine supressed the functional connectivity between the LC and MDTN [176]. Therefore, NMDAR may contribute to the efficient switching between hippocampus-dependent and hippocampus-independent learning processes [177], leading to the regulation of attention and memory consolidation/reconsolidation processes [32,34,35,36,37,38,162,166,178,179].
Traditionally, the function of the MDTN on cognition has been considered to be mapped in specific memory recognition and exclusive cognitive domains [180]; however, abundant recent evidence indicates that several neural circuits including the MDTN are involved in several neuropsychiatric abnormalities in which the cognitive impairments are not restricted to memory functions [181]. In particular, it has been widely shown that the MDTN receives various inputs from the amygdala, and the cortical and subcortical regions associated with learning, memory, emotion, and perceptual integration [182,183,184], but the MDTN is mainly regulated by GABAergic inhibition from the RTN, which is activated by noradrenergic input from the LC, and directly receives serotonergic input from the DRN [32,34,35,36,38,166,178,185]. The MDTN projects glutamatergic terminals to various cortical regions such as mPFC, insula, orbitofrontal cortex (OFC) and basal ganglia [32,33,34,35,36,37,41,42,162,166,171,178,179,186,187,188]. These thalamocortical pathways have mainly been explored through experiments in rodents, primates and humans, and these functional interpretations of the cognitive mechanisms have been shown to translate from rodents to humans [180] (but this pathway is speculated to be weak in rodents [189]). This section tries to discuss how such neuroscientific understanding will propel future efforts into development of a rapid-acting antidepressant class that does not result in cognitive dysfunction.

5.2.1. Supressive Regulation of Enhanced Thalamocortical Glutamatergic Transmission

Inhibition of NMDAR in RTN and MDTN enhanced thalamocortical glutamatergic transmission from the MDTN to mPFC, insula and OFC [32,33,34,35,37,162,166]. Glutamatergic neurones in the MDTN receive postsynaptic excitatory 5-HT receptor type 7 (5-HT7R) [34,35] and extrasynaptic group II metabotropic glutamate receptors (II-mGluR) [37,162]. Glutamatergic terminals in the frontal cortex receive inhibitory II-mGluR and group III metabotropic glutamate receptors (III-mGluR) presynaptically [36,37,162,166].
Hyperactivation of thalamocortical glutamatergic transmission due to intrathalamic GABAergic disinhibition was supressed by several atypical antipsychotics: aripiprazole through enhancement of II-mGluR [162], clozapine through enhancement of III-mGluR [166,190], and lurasidone through inhibition of postsynaptic 5-HT7R [34,35]. Interestingly, the suppression of thalamocortical glutamatergic transmission associated with II-mGluR and III-mGluR were possibly mediated by astroglial transmission but not by neurotransmission, since astroglial release of L-glutamate from system Xc- and hemichannel stimulated II-mGluR and III-mGluR [36,37,166,191]. Both memantine and N-acetyl-L-cysteine inhibited MK801-induced L-glutamate release in the frontal cortex (thalamocortical glutamatergic transmission) via activation of astroglial L-glutamate release through system Xc- [37,162,166]. Indeed, behavioural deficits in rat phencyclidine models are addressed by N-acetyl-L-cysteine administration [192].
Both systemic administration and local administration into the MDTN of a 5-HT transporter inhibitor increased extracellular 5-HT level in the MDTN, resulting in partially enhanced thalamocortical glutamatergic transmission [33,34,35]. The 5-HT7R antagonists, SB266970 and lurasidone, compensate for hyperactivation of glutamatergic transmission induced by enhanced serotonergic transmission [33,34,35]. Pharmacological behavioural preclinical studies demonstrated that SB266970 has an antipsychotic action with rapid-acting antidepressant effects, as opposed to conventional monoaminergic antidepressants, and it augments the actions of conventional monoaminergic antidepressants [193]. In addition to the acute effects of 5-HT7R antagonists, 5-HT7R signalling contributes to synapse remodelling and neural network formation, which is the target of event-related structural and functional plasticity. However, after maturation of neural circuits during adolescence and adulthood, 5-HT7R inhibition provides the protection of generation of abnormal neural circuits induced by chronic exposure to severe stress via preventions of disruption and/or regeneration [34,35]. The effects of serotonin receptor type 1A (5-HT1AR) and 5-HT7R are opposite in regard to neurotransmission and cognition [34,35,194], but the effect of 5-HT1AR is predominant rather than that of 5-HT7R, resulting in insufficient understanding of the function of 5-HT7R in psychopharmacology. Although combination therapy between SSRI/SNRI and ketamine/esketamine [81,90] has been studied, the interaction between 5-HT7R antagonistic agents and NMDAR antagonists in treatment-resistant depression represents a novel aspect of the development of rapid-acting antidepressants.

5.2.2. Stimulatory Regulation of Enhanced Thalamocortical Glutamatergic Transmission

Contrary to the NMDAR antagonist schizophrenia model, it is well known that dysfunction of MDTN plays a role in the cognitive dysfunction of ADHD, autism and intellectual disability [195,196,197]. Thalamocortical glutamatergic transmission is impaired in experimental animal models of ADHD and autism [178,179,187,188]. Physiological activation of the thalamic activity reduced distraction in attention tests [198], whereas the pathological enhancement of the thalamocortical glutamatergic transmission induced by phencyclidine disturbs working memory, which is compensated by a therapeutic-relevant dose of guanfacine [199].
Catecholaminergic neurones in the LC project at least three terminals; selective noradrenergic terminals to deeper layers of the frontal cortex [41,42,200,201] and RTN [32,37], and catecholaminergic co-releasing terminal (co-releasing norepinephrine and dopamine) to the superficial layers of the frontal cortex [41,42,200,201]. GABAergic neurones in the RTN receive excitatory noradrenergic input from the LC via the α1 adrenoceptor [32,178]. The intrathalamic GABAergic pathway is regulated by the inhibitory presynaptic α2A adrenoceptor in the MDTN [32,178]. Therefore, systemic administration of guanfacine supresses GABAergic inhibition of glutamatergic neurones in the MDTN via activation of the α2A adrenoceptor in the LC and MDTN, resulting in enhanced thalamocortical glutamatergic transmission [178]. If the hyperfunction of thalamocortical glutamatergic transmission contributes to the fundamental mechanisms of NMDAR antagonist-induced cognitive deficit, the suppressive effects of guanfacine on GABAergic inhibition in the MDTN apparently aggravate NMDAR antagonist-induced cognitive deficits. The discrepancy between NMDAR antagonists and guanfacine on cognition leads us to hypothesise that the regulation mechanisms in GABAergic inhibition of cognition are important. GABAergic disinhibition induced by NMDAR inhibition and α2A adrenoceptor activation generate tonic/persistent and phasic/transient GABAergic disinhibition, respectively [32,34,178] (Figure 2). Therefore, tonic GABAergic disinhibition by NMDAR inhibition abolishes input signalling from other regions via continuous hyperactivation, whereas, conversely, phasic GABAergic disinhibition by α2A adrenoceptor activation possibly leads to input optimization [32,36,37].

6. Conclusions and Remaining Challenges

Numerous clinical and preclinical investigations have already provided us with a glimpse into the several candidate pathomechanisms of the various conditions behind conventional monoaminergic antidepressant-resistant depression. There is no doubt that inhibition of upregulated NMDAR on GABAergic interneurones induced by chronic exposure to stress is one of the pragmatic mechanisms of the improvement of conventional monoaminergic antidepressant-resistant depression. Current findings show the possible potential of NMDAR inhibition, where it, at least partially, improves dysfunction of emotional perception/cognition (anhedonia and suicidal ideation) and displays rapid-acting antidepressant effects in conventional monoaminergic antidepressant-resistant depression.
The majority of individuals that take ketamine/esketamine have to overcome various dose-dependent dissociation cognitive deficits and psychotomimetic responses before getting the excellent beneficial clinical effects of ketamine. Furthermore, the antidepressant effect of ketamine/esketamine is comparatively short-lived (can last 1~2 weeks), whereas individuals who positively respond to ketamine usually relapse [80,88]. Therefore, NMDAR-inhibiting antidepressive medication is a double-edged sword therapy that carries the risk of severe persistent schizophrenia-like psychosis and long-lasting memory/cognitive deficits induced by chronic/repeated intake of an NMDAR antagonist. Unfortunately, the threshold dosage for antidepressive and psychotomimetic actions of ketamine is almost equal (cannot be discriminated).
The interpretation of the various pharmacological mechanisms of rapid-acting antidepressant effects and the neuropsychiatric adverse response of ketamine, obtained from both clinical and preclinical investigations, is not of any pharmacological value unless a critical separation between their neuropharmacological processes can be understood. In spite of the potential rapid-acting antidepressive, anti-anhedonia and anti-suicidal ideational actions of NMDAR antagonists, several challenges remain to be resolved to produce effective clinical applications of NMDAR antagonists for treatment in conventional monoaminergic antidepressant-resistant depression. Finally, we summarize the remaining challenging targets to progress rapid-acting antidepressive therapy.
  • Ideally, when a clear pharmacodynamic/pharmacokinetic distinction between the antidepressive and neuropsychotomimetic effects of NMDAR antagonists is achieved, then, according to the novel strategy, we can develop a new class of rapid-acting antidepressant for treatment of conventional monoaminergic antidepressant-resistant depression.
  • Unfortunately, current findings suggest the induction mechanisms of NMDAR antagonists associated with antidepressive and neuropsychotomimetic effects are possibly identical. Therefore, it is important to identify the strategy of adjunctive therapies that gives antipsychotic effects without affecting the antidepressant effects of NMDAR antagonists.
  • The high affinity dopamine D2 receptor partial agonistic action of ketamine possibly contributes to either its antidepressive or neuropsychotomimetic actions. Therefore, determination of the effects of adjuvant medication (typical and atypical antipsychotics) on the antidepressive and neuropsychotomimetic effects of ketamine is a rational strategy for the rapid-acting monoaminergic antidepressant-resistant depression therapy.
  • If these above trials do not show beneficial outcomes, we should explore other neuromodulation therapies for prevention of the acute and chronic adverse effects of ketamine without affecting its antidepressive action.
  • Preclinical findings suggest that distinct hippocampal and thalamic non-dopaminergic mechanisms play important roles in the ketamine-induced cognitive/memorial deficits. Thalamic nuclei that receive various inputs from cortical and subcortical regions integrate to give precise output to the frontal cortex. Therefore, conversion from tonic activation of thalamic activity induced by NMDAR inhibition to phasic activation/inhibition can lead to the development of cognitive promoting medication.

