Glutamate as a therapeutic target in psychiatric disorders
1Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research/New York University
School of Medicine, Orangeburg, NY 10962, USA
Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic
neurotransmission may be modulated at multiple levels, only a minority of which are currently
being exploited for pharmaceutical development. Ionotropic receptors for glutamate are
divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR
have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of
the NMDAR is currently a favored therapeutic target, with several modulatory agents currently
undergoing clinical development. Of these, the full agonists glycine and D-serine have both
shown to induce significant, large effect size reductions in persistent negative and cognitive
symptoms when added to traditional or newer atypical antipsychotics in double-blind,
placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT)
transporters, which regulate glycine levels, represent additional targets for drug development,
and may represent a site of action of clozapine. Brain transporters for D-serine have recently
been described. Metabotropic glutamate receptors are positively (Group I) or negatively
(Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are
currently under preclinical development for neuropsychiatric conditions, including schizo-
phrenia, depression and anxiety disorders. Other conditions for which glutamate modulators
may prove effective include stroke, epilepsy, Alzheimer disease and PTSD.
Molecular Psychiatry (2004) 9, 984–997. doi:10.1038/sj.mp.4001551
Published online 27 July 2004
Keywords: NMDA receptors; glycine; D-serine; amino acid transporters; schizophrenia
Glutamate is the primary excitatory neurotransmitter
in the mammalian brain. Approximately 60% of
neurons in the brain, including all cortical pyramidal
neurons and thalamic relay neurons, utilize glutamate
as their primary neurotransmitter.1As a result,
virtually all thalamocortical, corticocortical and cor-
ticofugal neurotransmission in the brain is mediated
by glutamate. Glutamate is released from presynaptic
terminals in response to neuronal depolarization, and
is recycled by excitatory amino acid (EAA) transpor-
ters located on both neurons and glia.2Within glia,
glutamate is converted to glutamine and released into
extracellular fluid from which it is reabsorbed into
presynaptic terminals and converted back to gluta-
mate via action of neuronal glutaminase. Up to 2/3 of
brain energy metabolism is related to reuptake and
recycling of glutamate.3As such, functional imaging
modalities, such as PET and fMRI, indexing activity
primarily of brain glutamatergic systems.4
The exchange of glutamine from glia to neurons is
accomplished by coordinated actions of two transport
systems, systems N and A, both of which are members
of sodium-dependent neutral amino acid (SNAT) family
of transporters.5These transport systems also transport
precursors for cysteine and glycine, which are precur-
sors to glutathione synthesis.6As these transporters are
electrogenic, glutamate transporters may also participate
in cellular signaling.7As with glutamate and GABA
transporters, these recycling systems may constitute
interesting targets for psychopharmaceutical research.
Glutamate receptor subtypes
Receptors for glutamate are divided into two broad
families (Figure 1). Ionotropic receptors are differen-
tiated based upon sensitivity to the synthetic glutamate
derivatives N-methyl-D-aspartate (NMDA), AMPA and
kainate. Metabotropic receptors, which are G protein
coupled and mediate longer-term neuromodulatory
effects of glutamate, are divided into groups on the
basis of effector coupling and ligand sensitivity.
NMDARs are the most complex of the ionotropic
receptors and a primary therapeutic target for psy-
chiatric disorders. In addition to the recognition site
for glutamate, NMDARs contain neuromodulatory
sites for glycine that has especially been a recent
target for drug development. The glycine site, like the
benzodiazepine site of the GABA receptor, affects
channel open time and desensitization rate in the
presence of agonist (glutamate), but does not, of itself,
Received 05 January 2004; revised 10 May 2004; accepted 20 May
Correspondence: Dr DC Javitt, MD, PhD, Program in Cognitive
Neuroscience and Schizophrenia, Nathan Kline Institute for
Psychiatric Research, 140 Old Orangeburg Road, Orangeburg,
NY 10962, USA. E-mail: email@example.com
Molecular Psychiatry (2004) 9, 984–997
& 2004 Nature Publishing Group All rights reserved 1359-4184/04 $30.00
induce channel opening. As such, chronic treatment
with glycine in rodents has been found not to induce
excitotoxicity.8,9Well-characterized antagonists have
been developed for both the glutamate and glycine
recognition sites (Figure 1), permitting detailed
physiological investigation. In addition, the NMDAR
complex contains regulatory sites that are sensitive to
polyamines, Zn2þ, protons and redox agents such as
NMDARs are blocked in a voltage sensitive manner
by Mg2þ, which binds to a site within the NMDA ion
channel. As a result, NMDARs are uniquely voltage-
as well as ligand (glutamate)-sensitive, which permits
them to participate in multiple neurocognitive pro-
cesses including long-term potentiation,11nonlinear
amplification,12and coincidence detection.13The
long time constants of NMDAR responses relative to
other ionotropic receptors also permit NMDAR to
participate in time-dependent processes such as
attentional gating or motion detection.14,15As small
large effects on NMDA activation and ultimate
neuronal output, the NMDA synapse is a site at
which convergent neuromodulatory inputs may pro-
duce large-scale changes in functional neuronal
NMDA receptors are composed of multiple subunits
including at least one NR1 subunit and one or more
modulatory subunits, labeled NR2A-NR2D. NR1 sub-
units are synthesized to excess in neurons, but are
retained in the endoplasmic reticulum until they
assemble with NR2 subunits. NR2D subunits are
expressed primarily during development and nor-
mally decline to low levels in adult brain. In adults,
NR2A and NR2B predominate in the forebrain, and
NR2C in the cerebellum. NR2B receptors show
prolonged channel open times and increased perme-
ability relative to NR2A, facilitating LTP and devel-
opmental plasticity. With synaptic experience, the
level of NR2B-containing receptors declines and
levels of NR2A-containing receptors increases, dis-
couraging further LTP.16,17
In order to participate in synaptic transmission,
NMDAR must dock to the postsynaptic density via
protein–protein interactions. The primary docking
protein for NMDAR is PSD95, which is part of a larger
postsynaptic density complex that regulates NMDA
clustering.18,19However, NMDAR may also remain
unbound in the membrane at extrasynaptic sites,
where they are activated only by pathological ‘spill-
over’ from the synaptic cleft.20Given the migration of
receptors between synaptic and extrasynaptic pool,21
alterations in NMDAR function may occur in the
absence of absolute changes in NMDAR density.
