Targeting of NMDA Receptors in New Treatments for Schizophrenia

1. Introduction

2. Alterations in the

glutamine-glutamate-GABA

cycle in schizophrenia

3. Glycine modulatory site on the

NMDA receptor as a

therapeutic target

4. Redox site of the NMDA

receptor as a therapeutic

target

5. Conclusion

6. Expert opinion

Review

Targeting of NMDA receptors innew treatments for schizophreniaKenji HashimotoChiba University Center for Forensic Mental Health, Division of Clinical Neuroscience, Chiba,

Japan

Introduction: Abnormalities in glutamatergic neurotransmission mediated by

N-methyl-D-aspartate (NMDA) are implicated in the pathophysiology of

schizophrenia, although the precise mechanisms are unknown.

Areas covered: The author examines the role of the NMDA receptor in

schizophrenia, focusing on results from preclinical and clinical studies that

support the NMDA receptor hypothesis of schizophrenia. The author first

reviewed papers detailing alterations in the levels of endogenous substances

such as glutamine, glutamate, D-serine, L-serine, kynurenic acid and glutathi-

one (GSH), all of which can affect NMDA receptor function. Next, the author

reviewed clinical findings for glycine, D-serine, D-cycloserine, D-amino acid

oxidase inhibitors (e.g., sodium benzoate) and glycine transporter-1 inhibitors

(e.g., sarcosine, bitopertin), as potential therapeutic drugs. In addition, the

author outlined how oxidative stress associated with decreased levels of the

endogenous antioxidant GSH may play a role in the pathophysiology of

schizophrenia. Finally, the author reviewed N-acetylcysteine (NAC), a precur-

sor of GSH and an activator of the cystine--glutamate antiporter, as a potential

therapeutic drug.

Expert opinion: Given the NMDA receptor hypothesis of schizophrenia, the

glycine modulatory site on NMDA receptors is the most attractive therapeutic

target for this disease. In addition, both the kynurenine pathway and cystine-

glutamate antiporter represent credible potential therapeutic targets for

schizophrenia.

Keywords: cystine-glutamate antiporter, D-serine, glutamate, glutathione, glycine,

glycine transporter, kynurenic acid, N-acetylcysteine, NMDA receptor, sulforaphane

Expert Opin. Ther. Targets (2014) 18(9):1049-1063

1. Introduction

Schizophrenia is a chronic, debilitating psychiatric disease, affecting ~ 1% of theworlds population. This disease shows varied and severe symptoms that generallybegin in late adolescence or early adulthood, and usually continue throughoutlife. Although the precise cause of schizophrenia is unknown, both genetic and envi-ronmental factors, such as place and time of birth, infection, prenatal events, andobstetric complications, are thought to contribute to disease pathophysiology [1].

Glutamate (L-glutamic acid) plays an important role, as a well-established majorexcitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA)receptor is an ion-channel subtype of glutamate receptors and comprises differentsubunits responsible for varied biophysical and pharmacological properties (Figure 1).The NMDA receptor is composed of four subunits: two obligatory GluN1 subunitsand a combination of two GluN2 subunits (GluN2A, GluN2B, GluN2C andGluN2D) and/or GluN3 subunits (GluN3A and GluN3B) [2]. Multiple lines of evi-dence suggest that dysfunctional glutamatergic neurotransmission via the NMDAreceptor could underlie the pathophysiology of schizophrenia [3-11]. The NMDAreceptor hypothesis in schizophrenia was first proposed > 30 years ago [12]. This

10.1517/14728222.2014.934225 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 1049All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/ETT

hypothesis evolved from the clinical findings that phencycli-dine (PCP) and its congener, ketamine, which blocks theNMDA receptor (Figure 1), induce a schizophrenia-likepsychosis with positive and negative symptoms, as well ascognitive impairment in normal healthy humans, and thatPCP exacerbates symptoms in patients with chronic schizo-phrenia [3,13]. Therefore, to date, NMDA receptor antagonismprovides the best pharmacological model of schizophrenia. Astudy using postmortem brain samples showed a decrease inthe obligatory GluN1 subunit at both mRNA and protein lev-els in the dorsolateral prefrontal cortex from schizophrenia [14],supporting the hypothesis of NMDA receptor hypofunction inschizophrenia. Further evidence comes from genetic associa-tion studies showing the influence of schizophrenia risk genes,such as D-amino acid oxidase (DAAO), G72, neuregulin 1 anddysbindin on NMDA receptor function [15,16].In this article, the author reviews recent data on the NMDA

receptor as a new therapeutic target for schizophrenia.

2. Alterations in the glutamine-glutamate-GABA cycle in schizophrenia

In 1980, Kim et al. [17] reported decreased glutamate levels inthe cerebrospinal fluid (CSF) of patients with schizophreniaand proposed the glutamate hypothesis of schizophrenia.However, subsequent studies failed to replicate thesefindings [18,19]. Previously, we found an increased ratio ofglutamine to glutamate in the CSF of first episode anddrug-naive patients with schizophrenia, although individualCSF levels showed no differences between the two groups [20].In the brain, glutamine synthesis from glutamate and ammo-

nia occurs exclusively in astrocytes. Glutamine plays major rolesin nitrogen and carbon homeostasis, in the detoxification ofammonia and as a precursor in the synthesis of glutamate inexcitatory neurons (Figure 2). Released glutamate is taken upby surrounding astrocytes via the glutamate transporter, whereit is converted to glutamine, transported back to presynapticneurons and reconverted to glutamate. Thus, the glutamine-glutamate cycle as part of glia-neuron communication playsan important role in excitatory neurotransmission [21]. In