Author Contributions

Conceptualization, M.O.; Data curation, Y.K., K.F. and M.O.; Funding acquisition, M.O.; Methodology, M.O.; Project administration; M.O., Validation, M.O., E.M.; Writing original draft, M.O.; Writing review & editing, M.O. and T.S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by Japan Society for the Promotion of Science (15H04892 and 19K08073).

Conflicts of Interest

The authors state no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Abbreviations

II-mGluRgroup II metabotropic glutamate receptors
III-mGluRgroup III metabotropic glutamate receptors
5-HTserotonin
5-HT2ARserotonin receptor type 2A
5-HT7Rserotonin receptor type 7
ACTHadrenocorticotropic hormone
AMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AMPARα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/glutamate receptor
BDNFbrain-derived neurotrophic factor
DRNdorsal raphe nucleus
Erkextracellular Signal-regulated Kinase
EMAthe European Medicines Agency
FDAthe Food and Drug Administration
fMRIfunctional magnetic resonance imaging
GABAγ-aminobutyrate
LClocus coeruleus
MDTNmediodorsal thalamic nucleus
MK801dizocilpine
mTORmammalian target of rapamycin
NMDARN-methyl-D-aspartate/glutamate receptor
OFCorbitofrontal cortex
PPIprepulse inhibition
RTNreticular thalamic nucleus
SNRIserotonin norepinephrine reuptake inhibitor
SSRIselective serotonin reuptake inhibitor
VTAventral tegmental area