Because of the multiple modulatory sites, NMDAR
constitute a target-rich environment for drug research.
Extensive libraries of channel site (PCP receptor)
ligands have been developed, of which dizocilpine
(MK-801) is most potent and selective and serves as
the benchmark. A key identifying feature of the
channel site is its characteristic rank order of potency,
with MK-801 showing approximately 10-fold greater
potency than PCP, which in turn shows approxi-
mately 10-fold greater potency than ketamine.
Glycine22and D-serine23,24are endogenous ligands
for the glycine site of the NMDAR complex. D-
Cycloserine, an antituberculosis drug, fortuitously
crossreacts with the glycine site. However, it func-
tions as only a partial agonist, producing only
40–60% of the response seen with either glycine or
D-serine.25Attempts to modify glycine or D-serine to
produce synthetic glycine-site agonists have, so far,
been unsuccessful. Thus, aside from the use of
glycine or D-serine, indirect approaches must be taken
to activate NMDAR via the glycine site.
D-serine potentiates NMDAR-mediated neurotrans-
mission in vivo, suggesting that glycine sites are not
saturated under physiological conditions. Neverthe-
less, glycine sensitivity varies according to NR2
subunit, with NR2A-containing NMDAR showing
less sensitivity to glycine than those containing
NR2B subunits.26Because of differential saturation
under basal conditions, exogenously administered
D-serine may affect NR2A-containing
receptors to a greater extent than those containing
Glycine/D-serine modulatory processes
Glycine and D-serine bind to the NMDAR-associated
glycine binding site with affinity of approximately
100nM, yet are present extracellularly at concentra-
tions in the micromolar range27Thus, transport
processes must be present that regulate intrasynaptic
amino-acid levels relative to the larger extracellular
pool, and ‘protect’ the glycine-binding site from
overall brain glycine and D-serine levels.
Glycine is transported in the brain by several
transporters, including Type I (GLYT1) and Type II
NMDA¼N-methyl-D-aspartate; Gly¼glycine; PCP¼phen-
phencyclidine; AP5¼2-amino-5-phosphonovaleric acid; 7-
Schematic diagram of NMDA receptor complex—
Glutamate in psychiatric disorders
(GLYT2) glycine transporters, and System A-family
SNAT transporters.5,28,29GLYT1 and SNAT transpor-
ters, both of which are sensitive to inhibition by
sarcosine (N-methyl glycine) predominate in the
forebrain, whereas GLYT2 transporters are co-loca-
lized with strychnine-sensitive inhibitory glycine
receptors in the hindbrain.30As GLYT1 transporters
are coupled to only two Naþions, as opposed to
GLYT2 transporters, which are coupled to three, they
maintain relatively, shallow intracellelular to extra-
cellular gradients. As a result, GLYT1 transporters
most likely maintain synaptic glycine concentrations
in the high nanomolar range. Further, GLYT1 trans-
porters may function in either the forward or reverse
direction depending upon astrocytic membrane po-
tential, and may therefore dynamically regulate
extracellular glycine levels.31
System A transporters are expressed in both
neurons and glia, and transport a range of small
neutral amino acids (eg, glutamine, proline, serine)
along with glycine. The role of System A transporters
in glycine homeostasis is still under evaluation.
SNAT2-type System A transporters, for example,
mediate amino-acid efflux from the CNS across the
blood–brain barrier.32Blockade of these transporters,
therefore, would be expected to increase CNS levels
of glycine along with other small neutral amino acids.
D-Serine is synthesized in the brain from glycine via
serine racemase,33–35and degraded by actions of D-
amino acid oxidase (DAAO), which is primarily
expressed in the cerebellum with lower expression
in the forebrain. DAAO is modulated by the recently
described protein G72.36Mechanisms underlying
regulation of synaptic D-serine levels in the brain
are poorly understood. Traditional transport systems
show limited affinity for D-serine, although selective
high-affinity D-serine transporters have recently been
described.37,38As with glycine transporters, these may
represent selective targets for the modulation of brain
AMPA and kainate receptors mediate the majority of
fast glutamatergic in the brain. AMPA receptors are
composed of combinations of GluR1-4 subunits, and
work heavily in concert with NMDA receptors.
