Non-Anaesthetic Use of Ketamine

## **Chapter 9**

## Perspective Chapter: NMDA Treatments for CNS Disorders

*Chih-Hung Lin, Po-Chang Shih and Guochuan Emil Tsai*

### **Abstract**

The N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, mediates various physiological functions, such as synaptic plasticity, learning, and memory. Any homeostatic dysregulation of NMDAR may cause central nervous system (CNS) disorders, such as Alzheimer's disease, depression, and schizophrenia. The involvement of NMDA dysfunction promotes advanced research on developing NMDAR pharmaceutics for treating CNS disorders. NMDAR enhancers, by direct or indirect potentiating NMDAR functions, have been used to recover NMDAR functions for treating schizophrenia. Interestingly, NMDAR blockers, by direct or indirect inhibiting NMDAR functions, have also been utilized for CNS disorders, such as Alzheimer's disease and depression. In this chapter, the current strategy of NMDAR modulation for CNS disorders are elaborated on to discern underlying neurophysiological mechanisms of how homeostatic regulation of NMDAR plays a vital role in the normal and pathological states, respectively.

**Keywords:** NMDAR, CNS pathology, agonism, antagonism, homeostasis

#### **1. Introduction**

Glutamatergic signaling plays a critical role in the CNS function under physiological and pathophysiological states via two major types of receptor: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) [1]. mGluRs consist of three subgroups (Group I-III), while iGluRs comprise four subgroups (AMPARs, KARs, Gluδs, and NMDARs). Among all GluRs, NMDARs play a crucial role in brain development, mediating the physiological functions, such as synaptic plasticity, learning, and memory. NMDARs are voltage-dependent glutamate- or aspartate-gated cation channels with two prerequisites for channel opening: 1) depolarization-induced unblockage of magnesium ions; 2). concomitant binding of glutamate (or aspartate) and glycine (or D-serine). When the NMDARs are either aberrantly enhanced or encumbered opening, various CNS symptoms/ disorders may develop, such as depression, psychosis, and cognitive impairment.

CNS disorders still loom over many people's health with limited effective treatment. The role of NMDARs playing in CNS disorders has been gaining attention owing to the finding of ketamine as an antidepressant [2]. This new therapeutic mechanism promotes NMDARs as an emerging therapeutic target. Ketamine, a NMDAR antagonist, exerts rapid and robust antidepressant effects in depressed patients [3]. On the contrary, a NMDAR agonist, D-serine, could alleviate schizophrenic and depressive symptoms in the clinical trial [4]. These contrary

modulations on NMDAR further support the importance of NMDAR homeostasis leveraged by NMDAR modulators [5].

NMDAR modulators, with positive or negative modulation, have been designed to alleviate various symptoms of CNS through distinct mechanisms. Positive NMDAR modulators elevate NMDARs via direct and indirect approaches. Direct NMDAR enhancers fit into the glutamate site or glycine site of NMDARs, or they bind the allosteric pockets of the glutamate/glycine sites. In contrast to direct enhancement, several NMDAR enhancers improve NMDAR functions by modulating indirect pathways, for example, by inhibiting glycine transporter or D-amino acid oxidase (DAAO). Negative NMDAR modulators, on the contrary, work as competitive antagonists to directly occupy the glycine site, or bind an allosteric site (known as non-competitive antagonists), or block NMDAR channel pore (known as uncompetitive antagonists) [6]. All above modulators have shown potential for clinical use in CNS disorders but without one-size-fits-all approach.

## **2. CNS disorders alleviated by NMDAR modulators**

#### **2.1 Neurological disorders**

The excitatory neurotransmission of mammalian CNS is largely dictated through glutamate and its receptors, particularly NMDAR. Because its critical roles in mediating synaptic plasticity related to learning and memory formation, the dysfunction of the NMDAR-based signaling is implicated in the neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), as described below.

#### *2.1.1 Alzheimer's disease*

AD is the most common cause of dementia to induce not only cognitive impairments in memory and thought, but also behavioral and psychiatric symptoms [7]. Current understanding to AD relies on two main histopathological abnormalities: (1) amyloid plaques composed of amyloid ß (Aß) peptides cleaved from amyloid precursor proteins in the brain tissue, and (2) the formation of intraneuronal neurofibrillary tangles due to phosphorylated and aggregated tau proteins. Although Aß and tau serve as the most discussed mechanisms through which cause AD, no effective treatment was developed successfully. Coincidently, the neurotransmitter systems, including cholinergic, adrenergic and glutamatergic pathways are considered critical in AD progression and development [8]. In this chapter, we focus on the discussion of how NMDAR involves in AD.

NMDAR is the major regulator associated with long-term synaptic plasticity. Studies have reported that AD brains contain neurotoxins consisted of soluble Aß oligomers. The binding of Aß 42 oligomers to forebrain synaptosomes is associated with post-synaptic density complexes containing NMDAR subunits NR1 and NR2B [9]. Consistently, Aß oligomers were found to ablate long-term potentiation in hippocampal brain slices and the cortices of AD brains via overactivating extrasynaptic NMDAR containing NR2B [10]. The over-activation of extrasynaptic NMDAR linked to neurodegeneration in AD has also been supported by the pharmacotherapeutic use of NMDAR inhibitor memantine [11].

Indirect modulation of NMDAR via glutamate release or glycine transporter-1 (GlyT1) are considered feasible for AD. An escalated stimulation via glutamatergic signaling causes glutamate excitotoxicity that results in damaged nerve cells, and such neuronal toxicity is coined "excitotoxicity". In AD, glutamate uptake and

#### *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

recycling systems are severely impaired [12], which therefore increases glutamate availability, resulting in excessive NMDAR stimulation. Additionally, Aß peptides may increase glutamate availability by weakening glutamate uptake and recycling systems [13] that may contribute to AD pathology. On the other hand, at glutamatergic synapses, glycine is transported by GlyT1, a Na+ /Cl− -dependent carrier protein playing a major role in maintaining glycine concentration below saturation at postsynaptic NMDAR, sculpturing GlyT1 as an intriguing target for NMDAR modulation.

Overall, direct and indirect NMDAR inhibition strategies through the discussed mechanisms to attenuate the overactivation of NMDA function have shown rationale for developing medicine for late-stage AD to attenuate the neuronal death.

#### *2.1.2 Parkinson's disease*

PD, the second most common neurodegenerative disease, is a progressive disorder with symptoms of onset gradually, motor disturbances and cognitive impairment. Due to the rapidly aging population worldwide, PD also receives increasing attention from communities [14]. The pathophysiology of PD is due to the degeneration of pigmented dopaminergic neurons, resulting in functional changes to the circuitry of basal ganglia nuclei. Accordingly, levo-dopa, a precursor of dopamine, and dopamine receptor agonists have been serving as the standard treatments for PD. However, long-term use of these standard therapies contribute to the loss of efficacy and development of disfiguring motor complications [15]. Novel PD treatments based on different mechanism is long awaited.

Regulating glutamatergic receptors, particularly NMDAR, has been found to be altered in the basal ganglia of PD where NMDAR is widely expressed. Specifically, NR2B-containing NMDARs may significantly influence the PD pathology while NR2B was found to be substantially distributed in the striatum and other basal ganglia areas. An increasing body of literature has reported that not only experimental PD models but also PD patients present substantially elevated NMDA-sensitive glutamate binding in the striatum [16]. In levo-dopa-treated rodent and primate, GluN2A and the ratio of GluN2A/GluN2B are increased. The findings are also reported in PD patients [17], suggesting that attenuated NMDAR activity may help halt the progression of PD.