References

  1. U.S. Food and Drug Administration. FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available only at a Certified Doctor’s Office or Clinic. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified (accessed on 5 September 2020).
  2. European Medicines Agency. Esketamine Nasal Spray Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/spravato (accessed on 5 September 2020).
  3. Gaynes, B.N.; Warden, D.; Trivedi, M.H.; Wisniewski, S.R.; Fava, M.; Rush, A.J. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009, 60, 1439–1445. [Google Scholar] [CrossRef] [PubMed]
  4. Autry, A.E.; Adachi, M.; Nosyreva, E.; Na, E.S.; Los, M.F.; Cheng, P.F.; Kavalali, E.T.; Monteggia, L.M. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011, 475, 91–95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Singh, J.B.; Fedgchin, M.; Daly, E.J.; De Boer, P.; Cooper, K.; Lim, P.; Pinter, C.; Murrough, J.W.; Sanacora, G.; Shelton, R.C.; et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am. J. Psychiatry 2016, 173, 816–826. [Google Scholar] [CrossRef]
  6. DiazGranados, N.; Ibrahim, L.A.; Brutsche, N.E.; Ameli, R.; Henter, I.D.; Luckenbaugh, D.A.; Machado-Vieira, R.; Zarate, C.A., Jr. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry 2010, 71, 1605–1611. [Google Scholar] [CrossRef] [Green Version]
  7. Zarate, C.A.; Singh, J.B.; Carlson, P.J.; Brutsche, N.E.; Ameli, R.; Luckenbaugh, D.A.; Charney, D.S.; Manji, H.K. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 2006, 63, 856–864. [Google Scholar] [CrossRef]
  8. Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000, 47, 351–354. [Google Scholar] [CrossRef]
  9. Wilkinson, S.T.; Ballard, E.D.; Bloch, M.H.; Mathew, S.J.; Murrough, J.W.; Feder, A.; Sos, P.; Wang, G.; Zarate, C.A., Jr.; Sanacora, G. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am. J. Psychiatry 2018, 175, 150–158. [Google Scholar] [CrossRef]
  10. Lally, N.; Nugent, A.C.; Luckenbaugh, D.A.; Ameli, R.; Roiser, J.P.; Zarate, C.A. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl. Psychiatry 2014, 4, e469. [Google Scholar] [CrossRef] [Green Version]
  11. Moaddel, R.; Abdrakhmanova, G.; Kozak, J.; Jozwiak, K.; Toll, L.; Jimenez, L.; Rosenberg, A.; Tran, T.; Xiao, Y.; Zarate, C.A.; et al. Sub-anesthetic concentrations of (R, S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha7 nicotinic acetylcholine receptors. Eur. J. Pharmacol. 2013, 698, 228–234. [Google Scholar] [CrossRef] [Green Version]
  12. Ebert, B.; Mikkelsen, S.; Thorkildsen, C.; Borgbjerg, F.M. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur. J. Pharmacol. 1997, 333, 99–104. [Google Scholar] [CrossRef]
  13. White, P.F.; Schuttler, J.; Shafer, A.; Stanski, D.R.; Horai, Y.; Trevor, A.J. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br. J. Anaesth 1985, 57, 197–203. [Google Scholar] [CrossRef] [PubMed]
  14. Javitt, D.C. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J. Clin. Psychiatry 1987, 9, 12–35. [Google Scholar] [PubMed]
  15. Javitt, D.C.; Zukin, S.R. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 1991, 148, 1301–1308. [Google Scholar] [PubMed]
  16. Malhotra, A.K.; Pinals, D.A.; Adler, C.M.; Elman, I.; Clifton, A.; Pickar, D.; Breier, A. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 1997, 17, 141–150. [Google Scholar] [CrossRef]
  17. Malhotra, A.K.; Pinals, D.A.; Weingartner, H.; Sirocco, K.; Missar, C.D.; Pickar, D.; Breier, A. NMDA receptor function and human cognition: The effects of ketamine in healthy volunteers. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 1996, 14, 301–307. [Google Scholar] [CrossRef] [Green Version]
  18. Martin, V.; Riffaud, A.; Marday, T.; Brouillard, C.; Franc, B.; Tassin, J.P.; Sevoz-Couche, C.; Mongeau, R.; Lanfumey, L. Response of Htr3a knockout mice to antidepressant treatment and chronic stress. Br. J. Pharm. 2017, 174, 2471–2483. [Google Scholar] [CrossRef] [Green Version]
  19. Conn, P.J.; Lindsley, C.W.; Jones, C.K. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharm. Sci. 2009, 30, 25–31. [Google Scholar] [CrossRef] [Green Version]
  20. Lisman, J.E.; Coyle, J.T.; Green, R.W.; Javitt, D.C.; Benes, F.M.; Heckers, S.; Grace, A.A. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008, 31, 234–242. [Google Scholar] [CrossRef] [Green Version]
  21. Aan Het Rot, M.; Zarate, C.A., Jr.; Charney, D.S.; Mathew, S.J. Ketamine for depression: Where do we go from here? Biol. Psychiatry 2012, 72, 537–547. [Google Scholar] [CrossRef] [Green Version]
  22. Leon, A.C.; Fiedorowicz, J.G.; Solomon, D.A.; Li, C.; Coryell, W.H.; Endicott, J.; Fawcett, J.; Keller, M.B. Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders. J. Clin. Psychiatry 2014, 75, 720–727. [Google Scholar] [CrossRef]
  23. Beck, K.; Hindley, G.; Borgan, F.; Ginestet, C.; McCutcheon, R.; Brugger, S.; Driesen, N.; Ranganathan, M.; D’Souza, D.C.; Taylor, M.; et al. Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020, 3, e204693. [Google Scholar] [CrossRef] [PubMed]
  24. Krystal, J.H.; Karper, L.P.; Seibyl, J.P.; Freeman, G.K.; Delaney, R.; Bremner, J.D.; Heninger, G.R.; Bowers, M.B., Jr.; Charney, D.S. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 1994, 51, 199–214. [Google Scholar] [CrossRef]
  25. Monyer, H.; Burnashev, N.; Laurie, D.J.; Sakmann, B.; Seeburg, P.H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994, 12, 529–540. [Google Scholar] [CrossRef]
  26. Ulbrich, M.H.; Isacoff, E.Y. Rules of engagement for NMDA receptor subunits. Proc. Natl. Acad. Sci. USA 2008, 105, 14163–14168. [Google Scholar] [CrossRef] [Green Version]
  27. Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol. Rev. 2010, 62, 405–496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Dingledine, R.; Borges, K.; Bowie, D.; Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 1999, 51, 7–61. [Google Scholar] [PubMed]
  29. Tanahashi, S.; Yamamura, S.; Nakagawa, M.; Motomura, E.; Okada, M. Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes. Br. J. Pharm. 2012, 165, 1543–1555. [Google Scholar] [CrossRef] [Green Version]
  30. Gocho, Y.; Sakai, A.; Yanagawa, Y.; Suzuki, H.; Saitow, F. Electrophysiological and pharmacological properties of GABAergic cells in the dorsal raphe nucleus. J. Physiol. Sci. 2013, 63, 147–154. [Google Scholar] [CrossRef] [Green Version]
  31. Hu, H.; Jonas, P. A supercritical density of Na(+) channels ensures fast signaling in GABAergic interneuron axons. Nat. Neurosci. 2014, 17, 686–693. [Google Scholar] [CrossRef] [Green Version]
  32. Okada, M.; Fukuyama, K. Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus. Biomolecules 2020, 10, 990. [Google Scholar] [CrossRef]
  33. Okada, M.; Okubo, R.; Fukuyama, K. Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT1A Receptor with 5-HT3 Receptor Inhibition in Rats. Int. J. Mol. Sci. 2019, 20, 6235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Okada, M.; Fukuyama, K.; Ueda, Y. Lurasidone inhibits NMDA/glutamate antagonist-induced functional abnormality of thalamocortical glutamatergic transmission via 5-HT7 receptor blockade. Br. J. Pharm. 2019. [Google Scholar] [CrossRef]
  35. Okada, M.; Fukuyama, K.; Okubo, R.; Shiroyama, T.; Ueda, Y. Lurasidone sub-chronically activates serotonergic transmission via desensitization of 5-HT1A and 5-HT7 receptors in dorsal raphe nucleus. Pharmaceuticals 2019, 12, 149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Okada, M.; Fukuyama, K.; Nakano, T.; Ueda, Y. Pharmacological Discrimination of Effects of MK801 on Thalamocortical, Mesothalamic, and Mesocortical Transmissions. Biomolecules 2019, 9, 746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Okada, M.; Fukuyama, K.; Kawano, Y.; Shiroyama, T.; Ueda, Y. Memantine protects thalamocortical hyper-glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc. Pharm. Res. Perspect 2019, 7, e00457. [Google Scholar] [CrossRef] [Green Version]
  38. Nakano, T.; Hasegawa, T.; Suzuki, D.; Motomura, E.; Okada, M. Amantadine Combines Astroglial System Xc(-) Activation with Glutamate/NMDA Receptor Inhibition. Biomolecules 2019, 9, 191. [Google Scholar] [CrossRef] [Green Version]
  39. Tanahashi, S.; Yamamura, S.; Nakagawa, M.; Motomura, E.; Okada, M. Dopamine D2 and serotonin 5-HT1A receptors mediate the actions of aripiprazole in mesocortical and mesoaccumbens transmission. Neuropharmacology 2012, 62, 765–774. [Google Scholar] [CrossRef]
  40. Tanahashi, S.; Ueda, Y.; Nakajima, A.; Yamamura, S.; Nagase, H.; Okada, M. Novel delta1-receptor agonist KNT-127 increases the release of dopamine and L-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex. Neuropharmacology 2012, 62, 2057–2067. [Google Scholar] [CrossRef]
  41. Yamamura, S.; Ohoyama, K.; Hamaguchi, T.; Nakagawa, M.; Suzuki, D.; Matsumoto, T.; Motomura, E.; Tanii, H.; Shiroyama, T.; Okada, M. Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex. Br. J. Pharm. 2009, 157, 656–665. [Google Scholar] [CrossRef]
  42. Yamamura, S.; Ohoyama, K.; Hamaguchi, T.; Kashimoto, K.; Nakagawa, M.; Kanehara, S.; Suzuki, D.; Matsumoto, T.; Motomura, E.; Shiroyama, T.; et al. Effects of quetiapine on monoamine, GABA, and glutamate release in rat prefrontal cortex. Psychopharmacology 2009, 206, 243–258. [Google Scholar] [CrossRef]
  43. Stephenson, F.A. Structure and trafficking of NMDA and GABAA receptors. Biochem. Soc. Trans. 2006, 34, 877–881. [Google Scholar] [CrossRef] [PubMed]
  44. Salussolia, C.L.; Prodromou, M.L.; Borker, P.; Wollmuth, L.P. Arrangement of subunits in functional NMDA receptors. J. Neurosci. J. Soc. Neurosci. 2011, 31, 11295–11304. [Google Scholar] [CrossRef] [PubMed]
  45. Perez-Otano, I.; Larsen, R.S.; Wesseling, J.F. Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat. Reviews. Neurosci. 2016, 17, 623–635. [Google Scholar] [CrossRef]
  46. Pachernegg, S.; Strutz-Seebohm, N.; Hollmann, M. GluN3 subunit-containing NMDA receptors: Not just one-trick ponies. Trends Neurosci. 2012, 35, 240–249. [Google Scholar] [CrossRef]
  47. Gray, A.; Hyde, T.; Deep-Soboslay, A.; Kleinman, J.; Sodhi, M. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol. Psychiatry 2015, 20, 1057–1068. [Google Scholar] [CrossRef]
  48. Lin, E.; Kuo, P.-H.; Liu, Y.-L.; Yu, Y.W.-Y.; Yang, A.C.; Tsai, S.-J. A deep learning approach for predicting antidepressant response in major depression using clinical and genetic biomarkers. Front. Psychiatry 2018, 9, 290. [Google Scholar] [CrossRef] [Green Version]
  49. Zhang, C.; Li, Z.; Wu, Z.; Chen, J.; Wang, Z.; Peng, D.; Hong, W.; Yuan, C.; Wang, Z.; Yu, S. A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology 2014, 231, 685–693. [Google Scholar] [CrossRef] [PubMed]
  50. Weder, N.; Zhang, H.; Jensen, K.; Yang, B.Z.; Simen, A.; Jackowski, A.; Lipschitz, D.; Douglas-Palumberi, H.; Ge, M.; Perepletchikova, F. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J. Am. Acad. Child. Adolesc. Psychiatry 2014, 53, 417–424. e415. [Google Scholar] [CrossRef] [Green Version]
  51. Kaut, O.; Schmitt, I.; Hofmann, A.; Hoffmann, P.; Schlaepfer, T.E.; Wüllner, U.; Hurlemann, R. Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression. Eur. Arch. Psychiatry Clin. Neurosci. 2015, 265, 331–341. [Google Scholar] [CrossRef]
  52. Hellman, A.; Chess, A. Gene body-specific methylation on the active X chromosome. Science 2007, 315, 1141–1143. [Google Scholar] [CrossRef]