Mature AMPA receptors containing the GluR2 sub-
unit are Ca2þimpermeant,39and thus do not directly
trigger LTP. Nevertheless, AMPA receptors provide
the primary depolarization necessary to unblock
NMDA receptors and to permit calcium entry into
the cell. Synergistically, Ca2þ
blocked NMDA receptors triggers AMPA insertion
into the postsynaptic density and synaptic strength-
ening. AMPA receptors, however, are continuously
recycled, leading to gradual synaptic weakening. If
AMPA density falls below a critical threshold, levels
of depolarization are insufficient to unblock NMDA
channels, preventing subsequent AMPA activation.
Such synapses, despite containing histologically
entry through un-
identifiable NMDAR, are functionally silent, and
cannot be recovered by electrical stimulation alone.40
Selective, high-potency AMPA antagonists have
been developed, and may be effective in conditions
such as stroke or epilepsy, which are characterized by
hyperglutamatergia.41As AMPA receptors densensi-
tize rapidly following stimulation, direct AMPA
agonists are unlikely to be therapeutically useful.
However, compounds have been developed that
potentiate AMPA transmission without binding di-
rectly to the agonist binding site.42Termed AMPA-
processing in animals,14and are currently under
development for treatment of cognitive dysfunction
in various neuropsychiatric disorders.
Metabotropic receptors, which serve to regulate
glutamatergic neurotransmission both pre- and post-
synaptically, may serve as an alternative molecular
target for treatment of schizophrenia. Metabotropic
receptors are divided into three groups based upon
second messenger coupling and ligand sensitivity.
Group I receptors are positively linked to phospholi-
pase C, whereas both group II and III receptors are
negatively linked to adenyl cyclase.43As a result,
group I receptors function predominantly to potenti-
ate both presynaptic glutamate release and postsy-
naptic NMDA neurotransmission,44with mGLUR5
receptors showing significant colocalization with
NMDA receptors in rodents.45In contrast, group II
and III receptors, in general, serve to limit glutamate
release, particularly during conditions of glutamate
spillover from the synaptic cleft. Thus, group I
agonists or positive modulators would be expected
to stimulate NMDAR-mediated neurotransmission,
and group I antagonists to inhibit it. In contrast,
group II/III agonists or positive modulators would be
expected to inhibit presynaptic glutamate release. As
extrasynaptic levels of glutamate are low under
physiological conditions, group II/III antagonists
would have minimal effects.
PCP/NMDA models of schizophrenia
Schizophrenia is currently the best established of the
potential therapeutic targets for glutamate. Symptoms
of schizophrenia are divided into three main clusters:
positive, negative and cognitive. Negative and cogni-
tive symptoms, in particular, respond poorly to
current treatments approaches and are primary pre-
dictors of poor functional and therapeutic outcome in
Psychotomimetic effects of NMDAR antagonists
strongest line of evidence linking schizophrenia to
associated ionophore.46This finding has led, over
Glutamate in psychiatric disorders
recent years, to multiple theoretical formulations
focusing on either NMDAR47–49or glutamergic50,51
dysfunction in the etiology of schizophrenia.
The most widely recognized NMDAR antagonists,
phencyclidine (PCP) and ketamine, have been exten-
sively characterized in both animal models and
challenge studies with normal volunteers. Several
other PCP-like agents, however, have been developed
over the past several decades either as ‘designer drugs’
(eg, TCP) or by the mainstream pharmaceutical
industry (eg, dizocilpine, MK-801). The potency with
which these agents bind to the NMDA-associated PCP
receptor and block NMDA channels correlates closely
with their ability to induce behavioral change in
rodents, cognitive disruption in monkeys and psycho-
tomimetic effects in humans. Although NMDA ligands
such as PCP and ketamine may crossreact at high dose
with multiple receptors (eg, D2 and 5-HT2 receptors52),
the rank order of these interactions corresponds poorly
to the rank order for producing psychotomimetic
effects, limiting the usefulness of such observations.
Cognitive and neurochemical effects of NMDA
The ability of NMDAR antagonists, including both
PCP and ketamine, to induce symptoms closely
resembling those of schizophrenia was first docu-
mented over four decades ago.53–56More recent
studies have confirmed and extended these findings
with more modern neurocognitive measures. For
example, learning and memory are among the most
selectively affected processes in schizophrenia,57,58
consistent with the critical role played by NMDAR in
hippocampal LTP.59Similarly, PCP60and ketamine61
induce a pattern of thought disorder and sensory
dysfunction62that is statistically indistinguishable
from that of schizophrenia.
Individuals with schizophrenia show greater sensi-
tivity than normal individuals to psychotomimetic
effects of both PCP63and ketamine,64–66suggesting
that these compounds affect a system that is already
vulnerable in schizophrenia. Even among nonschizo-
phrenic individuals, reduced NMDAR activity, as
reflected in measures such as decreased amplitude of
mismatch negativity (MMN), predicts sensitivity to
psychosis during ketamine challenge.67
In rodents, NMDAR antagonists induce a range of
acute effects, including locomotor hyperactivity, pre-
pulse inhibition (PPI) deficits, prolongation of latent
inhibition (LI), and disruption of working memory,
many of which are highly reminiscent of symptom of
schizophrenia. In primates, NMDAR antagonists also
produce working memory68,69and PPI70–72deficits,
supporting the relevance of glutamate receptors as
therapeutic targets in schizophrenia.
Despite the similarity of effect especially between
animal find, care must be taken in use of these models
for predicting therapeutic response in schizophrenia.
Schizophrenia is a chronic disorder that develops
gradually over time, with negative symptoms and
cognitive dysfunction developing early and positive
symptoms emerging gradually as the prodrome
progresses. Thus, acute treatment models at most
can be viewed as reproducing the early symptoms of
schizophrenia. In humans, acute treatment with
ketamine induces high levels of anxiety that are not
typically seen in established schizophrenia, but fails
to reproduce the hallucinatory behavior that emerges
over time during the schizophrenia prodrome73,74
As an alternative to acute treatment models,
neurodevelopmental and chronic treatment models
may provide a more appropriate vehicle for drug
development. Prolonged NMDAR blockade can be
induced by repeated or continuous administration of
NMDAR antagonists in rodents75,76or primates.77,78
As compared with acute treatment in humans,
chronic treatment in monkeys leads to appearance
of hallucinatory-like behavior,77suggesting that dys-
regulation of relevant brain systems may emerge
gradually over time.
Over recent years, more ecological models of
schizophrenia have been reproduced by manipulation
of NMDAR expression. Initial studies were performed
with NR1-knockdown mice, which showed hyperac-
tivity and social withdrawal.79Similar effects have
been observed more recently with knockouts affecting
the mouse NRe1 subunit (equivalent to rat NR2A),80
and mutations affecting only the glycine/D-serine
binding site.81Both mutants show persistent hyper-
activity and stereotypic behaviors that are resistant to
reversal with either antipsychotics or benzodiaze-
pines, indicating that dysfunction of the glycine-site
itself is sufficient to cause schizophrenia-like beha-
vioral abnormalities. In contrast to knockdown mice,
NR1 overexpressing mice show increased learning
ability,82as do mice with partial GLYT1 receptor
knockouts,83emphasizing the potential importance of
NMDAR dysfunction to cognitive impairments in
A final approach has been the use of persistent
NMDAR antagonist treatment, followed by withdra-
wal. Studies with such models have shown persistent
alterations in cognitive performance and dopamine
turnover in frontal lobe.84,85A caution regarding such
models, however, is that psychotomimetic effects of
PCP or ketamine rarely persist for more than 1–2
weeks following discontinuation of abuse,63even
though repeated abuse may lead to persistent neuro-
cognitive deficits.86,87High doses of NMDAR antago-
nists, including PCP, ketamine and MK-801, lead to
well-described neurotoxic effects, particularly in
frontal and cingulate brain regions.88Thus, use of
NMDAR antagonist treatment/withdrawal models
may selectively model drug-induced neurodegenera-
tion, without specifically modeling schizophrenia.
Alternative glutamatergic models
treatment, NMDAR antagonists stimulate prefrontal
Glutamate in psychiatric disorders
induce schizophrenia-like impairment in cognitive
performance.89Support for a role of glutamatergic
ketamine-induced glutamate release and deficits in
working memory performance were reduced by
treatment with a metabotropic group II agonist.91
administered with ketamine.92Prefrontal glutamate
levels are also increased by chronic stress93and
ketamine-induced behavioral alterations are blocked
by AMPA/kainate antagonists as well as lamotrigine89
leaving unresolved the specificity of this finding to
which may independently
glutamate theory of schizophrenia is based upon the
observation that NMDAR antagonists, including PCP,
ketamine and MK-801 induce neurodegeneration of
administration.47,94In this model, often termed the
NRH model, it is proposed that symptoms of
schizophrenia do not reflect acute NMDA blockade,
but rather NMDA-induced apoptotic changes in
susceptible brain regions, particularly frontocingu-
late areas.47Many treatments are known to prevent
NMDA-antagonist induced neurotoxicity, including
clonidine, guanabenz, benzodiazepines, and LSD.47,95
Few of these treatments, however, reverse the acute
psychotomimetic effects of NMDAR antagonists or
ameliorate persistent symptoms of schizophrenia. It
is, therefore, unlikely that ongoing NMDAR-induced
apoptosis contributes directly to psychotic symptoms,
contribute to the gradual cognitive decline seen in
some individuals with schizophrenia.
Therapeutic targets based on glutamate models of
NMDAR glycine-site agonists
To date, the strongest clinical data validating gluta-
matergic approaches for schizophrenia come from
studies with NMDAR glycine-site agonists, which
function as positive allosteric modulators of the
NMDAR complex. Studies have been conducted with
three separate agents: glycine and D-serine, which
function as full agonists, and D-cycloserine, which
functions as a partial agonist. Glycine has been found
to be effective at a dose of 30–60g/day (0.4–0.8g/kg/
day); D-serine, at a dose of 2.1g/day (0.03g/kg/day)
and D-cycloserine at a dose of 50mg/day. With both
glycine and D-serine, effectiveness of higher doses has
not been explored so that maximal benefit obtainable
from glycine-site stimulation is unknown. With D-
cycloserine, doses in excess of 100mg cause symptom
exacerbation due to emergent NMDAR antagonist
effects, producing a narrow therapeutic window.96
Results of clinical trials conducted with NMDAR
agonists have been consistent across studies (Table 1).