addition, the inhibitory amino acid, GABA, is also synthesizedfrom glutamate via glutamic acid decarboxylase (Figure 2) [21].Therefore, it is not unlikely that abnormalities in glutamine-glutamate-GABA cycling play a role in the pathophysiology ofschizophrenia [20-22]. A study using 3T 1H-magnetic resonancespectroscopy (MRS) demonstrated an increased ratio of gluta-mine to glutamate in the medial prefrontal cortex derivedfrom schizophrenic brains, although there was no difference inthe levels of individual amino acids between the patients andcontrols [23]. A more recent study using 3T 1H-MRS foundan increased ratio of glutamine to glutamate in the dorsalanterior cingulate cortex of schizophrenia brains [24]. Thesefindings support our earlier hypothesis on abnormalities inglutamine-glutamate cycling in the brains of schizophreniapatients. Amino acids, including glutamate, glutamine, glycine,L-serine and D-serine, are capable of modulating neurotransmis-sion via the NMDA receptor [25]. However, using postmortembrain samples from the Stanley Foundation, we found nochanges in these amino acids in the prefrontal cortex of patientswith schizophrenia [25].

3. Glycine modulatory site on the NMDAreceptor as a therapeutic target

Accepting the NMDA receptor hypofunction hypothesis forschizophrenia, increasing NMDA receptor function throughpharmacological manipulation could potentially be a newstrategy for managing schizophrenia. At present, thestrychnine-insensitive glycine modulatory site on the NMDAreceptor is the most used therapeutic target for improvingsymptoms such as positive and negative symptoms, andcognitive impairment in schizophrenia [7-10,26].

3.1 GlycineGlycine is a well-established inhibitory neurotransmitter, viaits interaction with strychnine-sensitive glycine receptors.Glycine is also a full agonist at the strychnine-insensitiveglycine modulatory site associated with the NMDA receptor(Figure 1). Initial clinical studies with glycine were performedin the early 1990s. Glycine was found to ameliorate multipleschizophrenia symptoms (e.g., positive and negative symp-toms, cognitive impairment and depression) (Table 1) [27,28].However, glycine is extensively metabolized in the liver andshows poor distribution across the blood-brain barrier, neces-sitating large doses of glycine to effectively stimulate NMDAreceptor activation in the brain [9].

Serine hydroxymethyltransferase 1 (Shmt1) is an enzyme inthe reversible interconversion between glycine and L-serine(Figure 2). Maekawa et al. [29] reported that levels of Shmt1mRNA in the dorsolateral prefrontal cortex of schizophreniabrains were significantly higher than in control brains, sug-gesting that Shmt1 is associated schizophrenia pathophysiol-ogy. A study of Shmt1-deficient mice proposed that thisgene could be involved in hippocampus neurogenesis andcognition [30]. Since Shmt1 impacts on NMDA receptor

Article highlights.

. The NMDA receptor plays an important role in thepathophysiology of schizophrenia.

. Abnormalities in the glutamine-glutamate-GABA cycleare implicated in the pathophysiology of this disease.

. Glycine modulatory sites on the NMDA receptor are veryattractive therapeutic targets.

. The kynurenine pathway is also a new therapeutictarget for this disease.

. Abnormalities in the synthesis and metabolism of theantioxidant glutathione are also implicated in thepathophysiology of this disease.

This box summarizes key points contained in the article.

K. Hashimoto

1050 Expert Opin. Ther. Targets (2014) 18(9)

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function via the glycine-L-serine-D-serine cycle (Figure 2),Shmt1 could also be a possible therapeutic target.

3.2 D-CycloserineD-Cycloserine, a partial agonist at the NMDA receptor-associated strychnine-insensitive glycine modulatory site(Figure 1), is a less efficient NMDA receptor ligand, comparedwith endogenous full agonists, such as glycine and D-serine(Figure 1). At high doses, D-cycloserine acts as an antagonistby displacing more efficacious endogenous agonists, but atmoderate doses, D-cycloserine facilitates glutamatergic neuro-transmission via the NMDA receptor [9]. A retrospective studyand two meta-analyses show that glycine, D-serine and sarcosine(N-methylglycine) are more effective than D-cycloserine inimproving the overall psychopathology in medicated patientswith schizophrenia (Table 1) [27,28,31]. It is likely that D-cycloser-ine has a relatively narrow therapeutic window due to its partialagonist properties [9]. Recently, we reported that D-cycloserinemay act as a prodrug for D-serine, since brain levels of D-serineincreased after oral administration of D-cycloserine [32].

3.3 DAAO inhibitorsD-Serine is synthesized by serine racemase (SRR) from L-ser-ine (Figure 2) and is a full agonist at the NMDA receptor-associated strychnine-insensitive glycine modulatory site(Figure 1) [9,33]. Studies using SRR knockout (KO) micehighlighted SRR as the major enzyme responsible for D-serineproduction in the adult brain [34-36]. Interestingly, reducedlevels of D-serine and a reduced ratio of D-serine to total serine

have been demonstrated in both the blood and CSF ofpatients with schizophrenia [37-41]. Very recently, Lin et al.[42] reported higher plasma G72 (or DAAO activator) proteinlevels in medicated and drug-free patients with schizophrenia,suggesting that this protein could be a potential biomarker forschizophrenia. Moreover, abnormalities in genes such asDAAO and DAAO activator/G72, both of which regulateD-serine metabolism, have been reported [43-45]. These find-ings implicate aberrant synthesis and metabolism of D-serinein the pathophysiology of schizophrenia [9].

A number of clinical studies have demonstrated a therapeu-tic benefit for D-serine (30 -- 120 mg/kg/day) in patients withschizophrenia (Table 1) [28,46-49]. Despite its clinical efficacy,orally administered D-serine is metabolized substantially byDAAO (Figure 2), diminishing its oral bioavailability. Higherdoses of D-serine raise the potential for nephrotoxicity,although no significant adverse events have as yet beenobserved at doses of up to 4 g/day [50]. We have in the pastreported that coadministration of the DAAO inhibitor poten-tiated the bioavailability of D-serine in mice, thereby enhanc-ing the efficacy of D-serine in animal models of schizophrenia[51,52]. Taken together, it is likely that coadministration ofD-serine and a DAAO inhibitor could represent a novelapproach in the treatment of schizophrenia [9,51-54].

Recently, we reported that supplementation of D-serine inpreadolescent to adult stages may prevent the onset of psychosisin adult mice after neonatal inhibition of SRR [55], highlightingD-serine as an attractive therapeutic agent for early interventionin the onset of psychosis. A randomized, placebo-controlled

Polyamine

PCP receptor

GluN2 GluN1

Glutathione(GSH)

GlutamateNMDA

Ca2+, Na+

GlycineD-SerineKynurenic acid

PCPKetamine

Ma2+

Zn2+

Figure 1. NMDA receptors in the brain. Phencyclidine (PCP) and ketamine are ion-channel blockers of the NMDA receptor.

Glycine and D-serine are endogenous co-agonists of the glycine modulatory site on the GluN1 subunit. Kynurenic acid is an

endogenous antagonist at glycine modulatory sites. D-Cycloserine is a partial agonist at glycine modulatory sites. Glutamate

and NMDA are agonists at glutamate sites on the GluN2 subunit. Glutathione (GSH) and polyamine bind to the redox

modulatory and polyamine sites of the NMDA receptor, respectively.

Targeting of NMDA receptors in new treatments for schizophrenia

Expert Opin. Ther. Targets (2014) 18(9) 1051

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study of D-serine in subjects with schizophrenia prodrome isreported by Dr. Daniel Javitt [56]. They investigated the effectsof D-serine (16-week) on prodromal symptoms in 44 subjectsat high clinical risk for schizophrenia, based on StructuredInterview for Psychosis-Risk Syndromes/Scale of Psychosis-Risk Symptoms (SOPS) criteria. A highly significant reduction(p = 0.03, d = 0.68) was observed on SOPS negative symptoms.Furthermore, a > 20% improvement was observed in 9 out of10 subjects who completed all 16 weeks of treatment, comparedwith only 5 out of 11 placebo-treated subjects (p = 0.23). Twoplacebo-treated subjects and one D-serine-treated subjecttransitioned to psychosis during the study (Table 1) [56]. Thesedata suggested a potential for early intervention with D-serinein early stage schizophrenia, consistent with preclinicalreporting [55].

3.4 Sodium benzoateSodium benzoate is the sodium salt of benzoic acid and isoften used as a food preservative because of its antimicrobial

properties. Sodium benzoate is a competitive inhibitorof DAAO, which binds to the enzyme active site (Ki 16 M) [51,57]. A recent randomized, double-blind, placebo-controlled study demonstrated that benzoate (1 g/dayfor 6-week) significantly improved a variety of symptomdomains and cognition in patients with schizophrenia(Table 1) [58].

DAAO shows very low activity in adult forebrains, withhigh activity in the cerebellum. Previously, we reported thatDAAO inhibition had no effect on D-serine levels in adultmouse forebrains [52]. Therefore, it is possible that the increasein cerebellar D-serine levels by DAAO inhibition may, in part,confer antipsychotic activity, by augmenting D-serine-medi-ated regulation of the NMDA receptor in the cerebellum [59].Nonetheless, further detailed studies on sodium benzoate inpreclinical models of schizophrenia are needed. A very recentreport shows that sodium benzoate upregulated brain-derivedneurotrophic factor (BDNF) [60]. This data imply that thetherapeutic effect of sodium benzoate is through increases in

D-amino acid oxidaseD-Serine

L-Serine

3-Phosphoglyceratedehydrogenase

3-Phosphoglycerate

Glycine

NH3

NH3

NH3

Succinyl CoA

Succinate

Succinic semialdehydedehydrogenase

Succinicsemialdehyde

GABAtransaminase

GABA

Glutamic aciddecarboxylase

Glutamatedehydrogenase

L-GlutamateL-Glutamine

L-Cysteine

Glutathione synthetase

Glutathione

Glutaminase

Glutamine synthetase

-Keto-glutarate

-Glutamylcysteine

-Glutamylcysteine synthetase

-Ketoglutaratedehydrogenase

Serinehydroxymethyltransferase

Serine racemase

Figure 2. Amino acid synthetic and metabolic pathways. L-Glutamate, an excitatory amino acid, is synthesized from

L-glutamine by glutaminase, and metabolized to L-glutamine by glutamine synthetase. In addition, L-glutamate is

metabolized to GABA, an inhibitory amino acid, by glutamic acid decarboxylase. GABA is metabolized to succinic

semialdehyde by GABA transaminase. D-Serine is synthesized from L-serine by serine racemase and is metabolized by D-amino

acid oxidase. L-Serine is converted to glycine by serine hydroxymethyltransferase (SHMT). Glutathione is synthesized via

g-glutamylcysteine from L-glutamate, L-cysteine and glycine.

K. Hashimoto


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BDNF levels, as BDNF is a known causative agent in thepathophysiology of some psychiatric diseases [61-63].

3.5 Sarcosine (N-methylglycine)Glycine transporter-1 (GlyT-1), located on astrocytes and neu-rons, is responsible for glycine reuptake in forebrain areas, andin some regions, it may co-localize with glycinemodulatory siteson NMDA receptors [9,64]. Furthermore, GlyT-1 acts to main-tain local synaptic glycine at very low levels, suggestive of a rolein regulating glutamatergic neurotransmission via NMDAreceptors [64]. Previously, we reported that the GlyT-1 inhibitor,NFPS, improved cognitive deficits in rodents after administra-tion of NMDA receptor antagonists [65,66]. These findingsimply that increased synaptic glycine levels achieved throughinhibition of GlyT-1, lead to enhanced NMDA receptor activa-tion, in turn suggesting a potential role for GlyT-1 inhibition asa novel treatment for schizophrenia [9,64,67].

Sarcosine (N-methylglycine) is generated by the enzymatictransfer of a methyl group from S-adenosylmethionine toglycine, and this reaction is catalyzed by the enzyme, glycineN-methyltransferase (Figure 3) [64]. Treatment with sarcosine(2 g/day) conferred beneficial effects in patients treated withantipsychotics, such as risperidone [68], but not clozapine [69].A randomized, double-blind, placebo-controlled study dem-onstrated that the sarcosine (2 g/day) group showed greaterreductions in Positive and Negative Syndrome Scale (PANSS)

total scores than the placebo or D-serine (2 g/day) groups.This study proposes that sarcosine may offer superior resultsover D-serine, in that it benefits patients with long-term stableschizophrenia, as well as those in acute stages of the disease(Table 1) [48]. A randomized, double-blind study reportedthat sarcosine (2 g/day) alone was effective in the treatmentof acutely ill, symptomatic drug-free schizophrenics (Table 1)[70]. Additionally, a randomized, double-blind, placebo-controlled comparison study of sarcosine and D-serine dem-onstrated that sarcosine was superior to placebo in all fouroutcome measures of PANSS total, Scale for the Assessmentof Negative Symptoms, Quality of Life and Global Assess-ment of Functioning (GAF), while D-serine showed no signif-icant differences from placebo in these measures (Table 1) [71].Further large-scale, placebo-controlled, dose-finding studiesare needed to fully assess the beneficial effects of sarcosine,since the original data were based on small studies from a sin-gle group in Taiwan. Nonetheless, their findings suggest thatGlyT-1 inhibition could be a novel therapeutic target forenhancing NMDA receptor function [9,64,67].

An epidemiological study showed an ~ 40 -- 50% lower riskfor prostate cancer in male patients with schizophrenia [72]. In2009, Sreekumar et al. [73] identified sarcosine as a biomarkerin urine, which is highly increased during prostate cancer pro-gression to metastasis. The enzyme glycine N-methyltransfer-ase is typically expressed at high levels in prostate. It would

Table 1. Clinical trial of drugs in schizophrenics and subjects with prodromal syndrome.

Drugs Dose and duration Clinical outcome Ref.

Glycine Retrospective analysis andmeta-analysis

Improved positive and negative symptoms, cognitiveimpairment and depression

[27,28]

D-Cycloserine Retrospective analysis andmeta-analysis

Less effective than glycine, D-serine and sarcosine [27,28,31]

D-Serine 30 -- 120 mg/kg/day Improved positive and negative symptoms and cognitiveimpairment

[28,46-49]

60 mg/kg/day and 16 weeks Improved SOPS negative symptoms score in subjects withprodromal syndrome

[56]

Sodium benzoate 1 g/day and 6 weeks Improved PANSS total, positive subscale, negative subscale,SANS, GAF, QOLS, CGI, HDRS and MATRICS composite score

[58]

Sarcosine 2 g/day and 6 weeks Improved PANSS total, negative subscale, SANS, QOL andGAF

[68-71]

Bitopertin 10, 30 or 60 mg/day and8 weeks (Phase IIb)

Improved PANSS negative subscale [78]

10, 30 mg/day and4 weeks (Phase III)

No improvement of PANSS total in acute schizophrenia [81]

5, 10 or 20 mg/day and24 weeks (Phase III)

No improvement of PANSS negative subscale [79]

N-acetylcysteine (NAC) 1 g/day and 6 weeks Improved PANSS total, negative subscale and CGI [122]2 g/day and 60 days Improved MMN, not P300, in patients with schizophrenia [123]2 g/day and 2 months Modulated EEG synchronization [125]2 g/day and 8 weeks Improved PANSS total and negative subscale [126]2 g/day and 12 weeks Improved BACS-J total score in subjects with at-risk mental

state[128]

BACS-J: Brief Assessment for Cognition in Schizophrenia Japanese version; CGI: Clinical global impression; GAF: Global assessment of function; HDRS: Hamilton

depression rating scale - 17 items; MATRICS: Measurement And treatment research to improve cognition in schizophrenia; MMN: Mismatch negativity;

PANSS: Positive and negative symptoms scale; QOL: Quality of life; QOLS: Quality of life scale; SANS: Scales for the assessment of negative symptoms - 20 items;

SOPS: Scale of psychosis-risk symptoms.



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therefore be of interest to study whether blood (or urine) lev-els of sarcosine are altered in male schizophrenics, since sarco-sine levels may contribute to disease pathophysiology. Takentogether, it seems that the glycine--sarcosine pathway mayinfluence the lower risk for prostate cancer in male schizo-phrenics although further detailed studies are necessary toconfirm this hypothesis [74].

3.6 BitopertinThe selective and potent GlyT-1 inhibitor, RG1678 or bitoper-tin, was efficacious in in vivo studies using animal models ofschizophrenia, and oral administration produced a robust andsustained increase of extracellular glycine levels in ratstriatum [75,76]. A subsequent study showed increased CSFlevels of glycine in healthy volunteers after oral dosing with bito-pertin (3 -- 60 mg). Additionally, a positron emission tomogra-phy study found dose-dependent occupancy of GlyT-1 inhuman brains after oral administration of bitopertin [77].A Phase IIb multicenter, randomized, double-blind study of

bitopertin (using 10, 30 or 60 mg/day for 8 weeks) showedthat it was effective against negative symptoms in stable, med-icated, schizophrenics (n = 323) (Table 1) [78]. Changes in thePANSS negative symptom factor score demonstrated a statisti-cally significant improvement in patient symptoms after takingbitopertin (10 and 30 mg) compared to placebo (Table 1) [78].On the other hand, bitopertin did not improve cognition inpatients, although GlyT-1 inhibitors improved cognitive

deficits in an NMDA receptor hypofunction rodentmodel [65,66]. In January 2014, Roche reported negative resultsfrom two Phase III studies using bitopertin in schizophrenia(Table 1) [79]. Unexpectedly, the addition of bitopertin toantipsychotic therapy did not significantly reduce negativesymptoms at 24 week compared to placebo because of a highplacebo effect [79,80]. A randomized, double-blind, placebo-and active-controlled Phase II/III trial demonstrated thatbitopertin and olanzapine induced improved PANSS totalscores in patients with acute exacerbation of schizophrenia,although the changes were not statistically significant. How-ever, a greater proportion of patients receiving bitopertin(30 mg, 51.3%) or olanzapine (52.5%) compared with pla-cebo (32.9%) were ready for hospital discharge by week 4(Table 1) [81]. Further randomized, placebo-controlled studiesusing novel biomarkers to improve disease categorization andthus reduce the problem of patient heterogeneity are neededbefore the true efficacy of GlyT-1 inhibitors such as bitopertincan be ascertained [82].

Although the reasons underlying the lack of efficacy forbitopertin in Phase III trials are currently unclear, it seems thatglycine performs a more complex role than simply binding tothe GluN1 subunit of NMDA receptors. As mentioned before,glycine is an inhibitory neurotransmitter through its interactionwith strychnine-sensitive glycine receptors [64]. One possibility isthat the increased glycine interacts with strychnine-sensitive gly-cine receptors, thereby attenuating the beneficial effects of

NH2

S

O

HO

NH2

SH

OOH

OHHO

ONN

H2N

H2NN

N

O

OH

NH

O

OH

NH2

S

OOH

OHHO

ONN

H2N

N

N

Glycine

S-adenosylmethionine

Methionine

Sarcosine (N -methylglycine)

S-adenosylhomocysteine

GNMT

Figure 3. Sarcosine synthesis pathway. Sarcosine (N-methylglycine) is generated by the enzymatic transfer of a methyl group

from S-adenosylmethionine to glycine. This reaction is catalyzed by glycine N-methyltransferase (GNMT).

K. Hashimoto


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bitopertin. Another possibility may be an alteration of the gly-cine balance and activity of GlyT-1 and GlyT-2. GlyT-1 andGlyT-2 are two specific sodium/chloride-dependent high-affinity transporters, which regulate glycine synaptic levels inthe CNS. Finally, glycine is metabolized to L-serine byShmt1 (Figure 2) [29], and it is appropriate for this reaction tobe taken into consideration in this discussion.

3.7 Kynurenic acidKynurenic acid is synthesized from the essential amino acid,L-tryptophan, via L-kynurenine, and is produced and releasedby astrocytes in the brain (Figure 4). Tryptophan 2,3-dioxyge-nase (TDO2) is an enzyme in the first step of the kynureninepathway, while kynurenine 3-monooxygenase (KMO) is arate-limiting enzyme at the branching point of this pathway(Figure 4) [83]. In addition to its well-characterized action asa competitive antagonist of glycine modulatory sites onNMDA receptors (Figure 1), kynurenic acid also acts as a non-competitive antagonist at a7 nicotinic acetylcholine receptors(nAChRs). Both of these receptors are already implicated inthe pathophysiology of schizophrenia (Figure 4) [84-86].

Levels of kynurenic acid are increased in the CSF and brainsof patients with schizophrenia [87-90]. However, levels of3-hydroxykynurenine remained unchanged in the brain [89].Increased levels of TDO2 were reported in the anterior

cingulate cortex of schizophrenia [91], whereas KMO geneexpression and KMO enzyme activity were significantlydecreased in postmortem brain samples from schizophrenics [92].

Injections of L-kynurenine (100 mg/kg) increased extracel-lular levels of kynurenic acid (1500%) and induced cognitivedeficits in rats. Pretreatment with galantamine, a positivemodulator at a7 nAChRs, prevented these deficits [93].Increased kynurenic acid synthesis in the developing brainproduced long-lasting cognitive deficits in adult rats; however,these deficits could be restored to control levels by galant-amine [94]. Continuous administration of L-kynurenine dur-ing the prenatal period, but not adolescence, promotedcognitive deficits in adult rats. This implied that prenatalbut not adolescent exposure to L-kynurenine is sufficient tocause cognitive deficits in adulthood [95]. These findingssuggest that increased exposure to kynurenic acid duringdevelopment may result in cognitive deficits during adult-hood and that stimulation at a7 nAChRs could improve thesedeficits in rodents.

These combined results highlight the possibility thatincreased levels of kynurenic acid play a causative role in thepathophysiology of schizophrenia. Considering the possibleinteraction between the NMDA receptor and a7 nAChRsin schizophrenia, it is also likely that the kynurenine pathwaycould be a new therapeutic target in this disease [83-86,96].

L-Tryptophan

L-Kynurenine

Kynurenineaminotransferases

3-Hydroxykynurenine

Quinolinic acid

Kynurenic acid

7 nAch receptor

NMDA receptor

Serotonin5-Hydroxy

L-Tryptophan

KMO

IDO TDOTPH

N-Formylkynurenine

Formidase

Figure 4. L-Tryptophan in the serotonin and kynurenine pathways. The essential amino acid L-tryptophan is converted to

5-hydroxy L-tryptophan by tryptophan hydroxylase (TPH), and this is metabolized to 5-hydroxytryptamine (5-HT: serotonin)

by 5-hydroxytryptophan decarboxylase. The kynurenine pathway is initiated by the conversion of L-tryptophan to

N-formylkynurenine by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). N-Formylkynurenine is

metabolized to L-kynurenine by formidase. L-Kynurenine is metabolized to kynurenic acid by kynurenine aminotransferases.

L-Kynurenine is also metabolized to 3-hydroxykynurenine by kynurenine 3-monooxygenase (KMO) and then to quinolinic

acid. Kynurenic acid blocks both NMDA receptors and a7 nAChRs; both of which play a role in the pathophysiology ofschizophrenia.nAChRs: nicotinic acetylcholine receptors.



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4. Redox site of the NMDA receptor as atherapeutic target

4.1 GlutathioneGlutathione (GSH; L-glutamyl-L-cysteinyl-glycine), the most

abundant thiol present in mammalian cells, at concentrations

of up to 12 mM is a nucleophilic scavenger and an enzyme-

catalyzed antioxidant. It plays an important role in protecting

the brain against reactive oxidative stress and harmful xenobi-

otics [21,97,98]. GSH is synthesized in vivo in a two-step enzy-matic process by g-glutamylcysteine synthetase, therate-limiting enzyme that uses L-glutamate and L-cysteine as

substrates to form dipeptide g-glutamylcysteine. This is thencombined with glycine in a reaction catalyzed by GSH

synthetase to generate GSH (Figure 2). The balance of cellular

synthesis and consumption of GSH are regulated by feedback

inhibition of the g-glutamylcysteine synthetase reaction, bythe end product GSH (Figure 2) [21,97,98].GSH potentiates the NMDA receptor response to

glutamate [99] by acting at the redox modulatory site(s)(Figure 1) [100]. Do et al. [101] reported that the CSF levels ofGSH in drug-free patients with schizophrenia were a signifi-cant 27% lower than controls. A 1H-MRS study using adouble-quantum coherence filter technique demonstratedthat the levels of GSH in the medial prefrontal cortex ofpatients were 52% lower than controls [101]. However, a sub-sequent 1H-MRS study using stimulated echo acquisitionmode (STEAM) detected no differences in GSH levels inthe anterior cingulate cortex between chronically medicatedpatients and healthy control subjects [102]. Using MEGA-PRESS (MEscher-GArwood-Point RE-Solved Spectroscopy)sequence, we found a negative correlation between GSH levelsin the prefrontal cortex and the severity of negative symptomsin patients with schizophrenia, although no differences ofGSH levels were detected in the two groups [103]. By contrast,medial temporal lobe GSH levels in first-episode patients withschizophrenia were 22% higher than the control group and nosignificant relationship was observed between GSH levels andthe PANSS total score [104]. It is clear that further studies areneeded as current MRS study data are inconsistent.Decreased plasma levels of GSH and antioxidant enzyme

activities in both early and chronic schizophrenics have beenreported [105]. Furthermore, allelic variants of genes codingfor the key GSH synthesizing enzyme, glutathione cysteineligase modulatory (GCLM) and catalytic (GCLC) subunitsare associated with schizophrenia [106,107]. Polymorphisms oftrinucleotide repeats in the GCLC gene are associated withreduced enzyme activity and GSH levels [107]. These findingsimplicate dysfunctional regulation of GSH synthesis in thedisease pathophysiology of subjects with high-risk genotypes.It is therefore likely that abnormalities in the synthesis and

metabolism of GSH are active in the pathophysiology ofschizophrenia, pinpointing this system as a possible newtherapeutic target [108-111].

4.2 Effects of N-acetyl-L-cysteine in preclinical models

of schizophreniaN-acetyl-L-cysteine (NAC) is the N-acetyl derivative of theamino acid, L-cysteine. L-cysteine is rapidly oxidized tocystine, a substrate of the cystine-glutamate antiporter, inthe pro-oxidant milieu of the brain (Figure 5). This antiportertransports cystine into cells with a one-to-one counter-transport of glutamate. Inside the cell, cystine is reduced toL-cysteine, the rate-limiting component of GSH synthesis(Figure 5) [112,113]. As NAC has the capacity to regulate bothcystine-glutamate antiporter activity and the biosynthesis ofGSH, it is a highly attractive candidate to offer therapeuticbenefit for a number of neuropsychiatric diseases [112].

Previously, we reported that pretreatment with NAC attenu-ated behavioral abnormalities (e.g., hyperlocomotion andbehavioral sensitization) and dopaminergic neurotoxicity inrats after administration of the stimulant methamphetamine(METH) [114]. Furthermore, we reported that pretreatmentand subsequent treatment with NAC protected against dopami-nergic neurotoxicity in monkey striatum, after repeated doses ofMETH [115]. In addition, NAC reversed social withdrawalcaused by repeated dosing with the NMDA receptor antagonist,PCP, and this effect could be blocked by infusion of the cystine-glutamate antiporter inhibitor, (S)-4-carboxyphenylglycine,into the prefrontal cortex or systemic administration of thegroup II mGluR antagonist, LY341495 [116]. These findingsintimate that the effects of NAC require both cystine-glutamateantiporter and group II mGluR activation [116].

The GCLM gene KO mice, a model for increased oxidativestress, showed a selective decrease of parvalbumin-immunoreactivity (PV-IR) interneurons in CA3 and thedentate gyrus (DG) of the ventral hippocampus, and a con-comitant reduction of b/g oscillations [117]. At the end of ado-lescence/early adulthood, PV-IR neurons show impairment asoxidative stress increases or cumulates selectively in CA3 andDG of the ventral hippocampus [117]. Interestingly, treatmentwith NAC from gestation was able to normalize most neuro-chemical alterations in GCLM KO mice to wild-type lev-els [118]. In addition, GCLM KO mice show delayedmaturation of PV interneurons, and any additional oxidativechallenge in preweaning or pubertal, but not in young adultstages, reduces the number of PV-IR interneurons. Again,these effects were preventable by NAC treatment [119].Recently, it has also been reported that treatment with NAC(60 or 120 mg/kg/day) during developmental daysP42-P70 prevented increased sensitivity to amphetamine insocial isolation-reared mice [120]. It is highly plausible thatNAC may represent a potentially useful medication to preventconversion to schizophrenia in at-risk subjects [121].

4.3 Clinical findings for NAC in patients with

schizophreniaNAC has been in clinical use for over 30 years as an antidote inparacetamol overdose, a mucolytic for chronic obstructive

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pulmonary disease, a renal protectant in contrast-inducednephropathy and a therapeutic agent in the management ofHIV [112]. A randomized, multicenter, double-blind, placebo-controlled study showed that NAC (1 g/day for 24 weeks)improved the PANSS total score, PANSS negativesubscale score and Clinical Global Impression (CGI) scores(Table 1) [122]. Subsequent to this, Lavoie et al. [123] reportedthat treatment with NAC (2 g/day) improved impaired mis-match negativity (MMN) generation in schizophrenia patients,compared with the placebo group (Table 1). However, pretreat-ment with NAC (3 g) did not attenuate behavioral changes(such as psychotic-like symptoms, reductions in working mem-ory and sustained attention performance), impaired MMN andP300 event-related potentials in healthy subjects, after adminis-tration of ketamine (Table 1) [124]. A randomized, double-blind,placebo-controlled study demonstrated that NAC (2 g/day)modulated EEG synchronization in the brains of schizophrenics(Table 1) [125]. Additionally, a recent randomized, double-blind,placebo-controlled study demonstrated that augmentation withNAC (up to 2 g/day) promoted significantly greater improve-ment in PANSS total (p = 0.006) and negative subscale(p < 0.001) scores compared with the placebo group, indicatingthat NAC add-on therapy could be an effective augmentationstrategy for alleviating negative symptoms in schizophrenia(Table 1) [126]. These trials detected no significant differencesbetween NAC and placebo groups in the frequency of adverseeffects. A recent meta-analysis of 26 double-blind, randomizedcontrolled studies found that NAC (mean weighted effectsize = 0.45, n = 140) conferred significant beneficial effects in

patients with schizophrenia [127]. An open study demonstratedthat NAC (2 g/day for 12 weeks) improved scores on theSchizophrenia Cognition Rating Scale (SCoRS) and Schizo-phrenia Quality of Life Scale -- Japanese version (SQLS-J), infour subjects with at-risk mental state (Table 1) [128], implyingthat NAC may prevent the onset of psychosis.

It is likely that add-on of NAC could act as a therapeuticagent in schizophrenia, particularly since it is widely usedthroughout the world in a number of disorders [112,121,129].However, low bioavailability of NAC is an issue, necessitatingthe development of new compounds for the cysteine-glutamate antiporter or derivatives (e.g., NAC ethyl esterand NAC amide) of NAC [130,131].

5. Conclusion

This review provides an update on the therapeutic potential ofthe NMDA receptor in schizophrenia. The summarized dataseem to support the notion that abnormalities in variousendogenous substances able to impact on glutamatergicneurotransmission via the NMDA receptor may be implicatedin the pathophysiology of schizophrenia. Findings from anumber of preclinical and clinical studies put forward theNMDA receptor is a highly credible therapeutic target forthis disease. However, before the therapeutic potential oftargets based on the NMDA receptor hypothesis can beconfirmed, better categorization of this heterogenous diseaseis needed. This could be achieved by the use of novel diseasebiomarkers (e.g., blood levels of amino acids, oxidative

Cystine

Cystine-glutamateantiporter

Cystine

Extracellular

Intracellular

Glutathione (GSH)

N-acetylcysteine(NAC)

L-Glutamate

L-Glutamate

L-Cysteine

L-Cysteine

Figure 5. Regulation of the cystine-glutamate antiporter by N-acetylcysteine (NAC). Intracellular glutamate transports

extracellularly via the cystine-glutamate antiporter, while extracellular cystine moves intracellularly via the same mechanism.

NAC can increase extracellular L-cysteine levels, thereby activating L-glutamate release through the cystine-glutamate

antiporter. In turn released L-glutamate can potentiate glutamatergic neurotransmission via ion-channel and metabotropic

glutamate receptors. In the intracellular spaces, cystine can be reduced to L-cysteine, the rate-limiting component in the

synthesis of the key endogenous antioxidant, glutathione (GSH). GSH is synthesized from three amino acids, L-glutamate,

L-cysteine and glycine. Thus, administration of NAC can increase availability of L-cysteine, which in turn facilitates the

cystine-glutamate antiporter and the production of GSH in cells. This GSH can then potentiate NMDA receptor function.



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stress markers, inflammatory cytokines, neurophysiologicalmeasures, cognitive measures and gene analysis) [86,132-136].

6. Expert opinion

Schizophrenia is a chronic, debilitating psychiatric diseasethat affects ~ 1% of the worlds general population and is a lead-ing cause of disability. Despite recent advances in the psycho-pharmacological treatment of this disease, many patientsremain refractory to therapy or with residual symptoms, includ-ing negative symptoms (e.g., social withdrawal, lack of motiva-tion and reduced emotional reactivity) and cognitiveimpairment (e.g., processing speed and attention deficits, work-ing memory problems). Current antipsychotic drugs have a lim-ited impact on negative symptoms and cognitive impairment inschizophrenia. Added to this are treatment-resistant patientswho are largely resistant to current antipsychotic medications.A number of preclinical and clinical findings suggest

involvement of the NMDA receptor in the development ofnegative symptoms and cognitive impairment, since thisreceptor mediates the release of neurotransmitters, such asdopamine, glutamate, acetylcholine and GABA. Two recentPhase III studies found that addition of the GlyT-1 inhibitor,bitopertin, to antipsychotic therapy did not significantlyreduce prominent negative symptoms at 24 weeks, comparedwith placebo [79,80]. In addition, pomaglumetad methionil, ametabotropic glutamate mGluR2/3 agonist developed onthe basis of the glutamate hypothesis of schizophrenia, failedto significantly alleviate prominent negative symptoms inmedicated patients with schizophrenia [137,138]. On August29, 2012, Eli Lilly and Co. announced their decision tostop ongoing clinical studies investigating pomaglumetadmethionil in schizophrenia, due to a failure to meet the pri-mary end point [139]. Despite a number of preclinical modelsand translational efforts, clinical studies on these two drugshave not produced positive results. Since schizophrenia is aheterogenous disease, further randomized, placebo-controlledstudies using novel biomarkers and improved diagnoses, suchas Research Domain Criteria (RDoC) [140], will be necessaryto confirm the efficacy of new drugs developed in keepingwith the glutamate hypothesis of schizophrenia.Schizophrenia is typically diagnosed between the ages

16 and 25, indicating that onset of disease could be preventedby early intervention. Aversion of psychosis has become amajor objective in the field of clinical psychiatry. Approxi-mately one-third of subjects at high risk develop psychosiswithin 3 years, and most are diagnosed with schizophre-nia [141]. Epidemiological studies suggest that improvingnutrition and avoiding infection during pregnancy may pre-vent some cases of this illness [142]. For example, supplemen-tation with the correct amount of vitamin D in early lifecould decrease the risk of schizophrenia [141,142]. Interestingly,supplementation of omega-3 fatty acids in the form of fishoils could decrease the onset of psychosis for high-risk sub-jects, since omega-3 fatty acids are integral components of

neuronal membranes, which also act to dampen inflammationand oxidative stress [141,143].

Cognitive impairment is a core feature of schizophrenia, oftenpersisting even when positive symptoms (e.g., hallucinations,delusions and suspiciousness) have been treated successfully.A recent meta-analysis showed that adolescents and young adultsat high-risk for developing psychosis demonstrated cognitiveimpairment before the onset of psychosis [144]. Both preclinicaland clinical studies found that cognitive impairment could beimproved by current off-label drugs or supplements [145-149].As described above, the antioxidant NAC has the potential toprevent psychosis, although oral bioavailability of NAC ispoor. In a previous preclinical study, we reported that supple-mentation with D-serine during juvenile and preadolescentstages could prevent the onset of psychosis at the adult stage [55].A natural conclusion would be that supplementation with theendogenous, and therefore safe D-serine, could protect adoles-cents and young adults at high-risk of developing psychosis.

Sulforaphane (SFN) is obtained from cruciferous vegetables,such as broccoli and Brussels sprouts. SFN produces potent anti-oxidant and anti-inflammatory effects via the nuclear factorE2-related factor 2 (Nrf2)/Keap1 system. Previously, we reportedthat SFN conferred antipsychotic benefits in rodent models ofschizophrenia [150,151]. Interestingly, we found that supplementa-tion with SFN during juvenile stages could prevent the onset ofcognitive impairment in the preclinical PCP model of schizo-phrenia [152]. Therefore, supplementation with SFN-rich broc-coli sprout extract during childhood and pre-adolescence mayprevent the onset of psychosis in adulthood, assisted by the factthat this extract is widely available as a supplement.

These findings suggest that early intervention with safe sup-plements could improve cognitive impairment in adolescentsand young adults, and possibly prevent the onset of schizo-phrenia. Finally, we would like to propose a hypothesis thatnutrition in childhood and preadolescent stages could have ahigh impact on subsequent mental health at adolescent andadult stages, particularly the adequate intake of omega-3 fattyacid-rich fish and vegetables (e.g., SFN-rich broccoli sprout),and possibly prevent the onset of psychiatric diseases.

Acknowledgments

The author would like to thank the collaborators who workedon some papers described in this review article, and who arelisted as the co-authors of our papers in the reference list.

Declaration of interest

This study was supported by a Grant-in-Aid for ScientificResearch on Innovative Areas of the Ministry of Education,Culture, Sports, Science and Technology, Japan. The authorhas no other relevant affiliations or financial involvementwith any organization or entity with a financial interest in orfinancial conflict with the subject matter or materialsdiscussed in the manuscript apart from those disclosed.

K. Hashimoto


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39. Hashimoto K, Engberg G, Shimizu E,

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