  53. Calabrese, F.; Guidotti, G.; Molteni, R.; Racagni, G.; Mancini, M.; Riva, M.A. Stress-induced changes of hippocampal NMDA receptors: Modulation by duloxetine treatment. PLoS ONE 2012, 7, e37916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Chandley, M.J.; Szebeni, A.; Szebeni, K.; Crawford, J.D.; Stockmeier, C.A.; Turecki, G.; Kostrzewa, R.M.; Ordway, G.A. Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int. J. Neuropsychopharmacol. 2014, 17, 1569–1578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Karolewicz, B.; Stockmeier, C.A.; Ordway, G.A. Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2005, 30, 1557–1567. [Google Scholar] [CrossRef]
  56. Rodríguez-Muñoz, M.; Sánchez-Blázquez, P.; Callado, L.F.; Meana, J.J.; Garzón-Niño, J. Schizophrenia and depression, two poles of endocannabinoid system deregulation. Transl. Psychiatry 2017, 7, 1–12. [Google Scholar] [CrossRef] [Green Version]
  57. Feyissa, A.M.; Chandran, A.; Stockmeier, C.A.; Karolewicz, B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2009, 33, 70–75. [Google Scholar] [CrossRef] [Green Version]
  58. Beneyto, M.; Kristiansen, L.V.; Oni-Orisan, A.; McCullumsmith, R.E.; Meador-Woodruff, J.H. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2007, 32, 1888–1902. [Google Scholar] [CrossRef]
  59. Karolewicz, B.; Szebeni, K.; Gilmore, T.; Maciag, D.; Stockmeier, C.A.; Ordway, G.A. Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int. J. Neuropsychopharmacol. 2009, 12, 143–153. [Google Scholar] [CrossRef] [Green Version]
  60. Weickert, C.S.; Fung, S.; Catts, V.; Schofield, P.; Allen, K.; Moore, L.; Newell, K.A.; Pellen, D.; Huang, X.-F.; Catts, S. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol. Psychiatry 2013, 18, 1185–1192. [Google Scholar] [CrossRef] [Green Version]
  61. Akbarian, S.; Sucher, N.; Bradley, D.; Tafazzoli, A.; Trinh, D.; Hetrick, W.; Potkin, S.; Sandman, C.; Bunney, W.; Jones, E. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J. Neurosci. 1996, 16, 19–30. [Google Scholar] [CrossRef] [Green Version]
  62. Catts, V.S.; Derminio, D.S.; Hahn, C.-G.; Weickert, C.S. Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia. npj Schizophrenia 2015, 1, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Law, A.J.; Deakin, J. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 2001, 12, 2971–2974. [Google Scholar] [CrossRef] [PubMed]
  64. Gao, X.-M.; Sakai, K.; Roberts, R.C.; Conley, R.R.; Dean, B.; Tamminga, C.A. Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: Effects of schizophrenia. Am. J. Psychiatry 2000, 157, 1141–1149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Sokolov, B.P. Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of “neuroleptic-free” schizophrenics: Evidence on reversible up-regulation by typical neuroleptics. J. Neurochem. 1998, 71, 2454–2464. [Google Scholar] [CrossRef]
  66. Banerjee, A.; Wang, H.-Y.; Borgmann-Winter, K.E.; MacDonald, M.L.; Kaprielian, H.; Stucky, A.; Kvasic, J.; Egbujo, C.; Ray, R.; Talbot, K. Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. Mol. Psychiatry 2015, 20, 1091–1100. [Google Scholar] [CrossRef] [Green Version]
  67. Stone, J.M.; Erlandsson, K.; Arstad, E.; Squassante, L.; Teneggi, V.; Bressan, R.A.; Krystal, J.H.; Ell, P.J.; Pilowsky, L.S. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: A [(123)I] CNS-1261 SPET study. Psychopharmacology 2008, 197, 401–408. [Google Scholar] [CrossRef]
  68. Luby, E.D.; Cohen, B.D.; Rosenbaum, G.; Gottlieb, J.S.; Kelley, R. Study of a new schizophrenomimetic drug; sernyl. A.M.A. Arch. Neurol. Psychiatry 1959, 81, 363–369. [Google Scholar] [CrossRef]
  69. Domino, E.F.; Chodoff, P.; Corssen, G. Pharmacologic Effects of Ci-581, a New Dissociative Anesthetic, in Man. Clin. Pharmacol. Ther. 1965, 6, 279–291. [Google Scholar] [CrossRef] [Green Version]
  70. Lin, C.Y.; Liang, S.Y.; Chang, Y.C.; Ting, S.Y.; Kao, C.L.; Wu, Y.H.; Tsai, G.E.; Lane, H.Y. Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial. World J. Biol. Psychiatry 2017, 18, 357–368. [Google Scholar] [CrossRef] [PubMed]
  71. Lane, H.Y.; Lin, C.H.; Green, M.F.; Hellemann, G.; Huang, C.C.; Chen, P.W.; Tun, R.; Chang, Y.C.; Tsai, G.E. Add-on treatment of benzoate for schizophrenia: A randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry 2013, 70, 1267–1275. [Google Scholar] [CrossRef] [PubMed]
  72. Fukui, K.; Miyake, Y. Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. J. Biol. Chem. 1992, 267, 18631–18638. [Google Scholar] [PubMed]
  73. Sasabe, J.; Miyoshi, Y.; Suzuki, M.; Mita, M.; Konno, R.; Matsuoka, M.; Hamase, K.; Aiso, S. D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc. Natl. Acad. Sci. USA 2012, 109, 627–632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Murrough, J.W.; Soleimani, L.; DeWilde, K.E.; Collins, K.A.; Lapidus, K.A.; Iacoviello, B.M.; Lener, M.; Kautz, M.; Kim, J.; Stern, J.B.; et al. Ketamine for rapid reduction of suicidal ideation: A randomized controlled trial. Psychol. Med. 2015, 45, 3571–3580. [Google Scholar] [CrossRef]
  75. Grunebaum, M.F.; Galfalvy, H.C.; Choo, T.-H.; Keilp, J.G.; Moitra, V.K.; Parris, M.S.; Marver, J.E.; Burke, A.K.; Milak, M.S.; Sublette, M.E.; et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am. J. Psychiatry 2018, 175, 327–335. [Google Scholar] [CrossRef] [PubMed]
  76. Murrough, J.W.; Perez, A.M.; Pillemer, S.; Stern, J.; Parides, M.K.; aan het Rot, M.; Collins, K.A.; Mathew, S.J.; Charney, D.S.; Iosifescu, D.V. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol. Psychiatry 2013, 74, 250–256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Diazgranados, N.; Ibrahim, L.; Brutsche, N.E.; Newberg, A.; Kronstein, P.; Khalife, S.; Kammerer, W.A.; Quezado, Z.; Luckenbaugh, D.A.; Salvadore, G.; et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 2010, 67, 793–802. [Google Scholar] [CrossRef] [PubMed]
  78. Zarate, C.A., Jr.; Brutsche, N.E.; Ibrahim, L.; Franco-Chaves, J.; Diazgranados, N.; Cravchik, A.; Selter, J.; Marquardt, C.A.; Liberty, V.; Luckenbaugh, D.A. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial. Biol. Psychiatry 2012, 71, 939–946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M.; Iqbal, S.; Pillemer, S.; Foulkes, A.; Shah, A.; et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am. J. Psychiatry 2013, 170, 1134–1142. [Google Scholar] [CrossRef]
  80. Lapidus, K.A.; Levitch, C.F.; Perez, A.M.; Brallier, J.W.; Parides, M.K.; Soleimani, L.; Feder, A.; Iosifescu, D.V.; Charney, D.S.; Murrough, J.W. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol. Psychiatry 2014, 76, 970–976. [Google Scholar] [CrossRef] [Green Version]
  81. Hu, Y.D.; Xiang, Y.T.; Fang, J.X.; Zu, S.; Sha, S.; Shi, H.; Ungvari, G.S.; Correll, C.U.; Chiu, H.F.; Xue, Y.; et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: Results from a randomized, placebo-controlled 4-week study. Psychol. Med. 2016, 46, 623–635. [Google Scholar] [CrossRef]
  82. Li, C.-T.; Chen, M.-H.; Lin, W.-C.; Hong, C.-J.; Yang, B.-H.; Liu, R.-S.; Tu, P.-C.; Su, T.-P. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study. Hum. Brain Mapp. 2016, 37, 1080–1090. [Google Scholar] [CrossRef]
  83. Su, T.-P.; Chen, M.-H.; Li, C.-T.; Lin, W.-C.; Hong, C.-J.; Gueorguieva, R.; Tu, P.-C.; Bai, Y.-M.; Cheng, C.-M.; Krystal, J.H. Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2017, 42, 2482–2492. [Google Scholar] [CrossRef] [PubMed]
  84. Grunebaum, M.F.; Ellis, S.P.; Keilp, J.G.; Moitra, V.K.; Cooper, T.B.; Marver, J.E.; Burke, A.K.; Milak, M.S.; Sublette, M.E.; Oquendo, M.A.; et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial. Bipolar Disord. 2017, 19, 176–183. [Google Scholar] [CrossRef] [PubMed]
  85. Fava, M.; Freeman, M.P.; Flynn, M.; Judge, H.; Hoeppner, B.B.; Cusin, C.; Ionescu, D.F.; Mathew, S.J.; Chang, L.C.; Iosifescu, D.V.; et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol. Psychiatry 2018, 25, 1592–1603. [Google Scholar] [CrossRef] [PubMed]
  86. Phillips, J.L.; Norris, S.; Talbot, J.; Birmingham, M.; Hatchard, T.; Ortiz, A.; Owoeye, O.; Batten, L.A.; Blier, P. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am. J. Psychiatry 2019, 176, 401–409. [Google Scholar] [CrossRef] [PubMed]
  87. Ionescu, D.F.; Bentley, K.H.; Eikermann, M.; Taylor, N.; Akeju, O.; Swee, M.B.; Pavone, K.J.; Petrie, S.R.; Dording, C.; Mischoulon, D.; et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. J. Affect. Disord. 2019, 243, 516–524. [Google Scholar] [CrossRef] [PubMed]
  88. Singh, J.B.; Fedgchin, M.; Daly, E.; Xi, L.; Melman, C.; De Bruecker, G.; Tadic, A.; Sienaert, P.; Wiegand, F.; Manji, H.; et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol. Psychiatry 2016, 80, 424–431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Daly, E.J.; Singh, J.B.; Fedgchin, M.; Cooper, K.; Lim, P.; Shelton, R.C.; Thase, M.E.; Winokur, A.; Van Nueten, L.; Manji, H. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry 2018, 75, 139–148. [Google Scholar] [CrossRef]
  90. Canuso, C.M.; Singh, J.B.; Fedgchin, M.; Alphs, L.; Lane, R.; Lim, P.; Pinter, C.; Hough, D.; Sanacora, G.; Manji, H.; et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am. J. Psychiatry 2018, 175, 620–630. [Google Scholar] [CrossRef]
  91. Popova, V.; Daly, E.J.; Trivedi, M.; Cooper, K.; Lane, R.; Lim, P.; Mazzucco, C.; Hough, D.; Thase, M.E.; Shelton, R.C.; et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am. J. Psychiatry 2019, 176, 428–438. [Google Scholar] [CrossRef]
  92. Fedgchin, M.; Trivedi, M.; Daly, E.J.; Melkote, R.; Lane, R.; Lim, P.; Vitagliano, D.; Blier, P.; Fava, M.; Liebowitz, M.; et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int. J. Neuropsychopharmacol. 2019, 22, 616–630. [Google Scholar] [CrossRef]
  93. Correia-Melo, F.S.; Leal, G.C.; Vieira, F.; Jesus-Nunes, A.P.; Mello, R.P.; Magnavita, G.; Caliman-Fontes, A.T.; Echegaray, M.V.F.; Bandeira, I.D.; Silva, S.S.; et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J. Affect. Disord. 2020, 264, 527–534. [Google Scholar] [CrossRef] [PubMed]
  94. Ochs-Ross, R.; Daly, E.J.; Zhang, Y.; Lane, R.; Lim, P.; Morrison, R.L.; Hough, D.; Manji, H.; Drevets, W.C.; Sanacora, G.; et al. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression—TRANSFORM-3. Am. J. Geriatr. Psychiatry 2020, 28, 121–141. [Google Scholar] [CrossRef] [PubMed]
  95. Preskorn, S.H.; Baker, B.; Kolluri, S.; Menniti, F.S.; Krams, M.; Landen, J.W. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 2008, 28, 631–637. [Google Scholar] [CrossRef]
  96. Ibrahim, L.; Diaz Granados, N.; Jolkovsky, L.; Brutsche, N.; Luckenbaugh, D.A.; Herring, W.J.; Potter, W.Z.; Zarate, C.A., Jr. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J. Clin. Psychopharmacol. 2012, 32, 551–557. [Google Scholar] [CrossRef] [Green Version]
  97. Zanos, P.; Moaddel, R.; Morris, P.J.; Riggs, L.M.; Highland, J.N.; Georgiou, P.; Pereira, E.F.R.; Albuquerque, E.X.; Thomas, C.J.; Zarate, C.A., Jr.; et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol. Rev. 2018, 70, 621–660. [Google Scholar] [CrossRef] [Green Version]
  98. Vollenweider, F.X.; Leenders, K.L.; Oye, I.; Hell, D.; Angst, J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 1997, 7, 25–38. [Google Scholar] [CrossRef]