All studies have demonstrated large effect-size (0.9–
2.1 SD units) improvement in negative and cognitive
symptoms when these agents are added to typical
antipsychotics, or newer atypicals. Percentage im-
provement in negative symptoms range from 16 to
39% (weighted mean 30%) for trials in the range of
6–12 weeks. Whether greater reduction occurs during
serine (DSER) and the partial agonist D-cycloserine (DCS) in combination with typical, atypical or mixed antipsychotics in
Summary of clinical findings with the full N-methyl-D-aspartate receptor glycine-site agonists glycine (GLY) and D-
Negative Cognitive Positive
Study Agonist AntipsychoticN % changeP % changeP % changeP Ref
Heresco-Levy et al (1999)
Javitt et al (2001)
Evins et al. (2000)
Tsai et al. (1998)
Tsai et al (1999)
Goff et al (1999)
Heresco-Levy et al (2002)
Goff et al (1999)
—¼not determined; NS¼not significant.
cSignificant difference with SANS only; PANSS difference not significant.
dPositive value represents significant worsening of symptoms.
Glutamate in psychiatric disorders
longer-term treatment, or whether tolerance develops,
is currently unknown. The level of cognitive and
positive symptom improvement, across studies, is
roughly 15%. In some, but not all, studies degree of
negative symptoms improvement correlated signifi-
cantly with baseline glycine levels, suggesting that
patients with lowest pretreatment levels respond best
to NMDAR agonist treatment.
In contrast to effects in combinations with typical
or newer atypical antipsychotics, glycine site agonists
may be ineffective when combined with clozapine. In
double-blind, placebo-controlled studies in which
glycine97or D-serine98have been added to clozapine,
no significant beneficial response has been observed,
while D-cycloserine is reported to lead to worsening
of symptoms when used in combination with cloza-
D-Cycloserine functions as a glycine site
agonist in the presence of high glycine concentra-
tions, and as an antagonist in the presence of high
concentrations.25A parsimonious explanation for the
D-cycloserine induced worsening of symptoms, there-
fore, is that clozapine may already increase synaptic
glycine levels through as yet unknown mechanisms.
Recently, clozapine has recently been shown to block
glycine and glutamine transport mediated by SNAT2-
like synaptosomal transporters, providing a potential
mechanism for both the differential therapeutic
effects of clozapine and the differential effects of
NMDAR modulators in the presence of clozapine vs
other antipsychotics.29This finding may also account
for the reported ability of clozapine to increase serum
glutamate levels,100and downregulate central gluta-
Glycine transport inhibitors
Both glycine and D-serine appear to be effective when
used in treatment resistant schizophrenia. However,
both must be given at gram-level doses in order to
significantly elevate CNS levels. An alternative
approach to increasing CNS levels is use of glycine
transport inhibitors (GTIs), which raise synaptic
glycine levels by preventing its removal from the
synaptic cleft. Use of GTIs to augment NMDA
functioning is analogous to use of selective serotonin
reuptake inhibitors (SSRIs) to raise synaptic serotonin
levels in depression.
Initial studies were performed using the relatively
nonselective glycine transport antagonist, glycyldo-
decylamide (GDA). This drug was shown to inhibit
glycine transport in cortical103or hippocampal104
synaptosomes, and inhibit amphetamine-induced
dopamine release105and PCP-induced hyperactivity
in rodents.106–108More recent studies have been
performed with selective, high-affinity GTIs such as
sarcosine (NFPS)109or Org 24598.110
As with GDA, high affinity GTIs have been found to
reverse PCP-induced hyperactivity111and dopaminer-
gic hyperreactivity112in rodents, and to potentiate
and NMDAR-dependent re-
sponses in prefrontal cortical neurons.114GTIs also
reverse PPI abnormalities in DBA/2J mice113and rats
with neonatal hippocampal lesions,115supporting a
potential role of GTIs in treatment of schizophrenia.
To date, only a single clinical trial using GTIs in
schizophrenia has been conducted. In that study,
sarcosine (N-methyl glycine) induced a highly sig-
nificant, approximately 15% reduction in negative
symptoms, along with significant reduction in posi-
tive and cognitive symptoms and total PANSS
score,116strongly supporting the potential therapeutic
utility of GTIs in schizophrenia.