Alternately, reshaping synaptic connections for PD patients via brief activation of NMDAR can increase axonal growth rate and axonal branching. The brief NMDAR activation can be achieved through inhibiting GlyT1 to increase levels of extracellular glycine [18]. In addition, activating NMDAR via weak NMDAR glycine binding agonists can also achieve similar effects. This hypothesis remains to be investigated.

#### *2.1.3 Huntington's disease*

HD is a progressive CNS disorder due to a single defective gene on chromosome 4 that encodes the protein huntingtin. The defect is hereditary and will eventually develop symptoms in lifetime. At the beginning of symptom onset, patients often have subtle abnormalities in mood, usually followed by a lack of coordination and unsteady gaits [19].

Since the altered function of huntingtin induces neuronal cell death, research focuses on mechanisms towards regulation of such cell death. It has been revealed that the formation of the nuclear protein aggregates, oxidative stress, and mitochondrial dysfunction are associated with neuronal cell death in HD [20]. NMDARs have also been found to regulate neuronal cell death of HD, and by modulating

NMDAR activity, psychotic symptoms of HD due to low NMDA function can be alleviated simultaneously. In this chapter, we focus on the discussion of NMDAR in HD.

Animal studies have shown that neuroexcitatory agonists kainic or quinolinic acids can induce lesions similar to those in HD, indicating that excitotoxicity from NMDAR over-activation could contribute to the progression of the disease [21]. Post-synaptic density protein 95 (PSD-95), a scaffolding protein, can bind huntingtin and the NR2 subunit of NMDAR. At the molecular level in HD, the presence of abnormal huntingtin protein causes the interruption of PSD-95 binding onto NMDAR. The unbinding of PSD-95 results in excitotoxicity and neuronal cell death consistent with HD [20]. Therefore, among the known mechanisms inducing HD progression, NMDAR remains a primary target to develop therapeutic intervention.

#### **2.2 Psychiatric disorders**

Existing high concentration of post-synaptic NMDAR in limbic structures [22] highlights the homeostasis of NMDAR activity as be of uttermost significance in behavioral regulation of the brain. The dysfunction of NMDAR can cause a variety of psychiatric disorders such as depression, schizophrenia, bipolar disorder (BD), and anxiety disorder [23].

#### *2.2.1 Depression*

Depression is a chronic mental disorder characterized by persistent low mood, loss of interest/pleasure, lack of appetite, sleep disturbance, low energy, and poor concentration. Depression can affect people irrespective of age, ethnicity, and gender. Major depressive disorder (MDD) is the most studied type of depression characterized by one or more major depressive events, that is, the presence of low mood and/or loss of interest for at least 14 days in company with depression symptoms. MDD leads to suicide that takes 2160 self-harm deaths per day in US [24]. Decades of research on depression have yielded several mechanisms that may explain its pathophysiology, including biogenic amine (e.g., monoamine) hypothesis, abnormal endocrine factors, genetic and environmental factors, neurogenesis, and the dysregulation of second messenger systems, which have been extensively reviewed elsewhere [25]. Among them, monoamine-based mechanisms were the most studied with successful development of antidepressants.

Although monoamine treatments are available for MDD, they have not been optimal. Currently, standard monoamine antidepressants require one month or more to exert antidepressant effects [26]. Such time lag has put MDD patients at risk of suicide and other self-harm acts. In recent decades, the NMDAR has emerged as a central player in MDD research, resulting in a paradigm shift from the monoamine-based to the NMDAR-based hypothesis. The NMDAR-based hypothesis of depression originated from early findings in the 1990's that NMDAR antagonists exerted quick antidepressant-like action [27]. Subsequently, many studies have reported abnormal glutamate levels in frontal and occipital cortices in MDD; however, these findings infer the complex role of NMDAR in the brain of MDD patients. The regionally decreased glutamate level in the brain demonstrates an association with the pathophysiology of MDD [28]; on the contrary, the elevated glutamate levels occurs in medication-free MDD patients during an active depressive episode, in remission, and in young people [29]. Since glutamate is a major excitatory neurotransmitter dictating the neural plasticity and process of learning and memory, the alteration to NMDAR causes region-specific maladaptive neurocircuitry in depression and decreases in cognitive controls over negative emotion.

#### *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

At the molecular level, postmortem brain analyses from MDD patients show alterations in the NMDAR subunit profile, such as reduced GluN2A and GluN2B subunits in locus coeruleus, and decreased GluN1 and GluN2A expression levels but no changes to those of GluN2B, GluN2C and GluN2D subunits in dorsolateral prefrontal cortex of MDD subjects [30]. Further studies have found that biologically, the activation of NMDAR requires both the binding of glycine and glutamate onto their binding sites, and therefore, modulating the release of the two amino acids into synapses are considered feasible. At glutamatergic synapses, glycine is transported by GlyT1, maintaining glycine concentration below saturation at postsynaptic NMDAR. Accordingly, GlyT1 has become an intriguing target for NMDAR activity modulation [31]. Alternatively, inhibiting glutamate levels at synapses renders reduced glutamate binding to NMDAR [32]. In summary, the above findings provide a solid basis for developing chemotherapeutics for treating MDD via modulating NMDA.

#### *2.2.2 Schizophrenia*

Schizophrenia is a psychotic illness presenting symptoms with processing thoughts and contents, and develops positive, negative and/or cognitive symptoms. Concurrently, depression and suicidal thoughts and attempts happen often in people suffering from schizophrenia. Because schizophrenia patients require lifelong treatment, early intervention may improve the long-term outlook. Conventional therapies for schizophrenia are developed based on a dopamine hypothesis which has been prevailing to explain symptoms associated with the positive symptoms. However, these treatments have not been optimal and often induce substantial adverse side effects [33].

Glutamate hypofunction hypothesis of schizophrenia has been supported by several lines of studies. Low level of glutamate in cerebrospinal fluid was reported in patients with schizophrenia [34]. The worsening of schizophrenic symptoms was observed in patients treated with NMDAR inhibitors such as ketamine. Healthy people administered with similar inhibitors were reported to develop symptoms of schizophrenia [35]. Building on these data, upregulating NMDA function serves as a promising target for treating schizophrenia [36].

Although NMDAR is a focus for antipsychotic drug development for schizophrenia, direct activation of the NMDAR via targeting the glutamate site is reported to cause excitotoxicity. The finding suggests the demand for targeting the glycine site as an alternative, but direct approach. To reduce glycine site vacancy, a number of studies have synthesized amino-acid derivatives to occupy it [37]. Alternatively, enhancing the glycine levels through GlyT1 inhibition has also shown promise, which is used as an adjunct to conventional therapies [38].

#### *2.2.3 Bipolar disorder*

BD, as its name suggested, causes extremes of mood fluctuations that a person will be either in emotional highs (mania or hypomania) or lows (depression). BD is a lifelong disease that episodes of mood swings may occur infrequently or several times in a year. Typically, BD patients spend more time in depressive mood than mania or hypomania. Currently, treatments for BD are limited to symptom reduction and prevention of the occurrence of mood episodes [39].

Neuroimaging [40] and genetic findings [41] have revealed that glutamatergic abnormality is associated with the pathophysiology of BD, indicating NMDAR may play a role in the disease. The use of NMDAR inhibitor further evidences the role of NMDAR in the regulation of BD. Ketamine has shown to improve depressive

symptom. One of possible mechanisms of ketamine in regulating BD symptoms is to increase presynaptic levels of glutamate which in turn binds to AMPAR instead of NMDAR. The increased ratio of AMPAR-to-NMDAR neurotransmission is implicated to induce the antidepressant effects of ketamine [42].

At the molecular level, postmortem findings suggest that BD is associated with a reduced expression of NR1 subunit in the prefrontal cortex [30]. The genetic polymorphisms in the 3'UTR region of GRIN2B gene that encodes for the NR2B subunit has been found to play a role in BD etiology, although its expression level is not significantly different from the control [43]. Together, these studies suggest NMDAR is associated with BD.

#### *2.2.4 Anxiety disorder*

Having occasional anxiety is a normal part of life. However, intense, excessive, and persistent worries and fear about specific situation would be in the category of anxiety disorder that needs intervention. Types of anxiety disorders include panic attack, generalized anxiety disorder, and separation anxiety disorder. An anxiety patient may experience one or more of them and can experience anxiety at very young age [44].

Benzodiazepine and selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended as first line drug treatment, because of their more favorable profile than tricyclic antidepressants and monoamine oxidase inhibitors. Nevertheless, some SNRIs are also antagonists of metabolic enzyme cytochrome P450, therefore causing drug–drug interactions [45]. In addition, discontinuation of SSRIs or SNRIs may experience withdrawal reactions [46]. These unwanted outcomes suggest an essential for developing next generation anxiolytic treatments based on novel mechanisms.

Fear often occurs together and share similar stress responses with anxiety, and therefore, both are often put into the same context when discussing the underlying mechanisms. Currently, studies have found that the neuronal modulatory systems in brain areas contributing to fear and anxiety share a high degree of overlap [47]. In particular, regulating extinction learning of fear through NMDAR within amygdala, medial prefrontal cortex, and hippocampus is considered critical among the neuronal modulatory systems [48]. Hippocampus and amygdala of the medial temporal lobe situate at the interface between cognition and emotion, which is believed to be potential sites where NMDAR inhibitors exert anxiolytic effects [49]. NMDAR regulates emotionality and cognition, and its antagonists have shown promising effects on them. In contrast to NMDAR antagonism, partial activation of NMDAR facilitates fear extinction in rodents. In clinical setting, partial agonists used as an adjuvant increase psychotherapeutic effects in patients suffering fear-related disorders [50]. These finding suggest that a balanced modulation of NMDAR activity can bring benefits for the patients with anxiety disorder.

#### **3. NMDAR modulators for CNS disorders**

#### **3.1 Positive NMDAR modulators**

In this section, positive NMDAR modulators for CNS disorders will be discussed (**Figures 1** and **2**, **Table 1**). To enhance NMDAR function, two approaches could achieve: direct or indirect modulation. For direct modulation, three types of enhancers are categorized according to their binding sites: glutamate site, glycine site, and allosteric site of NMDAR.

*Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

**Figure 1.**

*Scheme of direct agonism/antagonism via various binding sites of NMDAR. NAM, negative allosteric modulators; PAM, positive allosteric modulators.*

#### **Figure 2.**

*Indirect NMDAR agonism/antagonism through activation or inhibition on diverse channels or transporters or enzymes. ASCT-1, alanine/serine/cysteine transporter-1; DAAO, D-amino acid oxidase; EAAT2, excitatory amino acid transporter-2; GlyT1, glycine transporter-1; NMDAR, N-methyl-D-aspartate receptor; SNAT2, sodium-coupled neutral amino-acid transporter-2; VGSC, voltage-gated sodium channel.*

#### *3.1.1 Direct NMDAR enhancers*

#### *3.1.1.1 NMDAR glutamate site agonists*

Cognitive deficits occur often in elderly MDD patients, hardly to be relieved with the existing treatment. NMDA enhancement via the glutamate site has been proved to enhance cognitive functions in previous studies [81]. NMDA enhancer (NMDAE), binding the NMDAR glutamate site as an agonist, has been offered for the elderly (>55 years) and adults (18–55 years) with MDD. To testify the efficacy, safety, and the cognitive improvement of NMDAE in those patients, the NMDAE



*AD, Alzheimer's disease; BD, bipolar disorder; GlyT1, Glycine transporter-1; HD, Huntington's disease; MDD, major depressive disorder; NAM, negative allosteric modulators; PAM, positive allosteric modulators; PD, Parkinson's disease; SNAT2, sodium-coupled neutral amino-acid transporter-2.*

#### **Table 1.**

*NMDAR modulators for CNS disorders [6, 51, 52].*

treatment results were compared with sertraline (SSRI) and placebo. The results of those clinical studies are not disclosed as of August 2021 (NCT03414931 and NCT04637620). The potential risk of this approach is the excitotoxicity caused by overactivation through the glutamate-binding site.

#### *3.1.1.2 NMDAR glycine site agonists*

Another ligand binding site on NMDAR is the glycine site, which can also be targeted to modulate the NMDAR activation for the treatments of psychiatric disorders [82]. Glycine, acting as an agonist via binding the glycine site, can ameliorate negative symptoms in schizophrenia patients [53]. This preliminary finding encourages the development of other endogenous co-agonists, such as D-alanine. D-alanine, working as an add-on antipsychotic medication, improved schizophrenic symptoms without significant side effects, which further supports that the pathophysiology

of schizophrenia is due to the hypofunction of NMDA neurotransmission [54]. D-serine, an NMDAR co-agonist without psychotomimetic effects, emerges as a novel glutamatergic antidepressant as an adjuvant therapy in MDD patients (NCT04721249). On the other hand, the therapeutic effects of D-serine at low dose (30 mg/kg/d) in schizophrenic patients are inconsistent. Some clinical studies showed significant improvement in positive, negative, and cognitive symptoms [83], whereas others presented no significant improvement [84]. Interestingly, high doses of D-serine (≥60 mg/kg/d) could possess consistent significant improvement in negative symptoms, strongly suggesting a therapeutic dose–response of D-serine for the treatment of schizophrenia (NCT00322023).

D-cycloserine (DCS), a partial agonist of NMDAR with agonism at low doses but antagonism at high doses depending on the intrinsic tone of NMDA function [85], exhibits controversial therapeutic effects on CNS disorders. In some AD studies, a dose as high as 100 mg/d could improve the cognitive symptoms, while a low dose of 15 mg/d could improve memory deficits [55, 86]. However, other studies presented no cognitive improvement from low (10 mg/d) to high dose (500 mg/d) in AD patients [87].

When the high dose of DCS (≥ 500 mg/d) was employed in MDD patients, depressive symptoms could be improved (NCT00408031) [88]. These observations implied that NMDAR antagonism might be a potential target for the development of novel antidepressant. The clinical studies of DCS at a dose of 50 mg/d is argumentative, some claimed to possess significant clinical improvement [89], while the others found no clinical improvement [90]. In the dose finding phase, the dose of 100 mg/d of DCS seemed to be more effective than 50 or 250 mg/d in improving schizophrenic symptoms [56]. In combination with ketamine, DCS could ameliorate depression symptoms in BD (NCT01833897). Cognitive behavioral therapy with DCS also reduced social anxiety (NCT00515879) and PTSD [91]. Overall, the dose selection of DCS determines its agonistic vs. antagonistic effects on NMDAR, hence modulating its therapeutic efficacy for a variety of CNS disorders.

#### *3.1.1.3 NMDAR allosteric site enhancers (positive allosteric modulators (PAM))*

Rapastinel (GLYX-13/BV-102), an amidated tetrapeptide acting as a NMDA allosteric glycine site partial agonist, is administered intravenously to treat MDD in clinical trial (NCT01684163). Rapastinel infusion achieved antidepressant effects without psychotomimetic properties and serious adverse events, therefore acquiring FDA Fast-Track and Breakthrough Therapy designations for adjunctive treatment of MDD. However, rapastinel failed to meet primary and key secondary endpoints in three acute studies (RAP-MD-01, −02, −03 by Allergan).

Apimostinel (NRX-1074), a chemical structure like rapastinel with an additional benzyl group, is administered intravenously and orally under the studies of efficacy and safety evaluation for MDD patients and healthy individuals (NCT02067793 and NCT02366364). Benefiting from its molecular weight and orally stability, apimostinel is 100-fold more potent than rapastinel and is also well tolerated without psychotomimetic symptoms [92]. The findings of the studies are not available yet.

#### *3.1.2 Indirect NMDAR enhancers*

To enhance NMDAR function, "consolidating" amino acids (e.g., glycine or D-serine, glutamate, and aspartate) in the synaptic cleft could achieve that goal. With the use of inhibitors of amino acid transporters or degrading enzymes, the concentration of those specific amino acids could sustain in the synaptic cleft to boost NMDAR function [58]. Clozapine, a modest inhibitor of sodium-coupled neutral amino acid

#### *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

transporter-2 (SNAT2), indirectly activates NMDAR via augmenting synaptic glycine levels. Clozapine could also improve symptoms of psychosis, tremor, and dyskinesias in PD patients (NCT00004826) [58]. In addition to reducing the risk of hospital re-admission for MDD patients, clozapine administration also demonstrated higher efficacy than quetiapine by ameliorating depressive symptoms [57]. As approved by Food and Drug Administration (FDA) of the USA, clozapine is utilized to treat treatment-resistant schizophrenia and symptoms of self-harm in patients with schizophrenia. Clozapine is also more effective than other antipsychotics in improving treatment-resistant bipolar disorder [59]. However, clozapine can cause potentially lethal agranulocytosis.

Other than SNAT2 inhibitor, GlyT1 inhibitor could also increase synaptic glycine level by blocking the GlyT1 to enhance NMDAR function. BI 425809, a selective GlyT1 inhibitor, emerges as a potential treatment of cognitive impairment of AD and schizophrenia. Although BI 425809 failed to improve cognition in AD study (NCT02788513), it improved cognition in patients with schizophrenia (NCT02832037). Bitopertin (RO-4917838), a selective and potent GlyT1 inhibitor, modulates both glutamatergic and dopaminergic neurotransmission in animal models of schizophrenia [93]. In six active treatment arms across three clinical studies, only one of them proved improvement in symptoms of schizophrenia (NCT01235585) [94]. However, the magnitude of improvement was small. Because of its strong antagonism, bitopertin induces NMDAR internalization, counterproductive to improve the NMDA function.

Sarcosine, a potent endogenous non-selective GlyT1 inhibitor, was applied in cognitive- and mood-related clinical studies. In PD patients, sarcosine improved depression and neuropsychiatric symptoms, especially in patients with mild–moderate severity (NCT01785628). Both in animal models and in depressed patients, sarcosine improved depression-like behaviors, further strengthening GlyT1 inhibitor as a novel class of promising antidepressant (NCT00977353) [31]. In most clinical studies of sarcosine in patents with schizophrenia, improvement in schizophrenic symptoms were reported [60]. However, when being adjunctive with clozapine, sarcosine could not produce improvement in schizophrenic patients [95]. This phenomenon may be explained by the "ceiling effect": additional NMDAR activation may not be induced due to maximal NMDAR enhancement achieved by clozapine administration alone. In contrast, the combination therapy of sarcosine and sodium benzoate (a D-amino acid oxidase (DAAO) inhibitor) enhances the cognitive function of patients with schizophrenia [96].

DAAO, a flavoenzyme for D-amino acids (e.g., D-serine and D-alanine) degradation, could be strategically inhibited to increase endogenous D-serine levels at the synaptic cleft, resulting in strengthening NMDAR functions. In post-mortem studies, patients with schizophrenia possessed higher expression and activity of DAAO in the cortex and cerebellum [97]. Thus, DAAO inhibition provides a good rationale to be a novel therapeutic target for schizophrenia treatment. Sodium benzoate, a prototype competitive DAAO inhibitor, generated antipsychotic effects in the phencyclidine-induced model of schizophrenia [98]. In some clinical studies, sodium benzoate adjunctive therapy improved symptomatology of patients with schizophrenia [99], and a larger scale clinical trial is undergoing (NCT01908192). In patients with early-phase AD, sodium benzoate predominantly enhanced cognitive and universal functions [61]. Sodium benzoate may enlarge gray matter via synaptogenesis and neurogenesis in MDD treatment [62].

#### **3.2 Negative NMDAR modulators**

NMDAR antagonism has been a therapeutic strategy for a variety of CNS disorders [100]. To achieve NMDAR antagonism, several negative NMDAR modulators

have been offered to treat patients with CNS disorders through distinct underlying mechanisms: direct blocking in competitive, non-competitive, and uncompetitive ways, and indirect blocking. All negative NMDAR modulators are introduced in this section (**Figures 1** and **2**, **Table 1**).

### *3.2.1 Direct NMDAR blockers*

#### *3.2.1.1 Competitive NMDAR glycine site antagonists*

AV-101 (L-4-chlorokynurenine), a pro-drug of 7-Chlorokynurenic acid (7-CKA), is able to cross the blood–brain barrier and transform to 7-CKA in astrocytes [101]. 7-CKA is a potent and selective NMDAR glycine site antagonist [102]. In preclinical studies, AV-101 demonstrated dose-dependent antidepressant-like effects in animal models [103]. However, AV-101 monotherapy failed to produce the anti-depressant effects in the clinical study (NCT02484456) [104]. On the other hand, AV-101 treatment for patients with PD will be conducted (NCT04147949).

### *3.2.1.2 Non-competitive NMDAR antagonists (negative allosteric modulators (NAM))*

Dimebon (Latrepirdine), an NAM at the polyamine-binding site of NMDARs, was originally used as an antihistamine [51]. Assessed in clinical trials, dimebon significantly improved the neuropsychiatric symptoms of patients with mildto-moderate AD (NCT00377715) [105]. In patients with HD, short-term administration of dimebon is beneficial for cognitive improvement (NCT00497159) [106]. Dextromethadone (D-methadone/REL-1017), a non-competitive NMDAR antagonist, provided antidepressant activity via mTORC1-mediated synaptic plasticity in the mPFC in animal models [107]. As dextromethadone performs as a rapid-acting treatment for depression in clinical studies (NCT03051256), it gained FDA Fast-Track designation as an adjunctive treatment for MDD. A phase III clinical trial of dextromethadone is currently ongoing (NCT04688164). Rislenemdaz (CERC-301/MK-0657), a NMDAR NR2B-selective antagonist, induced antidepressant properties in patients with treatment-resistant MDD [108]. Nevertheless, in a phase II study, no obvious antidepressant effects were produced by rislenemdaz (NCT01941043).

#### *3.2.1.3 Uncompetitive NMDAR antagonists (NMDAR channel blockers)*

Amantadine, a low-affinity uncompetitive NMDAR antagonist with rapid blocking channel kinetics, could ameliorate several clinical symptoms in PD, and the long-term efficacy of chronic treatment with amantadine might improve apathy and fatigue in PD patients (NCT00632762) [109]. For Huntington chorea, amantadine treatment delivered no beneficial effects but brought subjectively better feelings to patients [63]. Memantine, an adamantane derivative like amantadine, is an uncompetitive, moderate affinity, open-channel NMDAR blocker with strong voltage dependency and rapid blocking and unblocking kinetics [110]. Despite being approved by the US FDA for treating moderate-to-severe AD with safe and well tolerated profile, the efficacy of memantine is inconsistent at best. Some studies proved the clinical improvement of memantine in patients with moderate to severe AD [64], while other studies showed little clinical benefits of memantine towards AD treatment [111]. Several clinical results of memantine treatment in PD were also contradictive [65]. In MDD and BD clinical studies, memantine failed to show antidepressant effects in patients [66, 68]. As treatment for schizophrenic

symptoms, adjunct memantine uncovered a beneficial effect in ten studies, but no effects in two studies [67]. One study of memantine revealed minimal improvement in seven patients with anxiety [69].

Dextromethorphan, an uncompetitive NMDA receptor antagonist, is used as a cough suppressant with sedative and dissociative effects. In recent research, dextromethorphan and dextromethorphan-based compounds are considered as potential rapid-acting antidepressants, and therefore its therapeutic effect in MDD is evaluated in the clinical study (NCT04226352). In a BD study, dextromethorphan had no significant antidepressant effects compared with placebo group. This might be due to DRD2/ANKK1 TaqIA polymorphism [70]. Nuedexta, an FDA approved treatment for the pseudobulbar affect, was also utilized to treat MDD and BD. The purpose of adding dextromethorphan with quinidine in this combination is to inhibit the cytochrome P450 2D6 (CYP2D6) isoform, a dominant metabolic pathway of dextromethorphan, hence augmenting the bioavailability of dextromethorphan in CNS [112]. A proof-of-concept clinical trial demonstrated that after Nuedexta treatment, the response and remission rates in the patients with treatment resistant depression were 45% and 35%, respectively (NCT01882829). In a retrospective chart review, Nuedexta induced significant improvement in Clinical Global Impression (CGI) in depressed patients with treatment resistant bipolar disorder, implying its possible effectiveness in the BD treatment [71].

AVP-786, another dextromethorphan-based compound, is in conjunction with quinidine and deuterium to decrease the metabolism of dextromethorphan in the liver and hence increase its blood exposure. Following FDA Fast-Track designation for agitation in AD [113], four AD-related clinical studies of AVP-786 are underway (NCT02442765, NCT02442778, NCT02446132, and NCT03393520). In patients with MDD and schizophrenia, the efficacy, safety, and tolerability of AVP-786 were evaluated in the clinical studies (NCT02153502 and NCT03896945). AXS-05 (Axsome) is in combination with dextromethorphan and bupropion, which acts as an inhibitor of CYP2D6 to enhance the bioavailability of dextromethorphan [114]. In the AXS-05 treatment of agitation in patients with AD, the efficacy and safety of AXS-05 will be compared to placebo (NCT04797715). Three phase III clinical studies on the safety and efficacy of AXS-05 in patients with MDD were conducted without results posted to date (NCT02741791, NCT04019704, and NCT04039022).

(R,S)-Ketamine, an anesthetic and analgesic via intravenous administration, and its derivates (S)-ketamine (esketamine) and (R)-ketamine (arketamine) open a new era for glutamatergic rapid-acting antidepressant. At high doses (1-2 mg/kg), ketamine inhibits NMDAR as an uncompetitive antagonist to produce anesthesia, while at low doses, ketamine induces analgesia against both acute and chronic pain (0.25–0.5 mg/kg). Importantly, rapid-acting antidepressant effects of ketamine at moderate doses (0.5 mg/kg) have been proved in preclinical and clinical studies [3]. In most clinical studies of MDD, (R,S)-ketamine administration decreased depression severity with robust and rapid antidepressant effects [72], in accordance with studies of BD [73] and anxiolytic effects in anxiety disorders [74]. The (S+) enantiomer of ketamine was approved by FDA for adults with MDD with acute suicidal ideation or behavior. Esketamine improved depressive symptoms and delayed relapse in many studies [75], but did not demonstrate significant improvement as an adjunctive therapy with oral antidepressants in elderly patients with treatmentresistant depression [115]. In the study of treatment-resistant bipolar depression, the efficacy, safety, and pharmacokinetics of inhaled esketamine are still being evaluated (NCT03965871). Another enantiomer of ketamine, arketamine, is a less potent NMDAR uncompetitive antagonist, but displays greater and longer antidepressant effects than esketamine without psychotomimetic side effects [116]. In an open-label pilot study, intravenous arketamine generated fast-onset and sustained

antidepressant effects in depressed patients [117], and the larger study is underway (NCT04108234).

Neramexane, a moderate-affinity NMDAR open-channel blocker, possesses similar kinetics and voltage-dependency to memantine. Although it was well tolerated at all administered doses in clinical studies, phase II/III clinical trials for moderate-to-severe AD yielded contradictory results [76]. Nitrous oxide, an uncompetitive NMDAR antagonist, is an inhaled anesthetic often used in obstetrics or dentistry [118]. One recently published research demonstrated that compared with 50% nitrous oxide, 25% nitrous oxide provides comparable antidepressant effects with a markedly lower rate of adverse effects [77]. Other studies are underway to evaluate the efficacy and safety of nitrous oxide in MDD (NCT03869736 and NCT03932825). Nitrous oxide acted as a pharmacologic treatment for lumbar puncture/other procedure-related anxiety (NCT02243826).

#### *3.2.2 Indirect NMDAR blockers*

Lamotrigine, inhibiting voltage-dependent Na<sup>+</sup> , Ca2+, and K+ channels, acts as a presynaptic glutamate release inhibitor [119]. FDA approved lamotrigine for the maintenance treatment of BD. Lamotrigine failed to achieve clinical improvement in five clinical studies of MDD, while it induced higher response rate than placebo in BD studies [52]. In a comprehensive meta-analysis, lamotrigine performed better than placebo in improving unipolar and bipolar depressive symptoms [78]. Five of nine clinical trials of lamotrigine in schizophrenia revealed clinical improvement in a range of outcome measures [67].

Riluzole (BHV-0223), a glutamate release inhibitor, was approved by the US FDA for the treatment of amyotrophic lateral sclerosis. The mechanisms that reduce extracellular glutamate by riluzole includes reduced glutamate release through presynaptic inhibition of voltage-gated sodium channels (VGSCs), increased glutamate uptake by astroglial cells, and enhanced AMPA trafficking [120]. In a current clinical study of AD, riluzole decreased the reduction in cerebral glucose metabolism, a positive correlation with cognitive measures [79]. Additionally, riluzole only ameliorated depressive symptoms in one of four placebo-controlled MDD studies, and failed to reach clinical improvement in a BD study [52]. In one trial of anxiety disorders, eighty percent subjects responded positively to riluzole [80], and the following functional neuroimaging studies proved the alterations in hippocampal N-acetylaspartate (NAA) concentrations and volumes were in correlation with riluzole-induced improvement on anxiety scales [121]. Troriluzole (BHV-4157), a tripeptide prodrug conjugate of riluzole, has been developed to improve the bioavailability, safety, and dosing of riluzole. As a glutamate modulator, troriluzole decreases the level of synaptic glutamate via strengthening glutamate uptake, mainly through excitatory amino acid transporters (i.e., EAAT2) located on glial cells. Both in clinical studies of AD and anxiety, the clinical efficacy of troriluzole is under assessment (NCT03605667 and NCT03829241).

#### **4. Conclusions**

Not only does the discovery of ketamine to act as a novel rapid-acting antidepressant trigger a strong interest in developing novel NMDAR-modulating agents by a variety of proof-of-concept studies for CNS disorders, but also, after exploring the potential pathological mechanisms for the major CNS disorders as described above, the aberrant NMDAR activity shows to play a pivotal role in regulating clinical symptoms, hence facilitating the development of positive and negative NMDAR *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

modulators against those pathological aberrances in NMDAR activity. Interestingly, but not surprisingly, monotherapy of single NMDAR modulators often failed in clinical studies, boosting the prosperity of combination treatment with multiple modulators, or even with the standard treatments, further implying the intricate mechanisms underlying the CNS pathology.

To date, numerous clinical studies of NMDAR modulators are still underway. With more successful clinical improvement by NMDAR modulators in clinical studies, the mysterious puzzles of CNS disorders could be dissolved gradually, further refining the utilization of NMDAR modulators as optimal treatment with less undesirable side effects for the sophisticated CNS disorders that involve vulnerability in NMDA homeostasis.

## **Acknowledgements**

The authors thank Hung-Chun Liu and Cheng-Shen Lee for their assistance in preparation of the manuscript.

## **Conflict of interest**

The corresponding author is the CEO of SyneuRx International Corp., which is developing CNS therapeutics.

## **Author details**

Chih-Hung Lin1 , Po-Chang Shih1 and Guochuan Emil Tsai1,2\*

1 SyneuRx, New Taipei City, Taiwan

2 Department of Psychiatry and Biobehavioral Sciences, School of Medicine, UCLA, CA, USA

\*Address all correspondence to: tsaimdphd@ucla.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Tsai GE. Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor. 1st ed. Vol. 76, Advances in Pharmacology. Elsevier Inc.; 2016. 257-309 p.

[2] Hansen KB, Yi F, Perszyk RE, Menniti FS, Traynelis SF. NMDA receptors in the central nervous system. Vol. 1677, Methods in Molecular Biology. 2017. 1-80 p.

[3] Kohtala S. Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms. Pharmacol Reports. 2021 Apr 1;73(2):323.

[4] Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res. 2018 Jan 1;191:70-79.

[5] Adell A. Brain NMDA receptors in schizophrenia and depression. Biomolecules. 2020;10(6):1-27.

[6] Li CT, Yang KC, Lin WC. Glutamatergic dysfunction and glutamatergic compounds for major psychiatric disorders: Evidence from clinical neuroimaging studies. Front Psychiatry. 2019;10(JAN):1-11.

[7] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's Dement. 2011.

[8] Huang Y-J, Lin C-H, Lane H-Y, Tsai GE. NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. Curr Neuropharmacol. 2012 Oct 2;10(3):272.

[9] Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007.

[10] Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble a β oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2Bcontaining NMDA receptors. J Neurosci. 2011;31(18):6627-6638.

[11] Xia P, Chen HSV, Zhang D, Lipton SA. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010.

[12] Li S, Mallory M, Alford M, Tanaka S, Masliah E. Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol. 1997.

[13] Fernández-Tomé P, Brera B, Arévalo MA, De Ceballos ML. β-amyloid25-35 inhibits glutamate uptake in cultured neurons and astrocytes: Modulation of uptake as a survival mechanism. Neurobiol Dis. 2004.

[14] Jankovic J, Tan EK. Parkinson's disease: Etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020.

[15] Dickson DW. Neuropathology of Parkinson disease. Park Relat Disord. 2018.

*Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

[16] Guo H, Camargo LM, Yeboah F, DIgan ME, Niu H, Pan Y, et al. A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine. Sci Rep. 2017.

[17] Mellone M, Stanic J, Hernandez LF, Iglesias E, Zianni E, Longhi A, et al. NMDA receptor gluN2A/gluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: From experimental models to patients. Front Cell Neurosci. 2015.

[18] Schmitz Y, Castagna C, Mrejeru A, Lizardi-Ortiz JE, Klein Z, Lindsley CW, et al. Glycine transporter-1 inhibition promotes striatal axon sprouting via NMDA receptors in dopamine neurons. J Neurosci. 2013.

[19] Paulsen JS. Cognitive impairment in Huntington disease: Diagnosis and treatment. Curr Neurol Neurosci Rep. 2011.

[20] Davies S, Ramsden DB. Huntington's disease. Journal of Clinical Pathology - Molecular Pathology. 2001.

[21] Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature. 1986.

[22] Tsapakis EM, Travis MJ. Glutamate and psychiatric disorders. Adv Psychiatr Treat. 2002.

[23] Frye MA, Tsai GE, Huggins T, Coyle JT, Post RM. Low Cerebrospinal Fluid Glutamate and Glycine in Refractory Affective Disorder. Biol Psychiatry. 2007;61(2):162-166.

[24] World Health Organization (WHO). Suicide worldwide in 2019: global health estimates. 2021. Licence: CC BY-NC-SA 3.0 IGO.

[25] Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model - are we there yet? Behavioural Brain Research. 2018.

[26] Nemeroff CB, Owens MJ. Treatment of mood disorders. Nat Neurosci. 2002;5(11s):1068-1070.

[27] Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990.

[28] Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012.

[29] Taylor MJ, Mannie ZN, Norbury R, Near J, Cowen PJ. Elevated cortical glutamate in young people at increased familial risk of depression. Int J Neuropsychopharmacol. 2011.

[30] Beneyto M, Meador-Woodruff JH. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.

Neuropsychopharmacology. 2008.

[31] Huang C-C, Wei I-H, Huang C-L, Chen K-T, Tsai M-H, Tsai P, et al. Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression. Biol Psychiatry. 2013 Nov 15;74(10):734-741.

[32] Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Molecular Psychiatry. 2004.

[33] Fleischhacker WW. New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand. 1995.

[34] Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmüller B. Low cerebrospinal fluid glutamate in schizophrenic patients and a new

hypothesis on schizophrenia. Neurosci Lett. 1980.

[35] Gilmour G, Dix S, Fellini L, Gastambide F, Plath N, Steckler T, et al. NMDA receptors, cognition and schizophrenia - Testing the validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology. 2012.

[36] Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav. 2012 Feb 1;100(4):665-677.

[37] Long KD, Mastropaolo J, Rosse RB, Manaye KF, Deutsch SI. Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain. Brain Res Bull. 2006.

[38] Hui C, Tsai GE. Inhibition of Glycine Transporter-1 Improves the Functional Outcome of Schizophrenia. Brain Prot Schizophr Mood Cogn Disord. 2010;9789048185535:577-610.

[39] Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. The Lancet. 2016.

[40] Chitty KM, Lagopoulos J, Lee RSC, Hickie IB, Hermens DF. A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder. European Neuropsycho pharmacology. 2013.

[41] De Sousa RT, Loch AA, Carvalho AF, Brunoni AR, Haddad MR, Henter ID, et al. Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders. Neuropsychopharmacology. 2017.

[42] Andreasen JT, Gynther M, Rygaard A, Bøgelund T, Nielsen SD, Clausen RP, et al. Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests. Neurosci Lett. 2013.

[43] Martucci L, Wong AHC, De Luca V, Likhodi O, Wong GWH, King N, et al. N-methyl-d-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels. Schizophr Res. 2006.

[44] Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017.

[45] Muscatello MR, Spina E, Bandelow B, Baldwin DS. Clinically relevant drug interactions in anxiety disorders. Human Psycho pharmacology. 2012.

[46] Stahl MMS, Lindquist M, Pettersson M, Edwards IR, Sanderson JH, Taylor NFA, et al. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol. 1997.

[47] Tovote P, Fadok JP, Lüthi A. Neuronal circuits for fear and anxiety. Nature Reviews Neuroscience. 2015.

[48] Wolosker H, Balu DT. D-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders. Translational Psychiatry. 2020.

[49] Barkus C, McHugh SB, Sprengel R, Seeburg PH, Rawlins JNP, Bannerman DM. Hippocampal NMDA receptors and anxiety: At the interface between cognition and emotion. European Journal of Pharmacology. 2010.

[50] Amaral OB, Roesler R. Targeting the NMDA receptor for fear-related

disorders. Recent patents on CNS drug discovery. 2008.

[51] Kalia L V., Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 2008 Aug;7(8):742-755.

[52] Małgorzata P, Paweł K, Iwona ML, Brzostek T, Andrzej P. Glutamatergic dysregulation in mood disorders: opportunities for the discovery of novel drug targets. Expert Opin Ther Targets. 2020;24(12):1187-209.

[53] Leiderman E, Zylberman I, Zukin SR, Cooper TB, Javitt DC. Preliminary investigation of high-dose oral glycine on serum levels and negative symptoms in schizophrenia: an open-label trial. Biol Psychiatry. 1996 Feb 1;39(3):213-215.

[54] Tsai GE, Yang P, Chang Y-C, Chong M-Y. D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia. Biol Psychiatry. 2006 Feb 1;59(3):230-234.

[55] Tsai GE, Falk WE, Gunther J, Coyle JT. Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. Am J Psychiatry. 1999 Mar;156(3):467-469.

[56] Forsyth JK, Bachman P, Mathalon DH, Roach BJ, Ye E, Asarnow RF. Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine. Schizophr Bull. 2017 Sep 1;43(5):1123-1133.

[57] Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J, et al. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. The Lancet Psychiatry. 2017 Jul 1;4(7):547-553.

[58] Gammon D, Cheng C, Volkovinskaia A, Baker GB, Dursun SM. Clozapine: Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric Disorders? Biomolecules. 2021.

[59] Delgado A, Velosa J, Zhang J, Dursun SM, Kapczinski F, de Azevedo Cardoso T. Clozapine in bipolar disorder: A systematic review and meta-analysis. J Psychiatr Res. 2020 Jun 1;125:21-27.

[60] Lane H-Y, Lin C-H, Huang Y-J, Liao C-H, Chang Y-C, Tsai GE. A randomized, double-blind, placebocontrolled comparison study of sarcosine (N-methylglycine) and d-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol. 2010 May 1;13(4):451-460.

[61] Lin C-H, Chen P-K, Chang Y-C, Chuo L-J, Chen Y-S, Tsai GE, et al. Benzoate, a D-Amino Acid Oxidase Inhibitor, for the Treatment of Early-Phase Alzheimer Disease: A Randomized, Double-Blind, Placebo-Controlled Trial. Biol Psychiatry. 2014 May 1;75(9):678-685.

[62] Lai C-H, Lane H-Y, Tsai GE. Clinical and Cerebral Volumetric Effects of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, in a Drug-Naïve Patient with Major Depression. Biol Psychiatry. 2012.

[63] O'Suilleabhain P, Dewey RB. A Randomized Trial of Amantadine in Huntington Disease. Arch Neurol. 2003 Jul 1;60(7):996-998.

[64] Herrmann N, Cappell J, Eryavec GM, Lanctôt KL. Changes in Nursing Burden Following Memantine for Agitation and Aggression in Long-Term Care Residents with Moderate to Severe Alzheimer's Disease. CNS Drugs . 2012 Aug 29;25(5):425-33.

[65] Vanle B, Olcott W, Jimenez J, Bashmi L, Danovitch I, IsHak WW. NMDA antagonists for treating the non-motor symptoms in Parkinson's disease. Transl Psychiatry. 2018 Dec 1;8(1):117.

[66] Zarate CA, Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA, et al. A Double-Blind, Placebo-Controlled Study of Memantine in the Treatment of Major Depression. Am J Psychiatry. 2006 Jan 1;163(1):153-155.

[67] Zhand N, Attwood DG, Harvey PD. Glutamate modulators for treatment of schizophrenia. Pers Med Psychiatry. 2019 Jul 1;15-16:1-12.

[68] Anand A, Gunn AD, Barkay G, Karne HS, Nurnberger JI, Mathew SJ, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2012 Feb 1;14(1):64-70.

[69] Feusner J, Kerwin L, Saxena S, Bystritsky A. Differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: an open-label trial. Psychopharmacol Bull. 2009;42(1):81-93.

[70] Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY, et al. The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder. J Affect Disord. 2012 May 1;138(3):295-300.

[71] Kelly TF, Lieberman DZ. The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. J Affect Disord. 2014 Oct 1;167:333-335.

[72] Domany Y, Bleich-Cohen M, Tarrasch R, Meidan R, Litvak-Lazar O, Stoppleman N, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled,

proof-of-concept study. Br J Psychiatry. 2019 Jan 1;214(1):20-26.

[73] Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biol Psychiatry. 2012 Jun 1;71(11):939-946.

[74] Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, et al. Ketamine's doserelated effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017 Apr 26;31(10):1302-1305.

[75] Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, 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 May 21;176(6):428-438.

[76] Rammes G. Neramexane: a moderate-affinity NMDA receptor channel blocker: new prospects and indications. Expert Rev Clin Pharmacol. 2014;2(3):231-8.

[77] Nagele P, Palanca BJ, Gott B, Brown F, Barnes L, Nguyen T, et al. A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med. 2021 Jun 9;13(597).

[78] Solmi M, Veronese N, Zaninotto L, van der Loos MLM, Gao K, Schaffer A, et al. Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials. CNS Spectr. 2016 Oct 1;21(5):403-418.

[79] Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, et al. *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain. 2021 Jun 18.

[80] Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. Open-Label Trial of Riluzole in Generalized Anxiety Disorder. Am J Psychiatry. 2005 Dec 1;162(12):2379-2381.

[81] Collingridge GL, Volianskis A, Bannister N, France G, Hanna L, Mercier M, et al. The NMDA receptor as a target for cognitive enhancement. Neuropharmacology. 2013 Jan;64:13.

[82] Peyrovian B, Rosenblat JD, Pan Z, Iacobucci M, Brietzke E, McIntyre RS. The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog Neuro-Psychopharmacology Biol Psychiatry. 2019;92:387-404.

[83] Tsai G, Yang P, Chung L-C, Lange N, Coyle JT. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998 Dec 1;44(11):1081-1089.

[84] Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999 Nov;156(11):1822-1825.

[85] Schade S, Paulus W. D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review. Int J Neuropsychopharmacol. 2016 Apr 1;19(4):1-7.

[86] Schwartz BL, Hashtroudi S, Herting RL, Schwartz P, Deutsch SI. d-Cycloserine enhances implicit memory in Alzheimer patients. Neurology. 1996 Feb 1;46(2):420-424.

[87] Tsai GE, Falk WE, Gunther J. A preliminary study of D-cycloserine treatment in Alzheimer's disease.

J Neuropsychiatry Clin Neurosci. 1998;10(2):224-226.

[88] Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsycho pharmacol. 2013 Apr 1;16(3):501-506.

[89] Goff DC, Tsai G, Manoach DS, Coyle JT. Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry. 1995;152(8):1213-1215.

[90] Goff DC, Herz L, Posever T, Shih V, Tsai G, Henderson DC, et al. A sixmonth, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacol. 2004 Oct 21;179(1):144-150.

[91] Baker JF, Cates ME, Luthin DR. D-cycloserine in the treatment of posttraumatic stress disorder. Ment Heal Clin. 2017;7(2):88-94.

[92] Fasipe OJ. The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents. IBRO Reports. 2019 Jun 1;6:95-110.

[93] Alberati D, Moreau JL, Lengyel J, Hauser N, Mory R, Borroni E, et al. Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology. 2012 Feb 1;62(2):1152-1161.

[94] Bugarski-Kirola D, Iwata N, Sameljak S, Reid C, Blaettler T, Millar L, et al. Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics: results from three phase 3, randomised, double-blind, parallelgroup, placebo-controlled, multicentre

studies in the SearchLyte clinical trial programme. The Lancet Psychiatry. 2016 Dec 1;3(12):1115-1128.

[95] Lane H-Y, Huang C-L, Wu P-L, Liu Y-C, Chang Y-C, Lin P-Y, et al. Glycine Transporter I Inhibitor, N-methylglycine (Sarcosine), Added to Clozapine for the Treatment of Schizophrenia. Biol Psychiatry. 2006 Sep 15;60(6):645-649.

[96] Lin C-Y, Liang S-Y, Chang Y-C, Ting S-Y, Kao C-L, Wu Y-H, et al. 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. 2015 Jul 4;18(5):357-368.

[97] V. Ferraris D, Tsukamoto T. Recent Advances in the Discovery of D-Amino Acid Oxidase Inhibitors and Their Therapeutic Utility in Schizophrenia. Curr Pharm Des. 2011 Mar 21;17(2):103-111.

[98] Matsuura A, Fujita Y, Iyo M, Hashimoto K. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr. 2015 Jan 20;27(3):159-167.

[99] Lane H-Y, Lin C-H, Green MF, Hellemann G, Huang C-C, Chen P-W, et al. Add-on Treatment of Benzoate for Schizophrenia: A Randomized, Doubleblind, Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor. JAMA Psychiatry. 2013 Dec 1;70(12): 1267-1275.

[100] Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14(6):383-400.

[101] Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate

signalling in depression: Progress and prospects. Nat Rev Drug Discov. 2017;16(7):472-486.

[102] Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 1988;85(17):6547.

[103] Zanos P, Piantadosi SC, Wu H-Q, Pribut HJ, Dell MJ, Can A, et al. The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/ GlycineB-Site Inhibition. J Pharmacol Exp Ther. 2015 Oct 1;355(1):76-85.

[104] Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, et al. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):417-425.

[105] Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-tomoderate Alzheimer's disease: a randomised, double-blind, placebocontrolled study. Lancet (London, England). 2008;372(9634):207-15.

[106] Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, et al. A randomized, placebo-controlled trial of latrepirdine in Huntington disease. Arch Neurol. 2010 Feb;67(2):154-160.

[107] Fogaça M V., Fukumoto K, Franklin T, Liu RJ, Duman CH, Vitolo O V., et al. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019. *Perspective Chapter: NMDA Treatments for CNS Disorders DOI: http://dx.doi.org/10.5772/intechopen.100528*

[108] Ibrahim L, Diazgranados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Joseph Herring W, et al. 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 Aug;32(4):551-557.

[109] Ory-Magne F, Corvol J-C, Azulay J-P, Bonnet A-M, Brefel-Courbon C, Damier P, et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease. Neurology. 2014 Jan 28;82(4):300-307.

[110] Rammes G, Danysz W, Parsons CG. Pharmacodynamics of Memantine: An Update. Curr Neuropharmacol. 2008 Mar 4;6(1):55-78.

[111] Ballard C, Thomas A, Gerry S, Yu L-M, Aarsland D, Merritt C, et al. A double-blind randomized placebocontrolled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer's disease (MAIN-AD). J Am Med Dir Assoc. 2015;16(4):316-322.

[112] Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. Pharmacology of dextromethorphan: Relevance to dextromethorphan/ quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016 Aug 1;164:170-182.

[113] Garay RP, Grossberg GT. AVP-786 for the treatment of agitation in dementia of the Alzheimer's type. Expert Opin Investig Drugs. 2017 Jan 2;26(1):121-32.

[114] Hecking J, Davoudian PA, Wilkinson ST. Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders. Chronic stress (Thousand Oaks). 2021 Jun 2;5.

[115] Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Foster K, et al. S114. Efficacy and Safety of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression. Biol Psychiatry. 2018 May 1;83(9):S391.

[116] Morris PJ, Moaddel R, Zanos P, Moore CE, Gould TD, Zarate CA, et al. Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites. Org Lett. 2017 Sep 1;19(17):4572-4575.

[117] Leal GC, Bandeira ID, Correia-Melo FS, Telles M, Mello RP, Vieira F, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci. 2020 Feb 20;271(3):577-582.

[118] Jevtović-Todorović V, Todorovć SM, Mennerick S, Powell S, Dikranian K, Benshoff N, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998 Apr;4(4):460-463.

[119] Grunze H, von Wegerer J, Greene RW, Walden J. Modulation of Calcium and Potassium Currents by Lamotrigine. Neuropsychobiology. 1998 Oct;38(3):131-138.

[120] Zarate CA, Manji HK. Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol. 2008 Sep;4(9):1223-1234.

[121] Abdallah CG, Coplan JD, Jackowski A, Sato JR, Mao X, Shungu DC, et al. A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD. Eur Neuropsychopharmacol. 2013 Apr 1;23(4):276-284.

## **Chapter 10**