  99. Short, B.; Fong, J.; Galvez, V.; Shelker, W.; Loo, C.K. Side-effects associated with ketamine use in depression: A systematic review. Lancet Psychiatry 2018, 5, 65–78. [Google Scholar] [CrossRef]
  100. Seeman, P.; Guan, H.C.; Hirbec, H. Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Synapse 2009, 63, 698–704. [Google Scholar] [CrossRef] [PubMed]
  101. Kokkinou, M.; Ashok, A.H.; Howes, O.D. The effects of ketamine on dopaminergic function: Meta-analysis and review of the implications for neuropsychiatric disorders. Mol. Psychiatry 2018, 23, 59–69. [Google Scholar] [CrossRef] [Green Version]
  102. Seeman, P.; Ko, F.; Tallerico, T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol. Psychiatry 2005, 10, 877–883. [Google Scholar] [CrossRef]
  103. Kapur, S.; Seeman, P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol. Psychiatry 2002, 7, 837–844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Akhlaghi, N.; Payandemehr, P.; Yaseri, M.; Akhlaghi, A.A.; Abdolrazaghnejad, A. Premedication With Midazolam or Haloperidol to Prevent Recovery Agitation in Adults Undergoing Procedural Sedation With Ketamine: A Randomized Double-Blind Clinical Trial. Ann. Emerg. Med. 2019, 73, 462–469. [Google Scholar] [CrossRef]
  105. Chen, Y.M.; Lin, C.H.; Lane, H.Y. Survey of NMDA Receptor-related Biomarkers for Depression. Curr. Pharm. Des. 2020, 26, 228–235. [Google Scholar] [CrossRef]
  106. Singh, S.P.; Singh, V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011, 25, 859–885. [Google Scholar] [CrossRef]
  107. Levin, R.; Dor-Abarbanel, A.E.; Edelman, S.; Durrant, A.R.; Hashimoto, K.; Javitt, D.C.; Heresco-Levy, U. Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: Initial findings. J. Psychiatr. Res. 2015, 61, 188–195. [Google Scholar] [CrossRef] [PubMed]
  108. Zhao, Z.X.; Fu, J.; Ma, S.R.; Peng, R.; Yu, J.B.; Cong, L.; Pan, L.B.; Zhang, Z.G.; Tian, H.; Che, C.T.; et al. Gut-brain axis metabolic pathway regulates antidepressant efficacy of albiflorin. Theranostics 2018, 8, 5945–5959. [Google Scholar] [CrossRef]
  109. Homayoun, H.; Stefani, M.R.; Adams, B.W.; Tamagan, G.D.; Moghaddam, B. Functional interaction between NMDA and mGlu5 receptors: Effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2004, 29, 1259–1269. [Google Scholar] [CrossRef]
  110. Mouri, A.; Koseki, T.; Narusawa, S.; Niwa, M.; Mamiya, T.; Kano, S.-i.; Sawa, A.; Nabeshima, T. Mouse strain differences in phencyclidine-induced behavioural changes. Int. J. Neuropsychopharmacol. 2012, 15, 767–779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Xu, X.; Domino, E.F. Genetic differences in the locomotor response to single and daily doses of phencyclidine in inbred mouse strains. Behav. Pharmacol. 1994, 5, 623–629. [Google Scholar] [CrossRef]
  112. Castañé, A.; Santana, N.; Artigas, F. PCP-based mice models of schizophrenia: Differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacology 2015, 232, 4085–4097. [Google Scholar] [CrossRef] [Green Version]
  113. Giros, B.; Jaber, M.; Jones, S.R.; Wightman, R.M.; Caron, M.G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996, 379, 606–612. [Google Scholar] [CrossRef]
  114. Jentsch, J.D.; Tran, A.; Taylor, J.R.; Roth, R.H. Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: Behavioral and neurochemical evidence. Psychopharmacology 1998, 138, 89–95. [Google Scholar] [CrossRef]
  115. Sams-Dodd, F. Effect of novel antipsychotic drugs on phencyclidine-induced stereotyped behaviour and social isolation in the rat social interaction test. Behav Pharm. 1997, 8, 196–215. [Google Scholar]
  116. Adell, A.; Jiménez-Sánchez, L.; López-Gil, X.; Romón, T. Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr. Bull. 2012, 38, 9–14. [Google Scholar] [CrossRef] [PubMed]
  117. Broberg, B.V.; Oranje, B.; Glenthoj, B.Y.; Fejgin, K.; Plath, N.; Bastlund, J.F. Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia--gating of auditory-evoked potentials and prepulse inhibition. Behav. Brain Res. 2010, 213, 142–147. [Google Scholar] [CrossRef]
  118. Bakshi, V.P.; Tricklebank, M.; Neijt, H.C.; Lehmann-Masten, V.; Geyer, M.A. Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-D-aspartate receptor antagonists in rats. J. Pharm. Exp. 1999, 288, 643–652. [Google Scholar]
  119. Thomson, D.M.; McVie, A.; Morris, B.J.; Pratt, J.A. Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: Influence of clozapine. Psychopharmacology 2011, 213, 681–695. [Google Scholar] [CrossRef] [PubMed]
  120. Spielewoy, C.; Markou, A. Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2003, 28, 1106–1116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Neill, J.C.; Harte, M.K.; Haddad, P.M.; Lydall, E.S.; Dwyer, D.M. Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: A translational link to humans. Eur. Neuropsychopharmacol. 2014, 24, 822–835. [Google Scholar] [CrossRef]
  122. Jentsch, J.D.; Roth, R.H. The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 1999, 20, 201–225. [Google Scholar] [CrossRef] [Green Version]
  123. Egerton, A.; Reid, L.; McGregor, S.; Cochran, S.M.; Morris, B.J.; Pratt, J.A. Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats. Psychopharmacology 2008, 198, 37–49. [Google Scholar] [CrossRef] [PubMed]
  124. Maeng, S.; Zarate, C.A., Jr.; Du, J.; Schloesser, R.J.; McCammon, J.; Chen, G.; Manji, H.K. Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 2008, 63, 349–352. [Google Scholar] [CrossRef] [PubMed]
  125. Lindholm, J.S.; Autio, H.; Vesa, L.; Antila, H.; Lindemann, L.; Hoener, M.C.; Skolnick, P.; Rantamaki, T.; Castren, E. The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf(+)/(-) heterozygous null mice. Neuropharmacology 2012, 62, 391–397. [Google Scholar] [CrossRef] [PubMed]
  126. Yang, B.; Ren, Q.; Ma, M.; Chen, Q.X.; Hashimoto, K. Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the Social Defeat Stress Model. Int J. Neuropsychopharmacol 2016, 19, 1. [Google Scholar] [CrossRef] [Green Version]
  127. Garcia, L.S.; Comim, C.M.; Valvassori, S.S.; Reus, G.Z.; Stertz, L.; Kapczinski, F.; Gavioli, E.C.; Quevedo, J. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog. Neuro Psychopharmacol. Biol. Psychiatry 2009, 33, 450–455. [Google Scholar] [CrossRef]
  128. Reus, G.Z.; Abelaira, H.M.; dos Santos, M.A.; Carlessi, A.S.; Tomaz, D.B.; Neotti, M.V.; Liranco, J.L.; Gubert, C.; Barth, M.; Kapczinski, F.; et al. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors. Behav. Brain Res. 2013, 256, 451–456. [Google Scholar] [CrossRef]
  129. Reus, G.Z.; Carlessi, A.S.; Titus, S.E.; Abelaira, H.M.; Ignacio, Z.M.; da Luz, J.R.; Matias, B.I.; Bruchchen, L.; Florentino, D.; Vieira, A.; et al. A single dose of S-ketamine induces long-term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation. Dev. Neurobiol. 2015, 75, 1268–1281. [Google Scholar] [CrossRef]
  130. Reus, G.Z.; Nacif, M.P.; Abelaira, H.M.; Tomaz, D.B.; dos Santos, M.A.; Carlessi, A.S.; da Luz, J.R.; Goncalves, R.C.; Vuolo, F.; Dal-Pizzol, F.; et al. Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation. Neurosci. Lett. 2015, 584, 83–87. [Google Scholar] [CrossRef]
  131. Yang, C.; Shirayama, Y.; Zhang, J.C.; Ren, Q.; Yao, W.; Ma, M.; Dong, C.; Hashimoto, K. R-ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl. Psychiatry 2015, 5, e632. [Google Scholar] [CrossRef]
  132. Fukumoto, K.; Toki, H.; Iijima, M.; Hashihayata, T.; Yamaguchi, J.I.; Hashimoto, K.; Chaki, S. Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine. J. Pharm. Exp. 2017, 361, 9–16. [Google Scholar] [CrossRef] [Green Version]
  133. Li, N.; Lee, B.; Liu, R.-J.; Banasr, M.; Dwyer, J.M.; Iwata, M.; Li, X.-Y.; Aghajanian, G.; Duman, R.S. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010, 329, 959–964. [Google Scholar] [CrossRef] [Green Version]
  134. Markou, A.; Chiamulera, C.; Geyer, M.A.; Tricklebank, M.; Steckler, T. Removing obstacles in neuroscience drug discovery: The future path for animal models. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2009, 34, 74–89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Levinstein, M.R.; Samuels, B.A. Mechanisms underlying the antidepressant response and treatment resistance. Front. Behav. Neurosci. 2014, 8, 208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Jayatissa, M.N.; Bisgaard, C.; Tingstrom, A.; Papp, M.; Wiborg, O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2006, 31, 2395–2404. [Google Scholar] [CrossRef] [Green Version]
  137. Der-Avakian, A.; Mazei-Robison, M.S.; Kesby, J.P.; Nestler, E.J.; Markou, A. Enduring deficits in brain reward function after chronic social defeat in rats: Susceptibility, resilience, and antidepressant response. Biol. Psychiatry 2014, 76, 542–549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Kitamura, Y.; Araki, H.; Gomita, Y. Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test. Pharmacol. Biochem. Behav. 2002, 71, 63–69. [Google Scholar] [CrossRef]
  139. Sukoff Rizzo, S.J.; Neal, S.J.; Hughes, Z.A.; Beyna, M.; Rosenzweig-Lipson, S.; Moss, S.J.; Brandon, N.J. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl. Psychiatry 2012, 2, e199. [Google Scholar] [CrossRef] [Green Version]
  140. Belzung, C. Innovative drugs to treat depression: Did animal models fail to be predictive or did clinical trials fail to detect effects? Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2014, 39, 1041–1051. [Google Scholar] [CrossRef] [Green Version]
  141. Przegalinski, E.; Tatarczynska, E.; Deren-Wesolek, A.; Chojnacka-Wojcik, E. Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology 1997, 36, 31–37. [Google Scholar] [CrossRef]
  142. Layer, R.T.; Popik, P.; Olds, T.; Skolnick, P. Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715). Pharmacol. Biochem. Behav. 1995, 52, 621–627. [Google Scholar] [CrossRef]
  143. Cryan, J.F.; Mombereau, C. In search of a depressed mouse: Utility of models for studying depression-related behavior in genetically modified mice. Mol. Psychiatry 2004, 9, 326–357. [Google Scholar] [CrossRef] [PubMed]
  144. Dwyer, J.M.; Duman, R.S. Activation of mammalian target of rapamycin and synaptogenesis: Role in the actions of rapid-acting antidepressants. Biol. Psychiatry 2013, 73, 1189–1198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Jimenez-Sanchez, L.; Campa, L.; Auberson, Y.P.; Adell, A. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2014, 39, 2673–2680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Fitzgerald, L.W.; Ortiz, J.; Hamedani, A.G.; Nestler, E.J. Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: Common adaptations among cross-sensitizing agents. J. Neurosci. 1996, 16, 274–282. [Google Scholar] [CrossRef]
  147. Bartanusz, V.; Aubry, J.M.; Pagliusi, S.; Jezova, D.; Baffi, J.; Kiss, J.Z. Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience 1995, 66, 247–252. [Google Scholar] [CrossRef]
  148. Moghaddam, B. Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: Comparison to hippocampus and basal ganglia. J. Neurochem. 1993, 60, 1650–1657. [Google Scholar] [CrossRef]
  149. Pacheco, A.; Aguayo, F.I.; Aliaga, E.; Muñoz, M.; García-Rojo, G.; Olave, F.A.; Parra-Fiedler, N.A.; García-Pérez, A.; Tejos-Bravo, M.; Rojas, P.S. Chronic stress triggers expression of immediate early genes and differentially affects the expression of AMPA and NMDA subunits in dorsal and ventral hippocampus of rats. Front. Mol. Neurosci. 2017, 10, 244. [Google Scholar] [CrossRef]