Other ionotropic targets
As AMPAR function in concert with NMDAR, they
have been proposed as alternative therapeutic targets
in schizophrenia. In animal studies, AMPAkines act
synergistically with antipsychotics to reverse amphe-
tamine-induced hyperactivity.117To date, a single
clinical study has been performed with the AMPA-
kine CX-516 added to clozapine. In this study,
significant improvements in memory and attention
were observed despite lack of symptomatic improve-
ment.118CX-516 has also been studied as monother-
apy, with no clear beneficial effects.119Although
downregulation of AMPA receptors is less with
AMPAkines than with direct agonists, there is some
concern that downregulation may nonetheless occur
and may limit long-term treatment strategies.120
Lamotrigine, an antiepileptic that reduces presy-
naptic glutamate release, has also been proposed as a
potential adjunctive medication
nia.121,122In humans, lamotrigine prevented acute
psychotomimetic effects of ketamine, with greater
effects on positive than negative symptoms.121Im-
provements in positive and general symptoms have
been reported as well in small-scale studies of
lamotrigine in clozapine-treated patients with persis-
tent clinical symptoms.123,124If confirmed, these
results would suggest a greater potential role of
glutamatergic hyperactivity in persistent positive
symptoms of schizophrenia, and of NMDAR under-
activity in persistent negative symptoms.
Metabotropic modulators are currently in an early
stage of development for treatment of schizophrenia.
Studies attempting to validate metabotropic receptors
as therapeutic targets in schizophrenia have been
based on two alternative conceptualizations of the
disorder. Group I receptors potentiate presynaptic
glutamate release and NMDAR-mediated neurotrans-
mission. Therapeutic effectiveness of group I agonists
is therefore predicted based upon models which
postulate low NMDAR receptor activity and/or gluta-
mate levels as being pathophysiological in schizo-
phrenia. In contrast, Group II/III agonists inhibit
glutamate release. Use of these agents follows models,
which postulate that glutamatergic hyperactivity may
Glutamate in psychiatric disorders
Group I receptors
and mGLUR5 receptors, both of which stimulate
cascades.125,126Preclinical studies have evaluated the
ability of Group I antagonists to induce schizophrenia-
like behavioral effects, and Group I agonists to
reverse effects of amphetamine, PCP and other
psychotomimetics. The most widely used mGluR5
(MPEP), does not affect locomotor activity or PPI by
itselfbut potentiates PCP-induced
Similar effects have been observed with the more
recently develop compound 3-[(2-Methyl-1,3-thiazol-
disruptions of PPI, which respond poorly to known
treatments for schizophrenia,132supporting a potential
role of Group I receptors as therapeutic targets in
schizophrenia. Group I antagonists also produce
anxiolytic-like effects in several animal models of
anxiety, suggesting that they may be independent
targets for the treatment of anxiety disorders.133
Studies with Group I agonists have also been
supportive of potential therapeutic effectiveness, but
are more limited. For example, the mGluR5 agonist 2-
found to reverse PPI-disruptive effects of ampheta-
mine in rodents.128Similarly, both nonselective and
Group I selective agonists inhibit PCP-induced dopa-
mine release in rodent prefrontal cortex.134An issue
in the use of direct agonists is rapid receptor
desensitization, preventing chronic use. An alterna-
tive approach is the use of positive allosteric
modulators, which, do not bind directly to the
agonist-binding site. Positive modulators, in general,
have proven to be lipophilic and centrally acting,
making them attractive as potential pharmacological
Despite some encouraging results with Group I
agonists in animal models, clinical data remain
lacking. Further, group I receptors have a markedly
different cellular distribution in primates than ro-
Thus, primate studies and eventual
clinical trials will be needed to validate this target
for treatment of neuropsychiatric disorders.
Group I includes both mGLUR1
knockout mice show
Group II metabotropic agonists
metabotropic receptors are negatively linked to
glutamate release, and may limit endogenous release
under conditions of glutamate excess. Use of Group
II/III agonists in schizophrenia is therefore based
upon the hypothesis that increased glutamate levels
may be pathophysiological. Several high-affinity
agonists have been developed over recent years,
compound LY-354740, permitting characterization of
effects of Group II agonists in both preclinical and
Group II and III
An initial study with LY-379268 demonstrated
its ability to block PCP-induced increases in pre-
frontal glutamate, along with PCP-induced impair-
ments in working memory, suggesting a role of
glutamatergic hyperactivity in at least some forms of
prefrontal dysfunction.90,91Similarly, LY3279268 has
been shown by a variety of groups to inhibit PCP-
induced hyperactivity during both acute139,140and
repeated141administration, and reverse PCP-induced
behaviors in monoamine depleted mice.142Finally,
these drugs reverse ketamine-induced stimulation
which may also be linked to prefrontal hypergluta-
In contrast to its effects on glutamate, group II
agonists do not inhibit,90
NMDAR antagonist effects on PFC DA release,
suggesting a dissociation in the regulation of pre-
frontal glutamate and dopamine systems. Group II
agonists also do not reverse PCP-induced behavioral
sensitization,141PCP- or apomorphine-induced dis-
ruption of PPI,144or MK-801-induced disruption in
Based upon the effect of group II agonists on
prefrontal glutamatergic hyperactivity, it has been
proposed that these agents may be therapeutically
beneficial in treating persistent cognitive deficits in
PCP are related to alterations in glutamatergic vs
Clinical trials of mGluR2 agonists may thus help
clarify pathophysiological mechanisms in schizo-
phrenia. To date, no significant beneficial effects of
LY-354740 or other group II agonists have been
Group II receptors, like Group I receptors, may
desensitize during chronic treatment. As with Group I
receptors, therefore, positive allosteric modulators
may ultimately prove more useful than direct ago-
nists.90,135,145Group III metabotropic receptors are less
studied than groups I or II. Nevertheless, group III
agonists, like group II agonists, may induce antianxi-
ety and antidepressant effects, and may also represent
an appropriate therapeutic target.146
and may enhance,134
is not known.