  150. Sathyanesan, M.; Haiar, J.M.; Watt, M.J.; Newton, S.S. Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice. Stress 2017, 20, 197–204. [Google Scholar] [CrossRef] [Green Version]
  151. Masrour, F.F.; Peeri, M.; Azarbayjani, M.A.; Hosseini, M.-J. Voluntary exercise during adolescence mitigated negative the effects of maternal separation stress on the depressive-like behaviors of adult male rats: Role of NMDA receptors. Neurochem. Res. 2018, 43, 1067–1074. [Google Scholar] [CrossRef]
  152. Weiland, N.; Orchinik, M.; Tanapat, P. Chronic corticosterone treatment induces parallel changes in N-methyl-D-aspartate receptor subunit messenger RNA levels and antagonist binding sites in the hippocampus. Neuroscience 1997, 78, 653–662. [Google Scholar] [CrossRef]
  153. Dong, B.E.; Chen, H.; Sakata, K. BDNF deficiency and enriched environment treatment affect neurotransmitter gene expression differently across ages. J. Neurochem. 2020. [Google Scholar] [CrossRef] [PubMed]
  154. He, Y.; Zeng, S.Y.; Zhou, S.W.; Qian, G.S.; Peng, K.; Mo, Z.X.; Zhou, J.Y. Effects of rhynchophylline on GluN1 and GluN2B expressions in primary cultured hippocampal neurons. Fitoterapia 2014, 98, 166–173. [Google Scholar] [CrossRef] [PubMed]
  155. Koike, H.; Chaki, S. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav. Brain Res. 2014, 271, 111–115. [Google Scholar] [CrossRef] [PubMed]
  156. Zhang, K.; Yamaki, V.N.; Wei, Z.; Zheng, Y.; Cai, X. Differential regulation of GluA1 expression by ketamine and memantine. Behav. Brain Res. 2017, 316, 152–159. [Google Scholar] [CrossRef] [PubMed]
  157. Duman, R.S.; Shinohara, R.; Fogaça, M.V.; Hare, B. Neurobiology of rapid-acting antidepressants: Convergent effects on GluA1-synaptic function. Mol. Psychiatry 2019, 24, 1816–1832. [Google Scholar] [CrossRef]
  158. Hashimoto, K. Role of the mTOR signaling pathway in the rapid antidepressant action of ketamine. Expert Rev. Neurother. 2011, 11, 33–36. [Google Scholar] [CrossRef]
  159. Yang, C.; Ren, Q.; Qu, Y.; Zhang, J.C.; Ma, M.; Dong, C.; Hashimoto, K. Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model. Biol. Psychiatry 2018, 83, 18–28. [Google Scholar] [CrossRef] [Green Version]
  160. Abe, N.; Borson, S.H.; Gambello, M.J.; Wang, F.; Cavalli, V. Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J. Biol. Chem. 2010, 285, 28034–28043. [Google Scholar] [CrossRef] [Green Version]
  161. Klann, E.; Antion, M.D.; Banko, J.L.; Hou, L. Synaptic plasticity and translation initiation. Learn. Mem. 2004, 11, 365–372. [Google Scholar] [CrossRef] [Green Version]
  162. Fukuyama, K.; Hasegawa, T.; Okada, M. Cystine/Glutamate Antiporter and Aripiprazole Compensate NMDA Antagonist-Induced Dysfunction of Thalamocortical L-Glutamatergic Transmission. Int. J. Mol. Sci. 2018, 19, 3645. [Google Scholar] [CrossRef] [Green Version]
  163. Li, Z.; Boules, M.; Williams, K.; Peris, J.; Richelson, E. The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. Brain Res. 2010, 1311, 28–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Amargos-Bosch, M.; Lopez-Gil, X.; Artigas, F.; Adell, A. Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine. Int. J. Neuropsychopharmacol. 2006, 9, 565–573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Ohoyama, K.; Yamamura, S.; Hamaguchi, T.; Nakagawa, M.; Motomura, E.; Shiroyama, T.; Tanii, H.; Okada, M. Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex. Eur. J. Pharmacol. 2011, 653, 47–57. [Google Scholar] [CrossRef] [PubMed]
  166. Fukuyama, K.; Kato, R.; Murata, M.; Shiroyama, T.; Okada, M. Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor. Biomolecules 2019, 9, 234. [Google Scholar] [CrossRef] [Green Version]
  167. Fukuyama, K.; Ueda, Y.; Okada, M. Effects of Carbamazepine, Lacosamide and Zonisamide on Gliotransmitter Release Associated with Activated Astroglial Hemichannels. Pharmaceuticals 2020, 13, 117. [Google Scholar] [CrossRef]
  168. Ji, M.H.; Zhang, L.; Mao, M.-J.; Zhang, H.; Yang, J.J.; Qiu, L.L. Overinhibition mediated by parvalbumin interneurons might contribute to depression-like behavior and working memory impairment induced by lipopolysaccharide challenge. Behav. Brain Res. 2020, 383, 112509. [Google Scholar] [CrossRef]
  169. Page, C.E.; Shepard, R.; Heslin, K.; Coutellier, L. Prefrontal parvalbumin cells are sensitive to stress and mediate anxiety-related behaviors in female mice. Sci. Rep. 2019, 9, 19772. [Google Scholar] [CrossRef] [Green Version]
  170. Shepard, R.; Page, C.E.; Coutellier, L. Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: Relevance for sex differences in stress-related disorders. Neuroscience 2016, 332, 1–12. [Google Scholar] [CrossRef]
  171. Fukuyama, K.; Fukuzawa, M.; Shiroyama, T.; Okada, M. Pathomechanism of nocturnal paroxysmal dystonia in autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant alpha4 subunit of nicotinic ACh receptor. Biomed. Pharm. 2020, 126, 110070. [Google Scholar] [CrossRef]
  172. Yamamura, S.; Abe, M.; Nakagawa, M.; Ochi, S.; Ueno, S.; Okada, M. Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions. Neuropharmacology 2011, 60, 550–560. [Google Scholar] [CrossRef]
  173. Gerhard, D.M.; Pothula, S.; Liu, R.J.; Wu, M.; Li, X.Y.; Girgenti, M.J.; Taylor, S.R.; Duman, C.H.; Delpire, E.; Picciotto, M.; et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J. Clin. Investig. 2020, 130, 1336–1349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Kumari, V.; Antonova, E.; Zachariah, E.; Galea, A.; Aasen, I.; Ettinger, U.; Mitterschiffthaler, M.T.; Sharma, T. Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans. Neuroimage 2005, 26, 1052–1058. [Google Scholar] [CrossRef] [PubMed]
  175. Hazlett, E.A.; Buchsbaum, M.S.; Zhang, J.; Newmark, R.E.; Glanton, C.F.; Zelmanova, Y.; Haznedar, M.M.; Chu, K.W.; Nenadic, I.; Kemether, E.M.; et al. Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating. Neuroimage 2008, 42, 1164–1177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Liebe, T.; Li, M.; Colic, L.; Munk, M.H.J.; Sweeney-Reed, C.M.; Woelfer, M.; Kretzschmar, M.A.; Steiner, J.; von During, F.; Behnisch, G.; et al. Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype—A placebo controlled fMRI study. Neuroimage Clin. 2018, 20, 715–723. [Google Scholar] [CrossRef]
  177. Sarkisyan, G.; Hedlund, P.B. The 5-HT7 receptor is involved in allocentric spatial memory information processing. Behav. Brain Res. 2009, 202, 26–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Okada, M.; Fukuyama, K.; Kawano, Y.; Shiroyama, T.; Suzuki, D.; Ueda, Y. Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex. Neuropharmacology 2019, 156, 107547. [Google Scholar] [CrossRef]
  179. Fukuyama, K.; Fukuzawa, M.; Shiroyama, T.; Okada, M. Pathogenesis and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant alpha4 subunit of nicotinic ACh receptor. Br. J. Pharm. 2020, 177, 2143–2162. [Google Scholar] [CrossRef]
  180. Pergola, G.; Danet, L.; Pitel, A.L.; Carlesimo, G.A.; Segobin, S.; Pariente, J.; Suchan, B.; Mitchell, A.S.; Barbeau, E.J. The Regulatory Role of the Human Mediodorsal Thalamus. Trends. Cogn. Sci. 2018, 22, 1011–1025. [Google Scholar] [CrossRef] [Green Version]
  181. Golden, E.C.; Graff-Radford, J.; Jones, D.T.; Benarroch, E.E. Mediodorsal nucleus and its multiple cognitive functions. Neurology 2016, 87, 2161–2168. [Google Scholar] [CrossRef]
  182. McCormick, D.; Wang, Z. Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. J. Physiol. 1991, 442, 235–255. [Google Scholar] [CrossRef]
  183. Porrino, L.; Crane, A.; Goldman-Rakic, P. Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys. J. Comp. Neurol. 1981, 198, 121–136. [Google Scholar] [CrossRef] [PubMed]
  184. Russchen, F.; Amaral, D.G.; Price, J. The afferent input to the magnocellular division of the mediodorsal thalamic nucleus in the monkey, Macaca fascicularis. J. Comp. Neurol. 1987, 256, 175–210. [Google Scholar] [CrossRef] [PubMed]
  185. Halassa, M.M.; Sherman, S.M. Thalamocortical Circuit Motifs: A General Framework. Neuron 2019, 103, 762–770. [Google Scholar] [CrossRef]
  186. Kuramoto, E.; Pan, S.; Furuta, T.; Tanaka, Y.R.; Iwai, H.; Yamanaka, A.; Ohno, S.; Kaneko, T.; Goto, T.; Hioki, H. Individual mediodorsal thalamic neurons project to multiple areas of the rat prefrontal cortex: A single neuron-tracing study using virus vectors. J. Comp. Neurol. 2017, 525, 166–185. [Google Scholar] [CrossRef] [PubMed]
  187. Fukuyama, K.; Fukuzawa, M.; Okubo, R.; Okada, M. Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant alpha4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy. Pharmaceuticals 2020, 13, 58. [Google Scholar] [CrossRef] [Green Version]
  188. Fukuyama, K.; Fukuzawa, M.; Okada, M. Upregulated and hyperactivated thalamic connexin 43 plays important roles in pathomechanisms of cognitive impairment and seizure of autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor. Pharmaceuticals 2020, 13, 99. [Google Scholar] [CrossRef]
  189. Furtak, S.C.; Wei, S.M.; Agster, K.L.; Burwell, R.D. Functional neuroanatomy of the parahippocampal region in the rat: The perirhinal and postrhinal cortices. Hippocampus 2007, 17, 709–722. [Google Scholar] [CrossRef]
  190. Okada, M.; Fukuyama, K.; Shiroyama, T.; Murata, M. A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43. Int. J. Mol. Sci. 2020, 21, 7019. [Google Scholar] [CrossRef]
  191. Fukuyama, K.; Okubo, R.; Murata, M.; Shiroyama, T.; Okada, M. Activation of Astroglial Connexin is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine. Cells 2020, 9, 414. [Google Scholar] [CrossRef] [Green Version]
  192. Baker, D.A.; Madayag, A.; Kristiansen, L.V.; Meador-Woodruff, J.H.; Haroutunian, V.; Raju, I. Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2008, 33, 1760–1772. [Google Scholar] [CrossRef] [Green Version]
  193. Zmudzka, E.; Salaciak, K.; Sapa, J.; Pytka, K. Serotonin receptors in depression and anxiety: Insights from animal studies. Life Sci. 2018, 210, 106–124. [Google Scholar] [CrossRef] [PubMed]
  194. Eriksson, T.M.; Golkar, A.; Ekstrom, J.C.; Svenningsson, P.; Ogren, S.O. 5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT(1A) receptor stimulation on contextual learning in mice. Eur. J. Pharmacol. 2008, 596, 107–110. [Google Scholar] [CrossRef] [PubMed]
  195. Barbas, H.; Zikopoulos, B.; Timbie, C. Sensory pathways and emotional context for action in primate prefrontal cortex. Biol. Psychiatry 2011, 69, 1133–1139. [Google Scholar] [CrossRef]
  196. Schuetze, M.; Park, M.T.; Cho, I.Y.; MacMaster, F.P.; Chakravarty, M.M.; Bray, S.L. Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder. Neuropsychopharmacol. Publ. Am. Coll. Neuropsychopharmacol. 2016, 41, 2627–2637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Karlsen, A.S.; Korbo, S.; Uylings, H.B.; Pakkenberg, B. A stereological study of the mediodorsal thalamic nucleus in Down syndrome. Neuroscience 2014, 279, 253–259. [Google Scholar] [CrossRef] [PubMed]
  198. Bonaventure, P.; Aluisio, L.; Shoblock, J.; Boggs, J.D.; Fraser, I.C.; Lord, B.; Lovenberg, T.W.; Galici, R. Pharmacological blockade of serotonin 5-HT(7) receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission. PLoS ONE 2011, 6, e20210. [Google Scholar] [CrossRef] [Green Version]
  199. Schmidt, S.; Furini, C.; Zinn, C.; Cavalcante, L.; Ferreira, F.; Behling, J.; Myskiw, J.; Izquierdo, I. Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus. Neurobiol. Learn. Mem. 2017, 142, 48–54. [Google Scholar] [CrossRef]
  200. Devoto, P.; Flore, G. On the origin of cortical dopamine: Is it a co-transmitter in noradrenergic neurons? Curr. Neuropharmacol. 2006, 4, 115–125. [Google Scholar] [CrossRef] [Green Version]
  201. Devoto, P.; Flore, G.; Saba, P.; Fa, M.; Gessa, G.L. Stimulation of the locus coeruleus elicits noradrenaline and dopamine release in the medial prefrontal and parietal cortex. J. Neurochem. 2005, 92, 368–374. [Google Scholar] [CrossRef]
Ijms 21 07951 g001 550
Figure 1. Schematic regulation mechanisms associated with NMDAR in neural circuits of dopaminergic (DA), serotonergic (5-HT), noradrenergic (NE) and glutamatergic (Glu) pathways to the frontal cortex (medial prefrontal cortex, insular cortex and orbitofrontal cortex). Dopaminergic (from ventral tegmental area: VTA), serotonergic (from dorsal raphe nucleus: DRN) and noradrenergic (from locus coeruleus: LC) neurones project their terminals to deeper layers of the frontal cortex, and receive regional GABAergic inhibition, which is regulated by stimulatory NMDAR. Contrary to the monoaminergic mesocortical pathway, glutamatergic neurones project terminal from the mediodorsal thalamic nucleus (MDTN) to superficial layers of the frontal cortex. Glutamatergic neurones in the MDTN receive intrathalamic GABAergic inhibition mainly from the reticular thalamic nucleus (RTN) and the MDTN, which are also regulated by NMDAR. Yellow, blue, deep green, red and brown arrows indicate the projection terminals of DA, 5-HT, LC, GABA and Glu, respectively. Light green arrow indicates the catecholaminergic co-releasing projection (NE plus DA).
Figure 1. Schematic regulation mechanisms associated with NMDAR in neural circuits of dopaminergic (DA), serotonergic (5-HT), noradrenergic (NE) and glutamatergic (Glu) pathways to the frontal cortex (medial prefrontal cortex, insular cortex and orbitofrontal cortex). Dopaminergic (from ventral tegmental area: VTA), serotonergic (from dorsal raphe nucleus: DRN) and noradrenergic (from locus coeruleus: LC) neurones project their terminals to deeper layers of the frontal cortex, and receive regional GABAergic inhibition, which is regulated by stimulatory NMDAR. Contrary to the monoaminergic mesocortical pathway, glutamatergic neurones project terminal from the mediodorsal thalamic nucleus (MDTN) to superficial layers of the frontal cortex. Glutamatergic neurones in the MDTN receive intrathalamic GABAergic inhibition mainly from the reticular thalamic nucleus (RTN) and the MDTN, which are also regulated by NMDAR. Yellow, blue, deep green, red and brown arrows indicate the projection terminals of DA, 5-HT, LC, GABA and Glu, respectively. Light green arrow indicates the catecholaminergic co-releasing projection (NE plus DA).
Ijms 21 07951 g001
Ijms 21 07951 g002 550
Figure 2. Proposed hypothesis for the extended complicated neural circuit connectivities involved in the thalamocortical cognitive glutamatergic pathway, from the MDTN to the frontal cortex; the mesothalamic serotonergic pathway, from the DRN to the MDTN; the mesothalamic noradrenergic pathway, from LC to the RTN; the mesocortical catecholaminergic pathway, from the LC to the frontal cortex; the mesocortical serotonergic pathway from the DRN to the frontal cortex. Generally, both noradrenergic and serotonergic neurones project selective terminals to deeper layers of the frontal cortex; however, some neurones in the LC project catecholaminergic co-releasing terminal (co-releasing norepinephrine with dopamine) to superficial layers of the frontal cortex. Glutamatergic projection from the MDTN presynaptically activates catecholaminergic co-releasing terminals via AMPAR in the superficial layers of the frontal cortex. Glutamatergic neurones in the MDTN receive excitatory serotonergic input from DRN via 5-HR7R and inhibitory GABAergic inhibition from RTN. GABAergic neurones are regulated by excitatory NMDAR and receive excitatory noradrenergic input from LC via α1 adrenoceptors.
Figure 2. Proposed hypothesis for the extended complicated neural circuit connectivities involved in the thalamocortical cognitive glutamatergic pathway, from the MDTN to the frontal cortex; the mesothalamic serotonergic pathway, from the DRN to the MDTN; the mesothalamic noradrenergic pathway, from LC to the RTN; the mesocortical catecholaminergic pathway, from the LC to the frontal cortex; the mesocortical serotonergic pathway from the DRN to the frontal cortex. Generally, both noradrenergic and serotonergic neurones project selective terminals to deeper layers of the frontal cortex; however, some neurones in the LC project catecholaminergic co-releasing terminal (co-releasing norepinephrine with dopamine) to superficial layers of the frontal cortex. Glutamatergic projection from the MDTN presynaptically activates catecholaminergic co-releasing terminals via AMPAR in the superficial layers of the frontal cortex. Glutamatergic neurones in the MDTN receive excitatory serotonergic input from DRN via 5-HR7R and inhibitory GABAergic inhibition from RTN. GABAergic neurones are regulated by excitatory NMDAR and receive excitatory noradrenergic input from LC via α1 adrenoceptors.
Ijms 21 07951 g002
Table
Table 1. Completed double-blind, placebo-controlled trials assessing ketamine and other putative N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists. The present study searched MEDLINE using the keywords “ketamine”, “depression” and “randomized controlled trial” until January 1st, 2020. Relevant articles were obtained in full and assessed for inclusion independently by reviewers. The disagreement among reviewers was resolved via discussion to reach consensus. The reports that indicated the responder ratios are shown in Table 1.
Table 1. Completed double-blind, placebo-controlled trials assessing ketamine and other putative N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists. The present study searched MEDLINE using the keywords “ketamine”, “depression” and “randomized controlled trial” until January 1st, 2020. Relevant articles were obtained in full and assessed for inclusion independently by reviewers. The disagreement among reviewers was resolved via discussion to reach consensus. The reports that indicated the responder ratios are shown in Table 1.
DrugRegimenDiagnosisPlacebo (N)Outcome Responder Ratio [Drug vs. Placebo]Reference
Ketamine
Double-blind 0.5 mg/kg (40 min) single ivMajor and bipolar depressionSaline (9)Reduced HDRS 240 min (initial) 72 h (sustain)[8]
Double-blind0.5 mg/kg (40 min) single ivMajor depressionPropofol/fentanyl (70)Reduced HDRS 24 h [71% vs. 0%][7]
Double-blind0.5 mg/kg (40 min) single ivTreatment-resistant depressionSaline (18)Reduced HDRS 110 min (initial) 7 days (sustain) [71% vs. 0%][7]
Double-blind (added on mood stabilizer)0.5 mg/kg (40 min) single iv (maintained Li or VPA)Treatment-resistant bipolar depressionSaline (18)Reduced MADRS 40 min (initial) 3 days (sustained) [71% vs. 6%][77]
Double-blind (added on mood stabilizer)0.5 mg/kg (40 min) single iv (maintained Li or VPA)Treatment-resistant bipolar depressionSaline (15)Reduced MADRS 40 min (initial) 3 days (sustained) [71% vs. 0%][78]
Double-blind0.5 mg/kg (40 min) single ivTreatment-resistant depressionMidazolam (73)Reduced MADRS 24 h (initial) 7 days (sustained) [64% vs. 28%][74,79]
Double-blind50 mg intranasal administrationMajor depressionSaline (20)Reduced MADRS 24 h (initial) 7 days (sustain)[80]
Double-blind (added on SSRI)0.5 mg/kg (40 min) single ivMajor depressionSaline (30)Reduced MADRS 2 h min (initial) [92% vs. 57%][81]
Double-blind0.5 mg/kg (40 min) 2~3 times iv over 15 daysTreatment-resistant depressionSaline (67)Reduced MADRS 7 days (initial) 15 days (sustain) [69% vs. 9%][5]
Double-blind0.2, 0.5 mg/kg (40 min) single ivTreatment-resistant depressionSaline (64)Reduced HDRS 40 min (initial) [25% vs. 0%][82]
Double-blind0.2, 0.5 mg/kg (40 min) single ivTreatment-resistant depressionSaline (95)Reduced HDRS 40 min (initial) 28 days (sustain) [46% vs. 13%][83]
Double-blind0.5 mg/kg (40 min) single ivTreatment-resistant bipolar depressionMidazolam (16)Reduced HDRS 24 h (initial) [89% vs. 0%][84]
Double-blind0.5 mg/kg (40 min) single ivTreatment-resistant depressionMidazolam (80)Reduced HDRS 24 h (initial) [30% vs. 15%][75]
Double-blind0.1, 0.2, 0.5, 1.0 mg/kg (40 min) single ivTreatment-resistant depressionMidazolam (99)Reduced HDRS 24 h (initial) 21 days (sustain) [57% vs. 33%][85]
Double-blind0.5 mg/kg (40 min) 6 times iv over 14 daysTreatment-resistant depressionMidazolam (41)Reduced MADRS 24 h (initial) 7 days (sustained) [59%][86]
Double-blind0.5 mg/kg (45 min) 6 times iv over 21 daysTreatment-resistant depressionSaline (26)Reduced HDRS 21 days (sustain) [25% vs. 33%][87]
Esketamine
Double-blind0.2 or 0.4 mg/kg single ivTreatment-resistant depressionSaline (29)Reduced MADRS 2 h (initial) 35 days (sustain) [64% vs. 0%][88]
Double-blind 28, 56, 84 mg intranasal administration Treatment-resistant depressionSimulated placebo of esketamine taste (denatonium benzoate) (126)Reduced MADRS 2 h (initial) 74 days (sustain) [50% vs. 10%][89]
Double-blind 84 mg intranasal administration Treatment-resistant depressionSimulated placebo of esketamine taste (66)Reduced MADRS 4 h (initial) 25 days (sustain)
[50% vs. 10%]		[90]
Double-blind (added on SSRI or SNRI)56, 84 mg intranasal administration Treatment-resistant depressionSimulated placebo of esketamine taste (197)Reduced MADRS 24 h (initial) 74 days (sustain) [69.3% vs. 52%][91]
Double-blind (added on SSRI or SNRI)56, 84 mg intranasal administration (twice a week for 4 weeks)Treatment-resistant depressionSimulated placebo of esketamine taste (346)Reduced MADRS 24 h (initial) 28 days (sustain) [53.1% vs. 38.9%][92]
Double-blind Esketamine (0.25 mg/kg, 40 min, single iv)Treatment-resistant depressionKetamine (0.5 mg/kg, 40 min, single iv) (63)Reduced MADRS 24 h (initial)7 days [43.7% vs. 62.1%][93]
Double-blind (added on SSRI or SNRI)28, 56, 84 mg intranasal administration (twice a week for 4 weeks)Treatment-resistant depression (>65 years old) Simulated placebo of esketamine taste (denatonium benzoate) (137)Reduced MADRS 28 days (sustain) [27.0% vs. 13.3%][94]
CP-101,606
Double-blind (added on paroxetine)0.75 mg/kg CP-101,606 (90 min) 2 times iv for 6.5 hParoxetine-resistant major depressionSaline (30)Reduced HDRS 2 days (initial) 8 days (sustain) [60% vs. 20%] [95]
MK-0657
Double-blind4 mg/day (po) increased 4, 8, 12 mg/day until 12 daysTreatment-resistant depressionSaline (5)Reduced HDRS 5 days (initial) 12 days (sustain)[96]
Table
Table 2. Behavioural study assessing ketamine and other agents.
Table 2. Behavioural study assessing ketamine and other agents.
ModelAgentEffectReference
Schizophrenia
locomotor activity
stereotypical behaviour		MK801
Phencyclidine		hyperlocomotion[109]
[110,111,112]
prepulse inhibition (PPI)MK801 Phencyclidinedisruptions[117,118]
Depression
learned helplessnessKetaminerapid acting antidepressant effect[4,124]
forced swimmingKetamine
MK801
Ro25-6981
CPP
Imipramine
fluoxetine
NBQX