Although glutamate receptors have been studied most
intensively in relationship to psychotic disorders,
both ionotropic and metabotropic receptors may also
represent appropriate targets for other neuropsychia-
tric disorders. Stimulation of glutamatergic systems
may be beneficial in disorders associated with
primary memory disturbances, whereas inhibition
may be beneficial in disorders associated with
neurodegeneration. Effects of glutamatergic agents
have been studies most intensively with regard to
Alzheimers disease (AD), anxiety, depression and
Glutamate in psychiatric disorders
Alzheimer disease (AD), like schizophrenia, shows
widespread neuronal changes, indicating involve-
ment of cortical glutamatergic systems. In Alzheimers
disease, NMDAR antagonists have been used to
attempt to slow excitotoxic neurodegeneration. In
particular, memantine, a weak NMDAR channel
blocker, has shown safety and efficacy in slowing
decline in moderate to advanced AD.147The toler-
ability of memantine relative to other channel block-
ers (eg, PCP, MK-801) appears to be due to its low
affinity, fast unblocking kinetics and limited liability
for trapping within closed channels.148
In contrast to stroke or hypoxia where excitotoxi-
city is due to excessive phasic glutamate release,
excitotoxicity in AD has been proposed to result from
tonic glutamatergic overactivation, possibly due to
loss of normal voltage-dependent Mg2þblockade of
NMDAR. Memantine, which functions analogously to
Mg2þin producing voltage-dependent NMDAR block-
ade, may thus take over the physiological role of
Glutamatergic hyperactivity may be of
particular relevance to AD due to a specific role of a
beta-amyloid in the regulation of astrocytic glutamate
clearance mechanisms.150,151To the extent that this
process underlies neurodegeneration in other dis-
orders, memantine may prove effective as well.
Based upon effectiveness of memantine, other
glutamate-reducing treatments have also been pro-
posed for treatment of AD. These include Group I
metabotropic antagonists, which would be predicted
to reduce NMDAR activation,152and group II/III
agonists, which are reported to prevent neurodegen-
eration in a variety of clinical models.138To date,
however, clinical data are lacking.
As deficits in learning and memory are central to
AD, NMDAR and AMPAR agonists would be pre-
dicted to have immediate symptomatic benefit,
although potentially at the expense of increased
neurodegeneration. The most widely studied com-
pound to date has been D-cycloserine. A large-scale
double-blind, placebo controlled trial of 5, 15 and
50mg/day D-cycloserine for treatment of AD failed to
show overall significant benefit,153although some
effect on implicit memory was observed.154
Since then, conflicting results with higher doses
have been reported, with one study failing to find
efficacy in a dose-escalation study,155but another
study finding efficacy of a fixed dose of 100mg/day D-
cycloserine on cognitive functioning.156Limited ef-
fectiveness of NMDAR glycine-site agonists may
related to the reported loss of glycine binding sites
in AD,157although studies with full glycine-site
agonists appear warranted. AMPAkines are also under
active investigation for treatment of AD, with SBIR-
funded clinical trials scheduled for completion in the
second quarter of 2003.158
At present, the primary treatments for anxiety—
benzodiazepines and barbiturates—function by in-
creasing inhibitory, GABAergic neurotransmission.
On the simplest level, a similar neurochemical effect
could be achieved by reducing excitatory glutamater-
gic neurotransmission. Inhibitors of presynaptic glu-
tamate release, AMPA receptor antagonists, or group
II or III metabotropic agonists could in theory, achieve
such an effect. More specific data implicating gluta-
mate in anxiety disorders comes from findings that
both stress93and acute treatment with NMDAR
antagonists89,91increase prefrontal glutamate levels
in rodents. Although most studies emphasize the
psychotomimetic effects of acute NMDAR treatment
in humans, anxiogenic effects are equally pro-
nounced,73,74and, as opposed to psychotomimetic
and cognitive effects, can be reversed by treatment
Lamotrigine has proven effective in treatment of
agitation in rapid cycling bipolar disorder,160but no
data are yet available relating to treatment of primary
anxiety disorders with either lamotrigine or AMPA
effects have been reported for both group I antagonists
and group II metabotropic agonists.133Further, the
group II agonist LY-354740 was recently shown to be
effective in reducing fear-of-shock induced startle
potentiation and subjective anxiety in normal volun-
teers, although it was ineffective in potentiating
darkness-induced startle augmentation.161,162
agent also produces anxiolytic-like effects in rodents
supporting the concept that such agents may serve as
novel anxiolytics.162To the extent that group II
agonists ultimately prove more effective as anxioly-
tics than antipsychotics,163it would suggest that
preclinical glutamatergic hyperactivity may be more
relevant to anxiety disorders than psychosis.
agonists may prove effective, some data suggest a
therapeutic role for NMDAR antagonists in depres-
sion. The original observations date back to the
early 1960s, with the observation that tuberculosis
patients treated with D-cycloserine at NMDAR an-
At the time, interactions of
NMDAR had not yet been described, and the
observation with D-cycloserine was ignored in favor
of monoamine oxidase inhibitors. Since then, other
noncompetitive and competitive NMDAR antagonists
were also shown to have antidepressant like effects in
animal models, although clinical utility of these
agents is limited by psychotogenic potential in
Most recently, lamotrigine has proven effective in
treatment of persistent depression in bipolar disor-
der,160and single doses of ketamine have been
reported to produce antidepressant effects persisting
for over 72h following infusion in unipolar depressed
patients.166,167Preclinical antidepressant-like effects
have also been reported for group I metabotropic
antagonists, which would be expected to inhibit
Glutamate in psychiatric disorders
as for group II162and group III169metabotropic
At present, mechanisms underlying potential anti-
depressant effects of glutamate antagonists remain
unclear. One observation is that these agents induce
downregulation of b-adrenergic receptors, an effect
common to other antidepressant treatments.165De-
pression is also associated with disturbances in
hippocampal LTP170,171and neurogenesis,172,173which
might be affected either by NMDAR blockade or
subsequent rebound. The finding that antidepressant
effects of ketamine do not begin until after clearance
of ketamine from serum and cessation of its psycho-
tomimetic effects in particular support a rebound
hypothesis, and correspond to preclinical studies
showing increased neurogenesis 2–7days following
acute NMDAR antagonist treatment in rodents.174In
preclinical studies, chronic MK-801 treatment pre-
vents both neurochemical and behavioral conse-
quences of antidepressant treatment,175,176leaving
unresolved the ideal role of NMDAR antagonist
treatment in the management of persistent depres-
A final condition for which glutamate receptors might
serve as therapeutic targets is PTSD. In PTSD,
pathological associations are learned under condi-
tions of extreme stress, and must subsequently be
unlearned. Stress induced reductions in hippocampal
plasticity and neurogenesis may also contribute to
difficulties in memory unlearning
NMDAR play a highly selective role in reversal
learning. In animals, NMDAR antagonists produce
deficits in reversal learning at doses that do not
inhibit learning of primary tasks.177,178Further, low
dose D-cycloserine stimulates reversal learning in
septally179and hippocampally180lesioned rats.
In one pilot study, treatment with D-cycloserine
(50mg/day) significantly reduced PTSD symptoms
and improved cognitive performance as measured by
WCST.181However, similar behavioral effects were
observed in the placebo group, necessitating larger
scale studies with both partial and full NMDAR
agonists. Further, preclinical studies would suggest
that ideal use of these compounds would be in
combination with other forms of desensitization
Whereas the role of acetylcholine in neurotransmis-
sion was discovered in the 1920s, and that of
monoamines was discovered in the 1950s, glutamate
was not shown definitively to serve as a neurotrans-
mitter in the mammalian nervous system until the
1970s, and glutamate receptors were not differen-
tiated until the early 1980s. It is not surprising
therefore that therapeutic drug development for
glutamatergic neurotransmitters is substantially be-
hind that for other systems. To date, pharmaceutical
company activity has been geared primarily to the
creation of direct agonists and antagonists of the
various ionotropic and metabotropic receptors. More
nuanced treatment, however, may be possible with
agents that serve as modulators, rather than direct
agonists or antagonists of the various receptors.
Further, as with monoamine and acetylcholine sys-
tems, synthetic and degratory enzymes, and espe-
cially neurotransmitter reuptake sites, may prove
highly effective targets for psychotherapeutic devel-
In the case of NMDAR, the glycine regulatory site is
a target of active drug development, with glycine site
agonists such as glycine, D-serine and D-cycloserine
currently under development as treatments for per-
sistent negative symptoms of schizophrenia. High-
affinity antagonists for GLYT1-type glycine transpor-
ters have also been developed and shown to be
systemically active. More recently described D-serine
and small neutral amino-acid (SNAT) transporters
may serve as additional targets. Further, distinctive
clinical effects of clozapine may result from its
Alzheimers disease, potentially by blocking neuro-
toxic effects of tonically elevated synaptic glutamate
In the case of AMPA receptors, positive allosteric
modulators (AMPAkines) have been developed and
are undergoing clinical development for cognitive
neurocognitive disorders. Direct agonists, antagonists,
and allosteric modulators have been developed
for group I and group II metabotropic receptors,
and are undergoing clinical development for both
diseases that may respond to glutamatergic or
where rebound from NMDAR blockade may trigger
therapeutic neurogenesis, and PTSD, where positive
effective especially in combination with behavioral
At present, many of the key compounds required
for both preclinical and clinical testing in this area
remain proprietary. As these compounds become
more generally available, it is expected that progress
in development of glutamatergic therapies will con-
tinue to accelerate.
along with other
Preparation of this manuscript was supported in part
by USPHS Grants K02 MH01439, R01 DA03383, and
R37 MH49334, and by a Clinical Scientist Award in
Translational Research from the Burroughs Wellcome
Glutamate in psychiatric disorders
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