rapid acting antidepressant effect
rapid acting antidepressant effect rapid acting antidepressant effect
rapid acting antidepressant effect
no antidepressant effects
no antidepressant effects
no antidepressant effects
(supress antidepressant effects of
ketamine, MK801 and Ro25-6981)
[4,124,125]
[4,124,126]
[124]
[4,125]
[4]
[4]
[124]

sucrose consumption (anhedonia test) (after chronic mild stress)Ketamineno antidepressant effects antidepressant/antianhedonic effect antidepressant effect[4]
[127]
[4,127]
novelty-suppressed feeding (after chronic mild stress)Ketamineno antidepressant effects antidepressant effect[4]
[4]
fear conditioningketamineNo effect[4]
passive avoidance testsketaminenot impair fear memory retention.[124]
maternal deprivationketamineantidepressant effect[128,129,130]
TrkB knockout forced swimming novelty-suppressed feedingKetamine, MK801 ketamineno antidepressant effects no antidepressant effects[4]
[4]
BDNF knockout Forced swimming Ketamine MK801no antidepressant effects no antidepressant effects[125]
[4]
Arketamine/EsketamineArketamineEsketamine
learned helplessnessrapid acting antidepressant effectno antidepressant effect[131]
forced swimmingrapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]
tail suspension rapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]
social defeat stressrapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[131]
repeated corticosteronerapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Okada, M.; Kawano, Y.; Fukuyama, K.; Motomura, E.; Shiroyama, T. Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions. Int. J. Mol. Sci. 2020, 21, 7951. https://doi.org/10.3390/ijms21217951

AMA Style

Okada M, Kawano Y, Fukuyama K, Motomura E, Shiroyama T. Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions. International Journal of Molecular Sciences. 2020; 21(21):7951. https://doi.org/10.3390/ijms21217951

Chicago/Turabian Style

Okada, Motohiro, Yasuhiro Kawano, Kouji Fukuyama, Eishi Motomura, and Takashi Shiroyama. 2020. "Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions" International Journal of Molecular Sciences 21, no. 21: 7951. https://doi.org/10.3390/ijms21217951

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop