Schizophrenia Research 223 (2020) 59–70

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Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Glutamate in schizophrenia: Neurodevelopmental perspectives and

drug development
Alice Egerton a,⁎, Anthony A. Grace b, James Stone a, Matthijs G. Bossong a,c, Michael Sand d, Philip McGuire a
a
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
b
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA
c
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
d
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

a r t i c l e i n f o a b s t r a c t

Article history: Research into the neurobiological processes that may lead to the onset of schizophrenia places growing emphasis
Received 19 August 2019 on the glutamatergic system and brain development. Preclinical studies have shown that neurodevelopmental,
Received in revised form 12 August 2020 genetic, and environmental factors contribute to glutamatergic dysfunction and schizophrenia-related pheno-
Accepted 20 September 2020
types. Clinical research has suggested that altered brain glutamate levels may be present before the onset of psy-
Available online 16 October 2020
chosis and relate to outcome in those at clinical high risk. After psychosis onset, glutamate dysfunction may also
Keywords:
relate to the degree of antipsychotic response and clinical outcome. These findings support ongoing efforts to de-
Glutamate velop pharmacological interventions that target the glutamate system and could suggest that glutamatergic com-
Psychosis pounds may be more effective in specific patient subgroups or illness stages. In this review, we consider the
N-methyl-D-aspartate receptor updated glutamate hypothesis of schizophrenia, from a neurodevelopmental perspective, by reviewing recent
preclinical and clinical evidence, and discuss the potential implications for novel therapeutics.
© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction response is poor (Mailman and Murthy, 2010), even when there is ade-
quate dopamine receptor 2 (D2) occupancy (Nordstrom et al., 1993).
The glutamate hypothesis of schizophrenia, as proposed in the 1990s Furthermore, D2 antagonist antipsychotic drugs have relatively little ef-
(Javitt and Zukin, 1991), was based on observations that antagonists of fect on negative (e.g. poverty of thought, emotional and social with-
the N-methyl-D-aspartate glutamate receptors (NMDAR), such as phen- drawal) and cognitive symptoms (Mailman and Murthy, 2010), which
cyclidine (PCP) and ketamine, mimic positive, negative, and cognitive are key drivers of impairments in quality of life and functional outcome.
symptoms in healthy volunteers and exacerbate these symptoms in pa- Thus, although striatal dopamine elevation may account for the positive
tients with schizophrenia (Krystal et al., 2003). In this focused review, symptoms of psychosis, this may not be the case in all patients. While
we consider updated evidence for the glutamate hypothesis from a striatal dopamine elevation is unlikely to explain negative symptoms
neurodevelopmental perspective and discuss what this means for gluta- and cognitive impairment in schizophrenia, abnormalities in cortical
matergic drug development. dopamine and D1 receptor activation may contribute to cognitive defi-
Since the 1970s, abnormalities in dopaminergic neurotransmission cits (Goldman-Rakic et al., 2004). However the suggestion that cogni-
formed the basis of the neurochemical hypothesis of psychosis (Creese tive deficits and negative symptoms may be better explained by
et al., 1976; Seeman and Lee, 1975; Seeman et al., 1976). Previous concurrent abnormalities in the glutamatergic system (Javitt, 2010;
in vivo neuroimaging studies have reported an increase in the presynap- Moghaddam and Krystal, 2012) has become widely accepted.
tic dopamine synthesis capacity in the striatum in patients with
schizophrenia (Howes et al., 2012). However, while dopaminergic ab- 1.1. The NMDA receptor hypofunction hypothesis
normalities may be a core feature of psychosis, there are numerous fea-
tures of psychotic disorders that remain unexplained by dopamine The initial proposal of a glutamate hypothesis of schizophrenia arose
dysfunction alone (Moghaddam and Krystal, 2012; Stone et al., 2007). from the subsequently unreplicated finding of lower levels of glutamate
In many patients, conventional dopamine-blocking antipsychotic med- in the cerebrospinal fluid (Kim et al., 1980; Korpi et al., 1987; Perry,
ication is only partially effective, and in about a third the overall 1982). Twenty years earlier, observations that PCP produced effects
that resembled schizophrenia in healthy volunteers and intensified or
⁎ Corresponding author. reinstated stabilized symptoms when given to participants with schizo-
E-mail address: [email protected] (A. Egerton). phrenia (Luby et al., 1959; Rosenbaum et al., 1959), led to the

https://doi.org/10.1016/j.schres.2020.09.013
0920-9964/© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Egerton, A.A. Grace, J. Stone et al. Schizophrenia Research 223 (2020) 59–70

withdrawal of PCP from use as an anesthetic. The discovery in 1982 that Translation of NMDAR antagonist research is greatly facilitated
PCP noncompetitively blocks glutamatergic NMDAR ion channels (Anis through the availability of acute ketamine challenge as an across-
et al., 1983), allowed the psychotomimetic effects of PCP to be linked to species model (Moghaddam and Krystal, 2012). At subanesthetic
the glutamatergic system (Berry and Lodge, 1984). This key observation doses, acute ketamine administration produces reproducible changes
then led to the proposal that schizophrenia may be consequential to in brain electrophysiology, functional connectivity, task-related activa-
NMDAR hypofunction (Olney, 1989). tion and frontal glutamate concentration in healthy human volunteers
The NMDAR hypofunction hypothesis has since received extensive (Frohlich and Van Horn, 2014; Haaf et al., 2018). The ability of antipsy-
scientific exploration, and has made a major contribution to our current chotics and experimental compounds to attenuate these effects of keta-
biological understanding of schizophrenia (Snyder and Gao, 2013). A mine on neuroimaging biomarkers can be used as an experimental
principal pathophysiological model, the ‘disinhibition model’, suggests medicine model (Doyle et al., 2013; Gunduz-Bruce et al., 2012; Javitt
that hypofunction of NMDARs on fast-spiking γ-aminobutyric acid et al., 2018; Joules et al., 2015; Mehta et al., 2018). However, it is difficult
(GABA)-ergic interneurons in the cortex decreases GABAergic inhibition to qualitatively relate ketamine-induced brain functional changes to
of glutamatergic pyramidal neurons, leading to excessive glutamate schizophrenia pathophysiology, in part because in schizophrenia the
release (Homayoun and Moghaddam, 2007; Lisman et al., 2008; profiles of altered brain activity and neurochemistry may vary with ill-
Nakazawa et al., 2012; Olney et al., 1999; Pafundo et al., 2018; Snyder ness stage, in patient subgroups, with medication or other factors. Inter-
and Gao, 2013). Consistent with the disinhibition hypothesis, acute ad- estingly, there is an emerging suggestion that the effects of ketamine,
ministration of the NMDA antagonists such as ketamine increases corti- and thereby NMDAR hypofunction, may be more closely akin to those
cal glutamate levels. This is observed in rodents using microdialysis (Liu observed in the early stages of schizophrenia/psychosis, rather than
and Moghaddam, 1995; Lorrain et al., 2003; Moghaddam et al., 1997; the chronic stages of illness (Anticevic et al., 2015; Fleming et al., 2019).
Moghaddam and Adams, 1998) and may also be seen in humans using NMDAR antagonist administration to adult animals (or humans) is
glutamate neuroimaging (Bojesen et al., 2018; Javitt et al., 2018; extremely useful in understanding some aspects of schizophrenia path-
Rowland et al., 2005; Stone et al., 2012). An important distinction, ophysiology. Nonetheless, a pharmacological challenge will provide
therefore, is that while NMDARs may be hypofunctional in schizophre- only a limited representation of the complex brain alterations that
nia, glutamate release and signaling through non-NMDAR subtypes ap- give rise to schizophrenia, as this cannot fully capture the complexity
pears excessive. Thus, opportunities for the development of drugs of biological processes that occur during brain development, or the in-
targeting the glutamatergic system include both compounds that in- teraction of these processes with environmental factors. While gluta-
crease NMDAR activation as well as compounds that decrease gluta- mate mechanisms are the focus of this review, it should be
mate release. emphasized that other neurotransmitters including GABA, dopamine,
and serotonin play an important and interacting role, as may inflamma-
tory and other processes. Elevations in striatal dopamine release in
1.2. Pharmacological models of NMDA receptor hypofunction schizophrenia may be driven by glutamatergic abnormalities in the
frontal cortex and hippocampus (Breier et al., 1998; Howes et al.,
Pharmacological antagonism of NMDAR activity is now commonly 2015; Lodge and Grace, 2011; Miller and Abercrombie, 1996), as de-
used as a preclinical schizophrenia model to investigate potential gluta- scribed in more detail below. Serotonin interacts with both glutamate
matergic disease mechanisms and in screening therapeutic compounds and dopamine systems to regulate neurotransmission (for review, see
(Lodge and Mercier, 2015; Pratt et al., 2012). In rodents, NMDAR antag- de Bartolomeis et al., 2013; de Bartolomeis et al., 2013). For example,
onists, such as PCP or ketamine, produce behavioral effects that are modulation of intracellular signaling through the formation of
thought to mimic the positive symptoms of schizophrenia, but also pro- mGluR2/5-HT2A heterodimers (González-Maeso et al., 2008) and D2 /
duce social and cognitive deficits, particularly upon repeated adminis- 5-HT2A heterodimers (Łukasiewicz et al., 2010), may have relevance
tration (Egerton et al., 2008; Jentsch and Roth, 1999; Jones et al., for current and future therapeutic strategies (de Bartolomeis et al.,
2011; Neill et al., 2010). Compared with dopaminergic models (e.g. am- 2013). Healthy cortical function relies on the balance in coordinated
phetamine administration), animal models involving repeated NMDA activity of excitatory glutamatergic pyramidal neurons and inhibitory
administration may arguably better represent elicit social and cognitive GABAergic interneurons. These are tight and complex inter-
deficits. These behavioral changes are accompanied by neurobiological relationships and it is unknown which abnormalities in glutamatergic
effects relevant to the pathophysiology of schizophrenia, including ele- or GABAergic processes may be primary, secondary, or compensatory
vated striatal dopamine release (Abi-Dargham et al., 1998; Jentsch et al., (Krajcovic et al., 2019; Nakazawa et al., 2017). Indeed, recent analyses
1998; Laruelle et al., 1996), hypofrontality (Andreasen et al., 1992; of genetic evidence indicates that schizophrenia may arise from
Buchsbaum et al., 1990; Cochran et al., 2003; Tamminga et al., 1992; perturbed integration of multiple neurotransmitter receptor signaling
Wolkin et al., 1992), PFC glutamate release (Fattorini et al., 2008), and pathways at the synapse, extending glutamatergic and GABAergic pro-
brain structural damage (Farber et al., 1995; Olney and Farber, 1995; cesses to their broader network interactions (Devor et al., 2017;
Sharp et al., 2001; Tomitaka et al., 2000). Relevant to the development Fromer et al., 2014; Pocklington et al., 2015; Purcell et al., 2014).
of therapeutic compounds, some of the effects of NMDA antagonists These genetic advances expand the NMDAR hypofunction hypothesis
are reversed by ‘typical’ D2 receptor antagonist antipsychotics. How- of schizophrenia (Olney and Farber, 1995) to implicate a wide range
ever, attenuation of the effects of NMDA antagonists, particularly in as- of processes involved in synaptic signaling and in doing so may provide
says of social and cognitive deficits, is observed to a greater extent with alternative targets for intervention.
atypical antipsychotics such as clozapine, olanzapine, and quetiapine
(Pratt et al., 2012). This could relate to the contributing effects of 1.3. Neurodevelopmental perspectives
5HT2A inverse agonism and actions of these compounds at other 5HT re-
ceptors (Meltzer et al., 2011). Efforts to develop glutamate-acting drugs Schizophrenia is increasingly recognized as a neurodevelopmental
for schizophrenia that facilitate NMDAR activity (e.g. NMDAR glycine disorder (Insel, 2010; Marenco and Weinberger, 2000; McNeil and
site agonists) or reduce presynaptic glutamate release (e.g. mGluR2 ag- Kaij, 1978; Murray et al., 2017; Weinberger, 1987) with 65%–80% heri-
onists) have been supported by positive read-outs in NMDAR antago- tability (Cardno and Gottesman, 2000; Lichtenstein et al., 2009;
nist animal models, although ultimately clinical development has not Sullivan et al., 2003; Tandon et al., 2008) and associated with genetic
yet been successful. This is discussed further by Dunlop and Brandon, polymorphisms and risk loci (Mowry and Gratten, 2013; Psychiatric
2015 and Pratt et al., 2012 (Dunlop and Brandon, 2015; Pratt et al., GWAS Consortium Steering Committee, 2009; Ripke et al., 2013;
2012). Stefansson et al., 2009; The International Schizophrenia Consortium,

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2009) including those involved in aspects of glutamatergic synaptic sig- function during critical stages of development, which could lead to pro-
naling (Devor et al., 2017; Harrison and West, 2006; Kirov et al., 2012; gressive synaptic and neural circuit dysfunction and cumulate in the ex-
Pocklington et al., 2015; Schizophrenia Working Group of the pression of schizophrenia symptoms in early adulthood.
Psychiatric Genomics Consortium, 2014; Sundararajan et al., 2018). An
important question, particularly for intervention strategies, is the extent 1.4. Neurodevelopmental models of schizophrenia
to which glutamate dysfunction is present, and can be pharmacologi-
cally addressed, at the time of onset of clinically detectable psychotic The gestational methylazoxymethanol acetate (MAM) model is a
or prepsychotic symptoms in early adulthood, or whether the key win- developmental disruption model of schizophrenia that involves the
dow for intervention occurs earlier in brain development. administration of MAM to pregnant female rats, on gestational Day
Throughout pre- and postnatal development, extensive and com- 17, which results in neurochemical, behavioral, and anatomical def-
plex process of structural and neurochemical alterations in inhibitory icits in adult rats that are consistent with those observed in patients
and excitatory cortical neurons contribute to the maturation of prefron- with schizophrenia (Lodge and Grace, 2011). These include: a reduc-
tal cortical circuitry (Beneyto and Lewis, 2011; Hoftman et al., 2017; tion in cortical and subcortical volume; increased neuronal cell den-
Snyder and Gao, 2013). Disruptions in NMDA function during different sity in prefrontal/cingulate and insular/perirhinal areas; decreases in
temporal windows in brain development may contribute to schizophre- the thickness of the PFC, ventral perirhinal cortex, and hippocampus;
nia risk (Nakazawa et al., 2017). Preclinical studies of NMDAR impairment of pre-pulse inhibition of startle, executive function, and
hypofunction have demonstrated the link between dysregulation oc- reversal learning; and increased response to amphetamine and PCP-
curring during the early stages of postnatal development and increased locomotion in adult, but not prepubertal rats (Moore et al.,
schizophrenia-like behaviors in adulthood. This is most clearly seen 2006).
though studies showing schizophrenia-relevant phenotypes in mice In the MAM model, NMDAR dysfunction appears to arise during the
with genetic alterations that reduce NMDAR function (Belforte et al., period of heightened epigenetic vulnerability (Gulchina et al., 2017; Zhu
2010; Born et al., 2015; Carlen et al., 2012; Labrie et al., 2008; Mohn et al., 2017). Epigenetically mediated alterations in NMDAR subunit
et al., 1999; Rompala et al., 2013; Yasuda et al., 2017). For example, post- composition are observed in the prelimbic cortex of juvenile MAM-
natal reduction in NMDA NR1 subunit expression is associated with exposed animals (Gulchina et al., 2017). These alterations occur before
hyperlocomotion, social, and cognitive deficits as mice reach adoles- the emergence of dopaminergic hypersensitivity (Flagstad et al., 2004)
cence (Belforte et al., 2010). Expression of genes associated with the and cognitive deficits (Moore et al., 2006) in young adulthood. Thus, de-
GABAergic system is also important, for example in early development velopmental animal models, such as the gestational MAM model, can be
mutations in neuregulin 1 and its receptor ErbB4 may lead to subopti- used to test the extent to which deficits resulting from postnatal gluta-
mal GABAergic interneuron differentiation and inhibitory synapse for- matergic manipulations may be rescued by antipsychotic drugs or ex-
mation (Fazzari et al., 2010). Such early genetic influences on synaptic perimental compounds or environmental interventions at different
signaling will evoke compensatory mechanisms, in an attempt to nor- periods during brain development and in adult animals. Furthermore,
malize neurotransmission and brain function during development, it may also be possible to determine from these models whether, theo-
and NMDAR are dynamically regulated throughout the lifespan by key retically, glutamate activity might be rescued pharmacologically in peo-
processes such as phosphorylation, trafficking, stabilization, or removal ple showing early signs of psychosis in young adulthood (Boerner et al.,
from the synaptic membrane (Mao et al., 2009; Nong et al., 2004; 2017; Grannan et al., 2016).
Snyder and Gao, 2013). However, if compensatory mechanisms are in- In the MAM model, increased excitatory input from the hippocam-
adequate, the consequences of NMDA hypofunction in early postnatal pus to the nucleus accumbens reduces inhibition of the ventral pallidum
development could increase the risk of glutamatergic–GABAergic im- and leads to increased population activity of dopaminergic neurons
balance emerging in adolescence (Nakazawa et al., 2017). projecting to the striatum (Fig. 1) (Lodge and Grace, 2011). In this psy-
While it is only partially understood how NMDAR hypofunction may chosis model, striatal dopaminergic hyperfunction is driven by the hip-
arise during development and interact with environmental factors to in- pocampus and glutamate is critical in this process (Bossong et al., 2018;
crease risk of schizophrenia in adulthood, aberrant epigenetic regula- Schobel et al., 2013; Stone et al., 2010). MAM rats show a reduction in
tion of NMDAR subunit expression may play an important role parvalbumin (PV) interneuron density throughout the medial PFC
(Snyder and Gao, 2013). The expression and localization of NMDAR sub- (mPFC) and the ventral hippocampus that impacts gamma oscillations
units is age-dependent, and impacts NMDAR kinetics, pharmacological during task performance (Lodge et al., 2009). In people at clinical high
sensitivity, synaptic plasticity, and learning (Paoletti et al., 2013). The risk (CHR) for psychosis, resting blood flow and activity in the hippo-
developmental switch in NMDAR subunit composition (NR2B to campus are also increased (Allen et al., 2015; Modinos et al., 2015),
NR2A, and NR3A to NR3B) marks the transition to adult neural process- and may be related to mPFC GABA levels (Modinos et al., 2018). Schobel
ing (Dumas, 2005; Snyder and Gao, 2019; Snyder and Gao, 2013) and is et al., observed that hypermetabolism in the CA1 sub region of the hip-
regulated by epigenetic mechanisms (Rodenas-Ruano et al., 2012; pocampus spread to the subiculum after psychosis onset in patients at
Stadler et al., 2005). This switch may explain the temporal dependency CHR and predicted hippocampal atrophy (Schobel et al., 2013). As
of the effects of NMDAR antagonist administration during development acute ketamine produced similar pattern of hypermetabolism in mice,
on both the pattern and extent of the resulting neuronal damage these findings may be linked to NMDAR hypofunction (Schobel et al.,
(Farber et al., 1995; Ikonomidou et al., 1999; Olney and Farber, 1995). 2013). Postmortem studies in schizophrenia describe a selective loss
As NR2B subunits are replaced by NR2A subunits, NMDAR on fast- of GABAergic PV interneurons in the hippocampus and frontal cortex
spiking GABAergic neurons in the PFC undergo considerable changes (Zhang and Reynolds, 2002), and a corresponding deficit in GABAergic
(Wang and Gao, 2009; Xi et al., 2009). Relative to NR2B subunits, the signaling may also contribute to hyperactivity within the hippocampus
presence of NR2A decreases the affinity for glycine site co-agonists, de- (Lodge et al., 2009; Modinos et al., 2018).
creases calcium conductance and reduces vulnerability to excitotoxicity The use of multiple genetic or neurodevelopmental models may pro-
(Jantzie et al., 2015). Thus, this subunit switch may render NMDAR and vide the greatest opportunity for identifying changes precipitating the
fast-spiking GABAergic interneurons especially vulnerable to genetic or development of schizophrenia (Snyder and Gao, 2013). These models
environmental risks (Snyder and Gao, 2019; Snyder and Gao, 2013). For are valuable for detecting the neurons that express altered glutamate
example, maternal deprivation during early postnatal development dis- receptor subtypes (Snyder and Gao, 2013). They are also important to
rupts epigenetic activation and the switch to the mature NMDA subunit help determine if there is a point during development where brain cir-
phenotype (Rodenas-Ruano et al., 2012). Thus, adverse experiences and cuitry is sufficiently altered to the point that no interventions will halt
stress during childhood may impact on gene expression and NMDAR disease progression (Snyder and Gao, 2019; Snyder and Gao, 2013).

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A. Egerton, A.A. Grace, J. Stone et al. Schizophrenia Research 223 (2020) 59–70

than causing the disorder (Du and Grace, 2016). This may also indicate
that a main impact of genetic risk is to increase vulnerability to the im-
pact of stressful life events (Du and Grace, 2016). The susceptibility to
stress is critically dependent on its timing in adolescence (Gomes and
Grace, 2017).
Glutamatergic interactions between the mPFC, hippocampus, amyg-
dala, and ventral striatum mediate effects of stress. In control rats, mPFC
lesions are sufficient to induce anxiety at the prepubertal stage (Gomes
and Grace, 2017). Increased stress responsivity may therefore be medi-
ated by a failure of the mPFC to limit the impact of stress exposure, lead-
ing to abnormally high amygdala-hippocampal drive (Gomes and
Grace, 2017), and could potentially be modulated by glutamate-acting
therapeutics. Therapeutic approaches based on normalizing hippocam-
vHipp pal activity, rather than blocking the downstream effects of dopamine
NAc
elevation with a D2 antagonist antipsychotic, may show greater efficacy
and potentially less side effects (Gill et al., 2014). Of potential impor-
tance to translational drug development, dopamine supersensitivity,
resulting from previous D2 antipsychotic exposure, may interfere with
the ability of novel therapeutic compounds to reduce striatal dopamine
hyperactivity (Gill et al., 2014; Sonnenschein and Grace, 2020). This
could suggest that such therapeutics would have more observable effi-
cacy in individuals prior to the onset of psychosis or early in illness, be-
Ventral fore D2 antipsychotic treatment (Sonnenschein and Grace, 2020).
pallidum
2. Levels of glutamate in the human brain

It is possible to measure glutamate concentrations in the human

VTA brain in vivo using proton magnetic resonance spectroscopy (1H-
MRS). The most common approach is to estimate the total concentra-
tion of glutamate in a prespecified voxel of interest over around 10 mi-
Fig. 1. A schematic to show the regulation of dopamine neuron activity by the ventral nutes while the participant lies at rest in a magnetic resonance imaging
hippocampus. GABA, γ-aminobutyric acid; NAc, nucleus accumbens; vHipp, ventral (MRI) scanner. There are now more than 60 published 1H-MRS studies
hippocampus; VTA, ventral tegmental area.
of glutamate metabolites in individuals with established psychosis or
schizophrenia, or at risk for developing the disorder. Overall, meta-
For example, in a rat developmental model, administration of a gluta- analysis 1H-MRS studies found evidence of glutamatergic elevations in
mate modulating compound (a metabotropic glutamate-5 receptor schizophrenia (Merritt et al., 2016), as would be predicted by the
[mGluR5] positive allosteric modulator [PAM]) reversed adult-onset NMDA receptor hypofunction/disinhibition model. The majority of 1H-
deficits when administered during adolescence and prevented the MRS studies examining NMDAR hypofunction produced by ketamine
emergence of cognitive impairment (Clifton et al., 2013). A more recent infusion have also found increases in cortical glutamate (Bojesen et al.,
study also showed that juvenile administration of an mGluR2/3 agonist 2018; Javitt et al., 2018; Rowland et al., 2005; Stone et al., 2012). None-
prevented the learning and memory deficits and restored the dendritic theless, the results of individual 1H-MRS studies in schizophrenia have
spine loss that are observed in MAM-treated rats in adulthood (Xing been mixed. This could reflect clinical differences between the samples
et al., 2018). as well as methodological factors. Questions for translational research
include the extent to which 1H-MRS glutamate measures may predict
1.5. The role of stress the onset (Bossong et al., 2016; Bossong et al., 2019) and clinical course
of psychosis (Egerton et al., 2018), and whether they may provide bio-
Interactions between genetic and environmental risk factors such as markers for glutamate-targeted drug development in schizophrenia
stress may be particularly important during neurodevelopment. Stress- (Javitt et al., 2018).
ful stimuli may exacerbate positive and negative symptoms in schizo- In individuals at risk for developing psychosis, 1H-MRS studies have
phrenia (Lysaker and Salyers, 2007), and converging evidence from investigated whether glutamatergic differences are present prior to the
clinical and preclinical studies suggest that an inability to regulate stress onset of clinical symptoms. While an initial meta-analysis found that
early in life can lead to pathological changes, particularly in the hippo- medial frontal Glx (glutamate plus glutamine) was elevated in individ-
campus (Zimmerman et al., 2013). In the MAM model, rats show in- uals at high risk for psychosis (Merritt et al., 2016), a more recent meta-
creased prepubertal anxiety and response to stress on the elevated analysis found no overall difference compared with controls
plus maze, a measure of anxiety (Du and Grace, 2013; Du and Grace, (Wenneberg et al., 2019). However, as the majority of high-risk individ-
2016). MAM rats also show longer and more intense vocalizations and uals will not develop schizophrenia, it may be difficult to detect differ-
more freezing behavior (Zimmerman et al., 2013), as well as signifi- ences in this group as a whole. Potential differences in brain glutamate
cantly faster amygdala firing (Du and Grace, 2016). Similarly, in rats will be most marked in those at-risk individuals who go on to transition
stress exposure in the prepubertal, peripubertal, and adolescent stages to psychosis. Two longitudinal studies have reported that at-risk indi-
causes the hippocampus to become hyperactive post stress through to viduals who later transition to psychosis appear to have elevated gluta-
adulthood, and causes a loss of PV interneurons in the hippocampus mate levels in the striatum (de la Fuente-Sandoval et al., 2013) and in
(Zimmerman et al., 2013). This suggests that major stress alone during the hippocampus (Bossong et al., 2019) compared with healthy volun-
this critical prepubertal period could lead to PV interneuron loss and in- teers and at-risk participants who do not transition during the study ob-
duce a psychosis-like state (Gomes and Grace, 2017). Pretreatment with servation period. While replication is required, these studies are
diazepam has been shown to prevent the emergence of these changes, challenging as low transition rates mean that large baseline samples
which suggests that MAM is facilitating the impact of stress rather are required, and the clinical follow-up period can be several years.

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1
H-MRS studies in samples at risk for psychosis have also compared 2007). A total of 14 patients with schizophrenia, 15 patients with bipo-
subgroups according to functional outcome, or whether or not they lar II disorder, and 14 healthy volunteers underwent a 15-minute n-
still met ‘at-risk’ criteria for attenuated psychotic-like symptoms at back (0-back, 1-back, 2-back, and 3-back) task in a 48-second block de-
follow-up. In the study of Bossong et al., hippocampal glutamate levels sign during fMRS acquisition. The significant increase in Glx/Cr and Glu/
were also elevated in at-risk individuals with a ‘poor’ compared with a Cr that was observed in healthy controls with increasing task difficulty
‘good’ functional outcome as defined using the global assessment of (between the averaged last spectra of the 0-back and the first of the 2-
functioning scale (Bossong et al., 2019). When examining the relation- back task conditions) was absent in patients with schizophrenia or bi-
ship between glutamate levels in the thalamus and outcome, we ob- polar disorder. In contrast, during the relatively easy task condition
served that lower levels of thalamic glutamate were associated with (0-back) Glx levels were increased in the schizophrenia compared
the continued presence of attenuated symptoms at follow-up (Egerton with healthy control group (Jelen et al., 2019). These findings are similar
et al., 2014). While further research is required, these initial studies to those of the previous study that applied 1H-fMRS to measure task-
may suggest that regionally specific glutamatergic changes might related changes in dynamic glutamatergic concentrations in schizo-
occur during the prodromal period. phrenia, which acquired data in the ACC during the performance of a
The level of 1H-MRS-determined brain glutamate may also be re- color-word Stroop task at a field strength of 7 Tesla (Taylor et al.,
lated to clinical outcome under antipsychotic treatment in patients 2015). This study additionally included a sample with major depressive
with established psychosis or schizophrenia. Cross-sectional studies disorder (MDD) and healthy volunteers. While in healthy volunteers
have found glutamate or Glx elevation in the anterior cingulate cortex glutamate was increased during the initial period of the Stroop task,
(ACC) in patients with non-remission of symptoms, antipsychotic treat- this response was lacking in the schizophrenia and MDD groups
ment resistance, or clozapine resistance compared with those who have (Taylor et al., 2015). Together with the results of Jelen et al. (2019)
responded well to medication (Demjaha et al., 2014; Egerton et al., these studies suggest that schizophrenia may be associated with
2012; Iwata et al., 2019; Mouchlianitis et al., 2016; Tarumi et al., blunted activation of dynamic glutamate responses in the ACC to task
2020); although this has not been observed in all studies (Goldstein requirements.
et al., 2015). A recent longitudinal study in first-episode psychosis
showed that higher ACC glutamate levels at illness onset are associated 3. The glutamatergic hypothesis and drug development
with a higher likelihood of non-remission of symptoms following sub-
sequent antipsychotic treatment (Egerton et al., 2018). A longer-term 3.1. Typical and atypical antipsychotics
follow-up of a subgroup of the same cohort found that non-remission
was associated with increases in Glx in the thalamus over 9 months Rodent studies have shown that some, but not all, antipsychotics can
(Merritt et al., 2019). Together, these findings may suggest that there attenuate increases in glutamate efflux that arise on NMDA antagonist
may be a subgroup of patients with schizophrenia with higher brain administration (Abekawa et al., 2007; Carli et al., 2011; López-Gil
glutamate levels who are less likely to respond to antipsychotic treat- et al., 2009; López-Gil et al., 2007; Roenker et al., 2011), which could re-
ment, and by extension that glutamate-reducing therapeutics may late to antagonism at 5HT2A receptors (Ceglia et al., 2004; López-Gil
have particular benefit in this group. et al., 2009). We recently performed a systematic review of longitudinal
1
One question from these studies is whether measurement of brain H-MRS studies that have examined the effects of antipsychotic treat-
glutamate levels may accurately predict clinical outcome, in both indi- ment on glutamate or Glx levels in patients with schizophrenia
viduals at CHR and in established psychosis. Accurate prediction of out- (Egerton et al., 2017). This review found that the majority of studies re-
come could enable glutamate-based interventions to be targeted to ported a numerical reduction in glutamate metabolites during antipsy-
patient subgroups who are most likely to benefit. In our study predicting chotic treatment, and there was some evidence that reductions in
remission in first-episode psychosis, ACC glutamate levels correctly glutamate metabolites may correlate with symptomatic improvement.
classified 69% cases overall, and the predictive accuracy increased to As glutamate levels, particularly in the ACC, may remain elevated in pa-
75% when age and baseline symptom severity score were included in tients who do not respond adequately to antipsychotic treatment, to-
the model (Egerton et al., 2018). While these results were significant, gether this could suggest that standard antipsychotics are ineffective
they are not accurate enough to inform clinical decision-making. There- in modulating glutamate level in this subgroup. Interestingly, there is
fore, there is a requirement to improve predictive accuracy, which some suggestion that the additional efficacy of clozapine, an antipsy-
might be achieved by combining 1H-MRS glutamate levels with other chotic reserved for otherwise antipsychotic-resistant schizophrenia,
predictive factors in a multivariate model. may arise from its ability to reduce cortical glutamate levels or facilitate
A further consideration is whether technological advances may im- NMDAR activation (Abekawa et al., 2006; Amitai et al., 2012; Fukuyama
prove the accuracy and reliability of glutamate measurement. The ma- et al., 2019; Javitt et al., 2005; López-Gil et al., 2007; Melone et al., 2001;
jority of the studies described above applied 1H-MRS on 3 Tesla MRI Williams et al., 2004). Nonetheless, currently available antipsychotics,
systems. This technology is widely available and suitable for most par- including clozapine, are not effective in reducing positive symptoms in
ticipants, but does not fully separate resonances from glutamate and all patients and also do not adequately address negative symptoms
glutamine. It also provides an overall measure of glutamate in the and cognitive impairment. It is hoped that glutamate-acting drugs
voxel rather than glutamate involved in neurotransmission specifically. may have potential as future therapeutic compounds.
Some factors associated with accuracy of glutamate metabolite concen-
tration estimation may be improved by scanning at ultra-high field 3.2. Glycine transporter 1 inhibitors
strengths (Godlewska et al., 2017). An alternative approach is provided
by emerging developments in functional 1H-MRS (1H-fMRS), which Initial clinical trials targeting glutamatergic neurotransmission were
measures dynamic changes in glutamate occurring in response to a aimed at increasing NMDAR activation through increasing occupancy at
stimulus or psychological challenge and may more closely relate to glu- the glycine co-agonist site, by administering glycine, D-serine or d-
tamate release during neurotransmission (Jelen et al., 2018; Mullins, cycloserine. While smaller studies indicated beneficial effects, larger tri-
2018; Rowland et al., 2005). als did not detect separation from placebo (Girgis et al., 2018). These in-
One of the authors recently conducted a preliminary study to deter- terventions are also limited by tolerability. More recently, strategies
mine whether 1H-fMRS at 3 Tesla is sensitive enough to detect dynamic have focused on reducing glycine reuptake, via inhibition of glycine
changes in ACC glutamate, and to assess any differences in these transporter 1 (GlyT1), a key regulator of synaptic glycine levels
changes between healthy volunteers and patients with schizophrenia (Supplisson and Bergman, 1997). Various GlyT1 inhibitors have been
using an n-back task, a continuous-recognition measure (Kane et al., trialed; however, bitopertin is the only compound to have reached

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A. Egerton, A.A. Grace, J. Stone et al. Schizophrenia Research 223 (2020) 59–70

Phase III clinical trials (Singer et al., 2015) and, due to lack of signals of function (Tyszkiewicz et al., 2004), regulate long-term depression and
efficacy, is no longer being developed for use as an antipsychotic long-term potentiation in the PFC and hippocampus, respectively
(Bugarski-Kirola et al., 2017; Kantrowitz et al., 2017). (Walker et al., 2017; Walker et al., 2015), and reduces excessive activity
at glutamatergic synapses in the PFC (Homayoun et al., 2005).
3.3. D-Amino acid oxidase inhibitors Inhumans, these findings were supported by the demonstration that
mGluR2/3 agonist administration can attenuate the disruptions in
A further approach is to manipulate the metabolism of D-serine, an working memory that are produced by the NMDAR antagonist keta-
endogenous ligand of the NMDA modulatory site, which is degraded mine (Krystal et al., 2005). However, although the mGluR2/3 agonist,
in the brain by D-amino acid oxidase (DAAO) (Sershen et al., 2016). pomaglumetad methionil showed beneficial effects on both positive
DAAO inhibitors may therefore be novel treatments to increase NMDA and negative symptoms in early clinical trials, subsequent Phase III trials
activity via the elevation of endogenous D-serine concentrations were disappointing (Caraci et al., 2017). Interestingly, a post hoc analysis
(Sershen et al., 2016). Indeed, a previous study with the DAAO inhibitor of trial data suggested that pomaglumetad methionil may be selective in
5-chloro-benzo[d]isoxazol-3-ol (CBIO) found that co-administration of subgroups of patients, and particularly those who are in the earlier
CBIO with D-serine significantly attenuated pre-pulse inhibition deficits phases of illness, or who had been previously treated with a predomi-
instigated by administration of dizocilpine, an NMDAR antagonist nantly D2 antagonist over 5HT2A antagonist antipsychotic (Kinon et al.,
(Hashimoto et al., 2009). In another study, acute administration of 2015). This may relate to the level of glutamatergic tone as glutamate
CBIO had no effect on PCP-induced locomotor activity when adminis- level may vary with illness stage or treatment response (Egerton et al.,
tered alone, but led to reductions when co-administered with D-serine 2018; Merritt et al., 2016). One possibility is therefore that mGluR2/3
(Sershen et al., 2016). However, this effect was also observed when agonists may be effective if applied earlier in illness, and potentially
the vehicle was tested with D-serine, indicating that the decrease in lo- even before the onset of psychosis. This is suggested by studies in the
comotor activity was potentially unrelated to DAAO inhibition. It was MAM rodent model showing that NMDAR hypofunction and cognitive
concluded from this study that the precise mechanisms of DAAO inhib- deficits were prevented by mGluR2 agonist administration in juvenile
itors are yet to be determined, but that, together with existing findings, but not adult rats (Li et al., 2017; Li et al., 2015; Xing et al., 2018). Fur-
continued glutamatergic drug development is supported (Sershen et al., thermore, the potential lack of efficacy of pomaglumetad methionil in
2016). None of the identified human DAAO inhibitors have yet been ap- patients previously treated with ‘atypical’ antipsychotics may be ex-
proved for the treatment of schizophrenia. The primary limitations of plained by downregulation frontal cortical mGluR2 receptors, occurring
these agents include poor bioavailability, high clearance rate, and poor via decreased histone acetylation following 5HT2A antagonism (Kurita
ability to cross the blood–brain barrier (Molla, 2017). et al., 2012). This might indicate that histone deacetylase (HDAC) inhib-
itors could have therapeutic benefit via modulation of expression of
3.4. mGluR agonists genes encoding mGluR2 and other proteins (Fischer et al., 2010).

mGluRs are an alternative target and pharmacological advance- 3.5. Phosphodiesterase inhibitors
ments have allowed for the attainment of subtype specificity of mGluRs
through the development of allosteric modulators (Stansley and Conn, Phosphodiesterase (PDE) enzymes play a key role in regulating the
2018). PAMs operate to potentiate endogenous glutamate signaling, activity of signaling pathways downstream of both glutamate and dopa-
whereas negative allosteric modulators reduce receptor responsiveness mine receptors (Snyder and Vanover, 2017). The human PDE family
to glutamate (Conn et al., 2009). Drug discovery efforts in the field of contains 11 subfamilies, each displaying a unique pattern of tissue-
CNS have clarified the beneficial modes of action for allosteric modula- specific distribution (Heckman et al., 2018). Preclinical evidence sug-
tors that target the various subtypes of mGluRs (Stansley and Conn, gests that at least four PDE subfamilies (PDE4, PDE9, PDE10, and
2018). Group I mGluRs, which are coupled to signaling proteins, consist PDE11) play a role in glutamatergic neurotransmission. Rolipram, an in-
of mGluR1 and mGluR5 (Stansley and Conn, 2018). The mGluR5 recep- hibitor of the PDE4 subfamily, blocks hyperlocomotion in both the PCP
tor subtype has been considered an attractive therapeutic target due to and amphetamine models of schizophrenia (Kanes et al., 2007; Snyder
its interaction with NMDARs through structural connections with scaf- and Vanover, 2017). BI 409306 has been shown to be a potent and selec-
folding proteins (Tu et al., 1999). In addition, positive allosteric modula- tive PDE9A inhibitor in rodents, which induced a dose-dependent in-
tion of mGluR5s has been reported to enhance long-term synaptic crease in cGMP levels in the PFC and CSF (Rosenbrock et al., 2015). In
plasticity in the hippocampus and has beneficial cognitive effects in ro- a first-in-human trial, single doses of BI 409306 showed an acceptable
dents (Ayala et al., 2009). mGluR5 therefore presents a target that could safety and tolerability profile for young, healthy males (Moschetti
be efficacious for positive, negative, and cognitive symptoms of schizo- et al., 2016). Inhibition of PDE10 appears to be beneficial against both
phrenia, although this will be dependent on the possibility to develop positive and negative symptoms in the PCP model (Grauer et al.,
mGluR5 PAMs that do not cause adverse events (Stansley and Conn, 2009). The PDE11A isoform, meanwhile, is thought to support gluta-
2018). matergic neurotransmission in regions of the hippocampus and ex-
The mGluR1 receptor subtype has received less attention; however, tended amygdala that may be related to social dysfunction in
it has been reported that mutations associated with schizophrenia lead schizophrenia (Snyder and Vanover, 2017). To date, the clinical effects
to a reduction in mGluR1 signaling in vitro (Cho et al., 2014). Further- of PDE4, PDE9, and PDE11 inhibition in schizophrenia remains unre-
more, a range of highly selective mGluR1 receptor PAMs can potentiate ported. PDE10 inhibitors have been the subject of intense and ongoing
responses to activation of these mutant receptors (Cho et al., 2014). This neuropsychiatric research but clinical development has been hindered
may suggest that mGluR1 PAMs could reverse deficits in mGluR1 signal- by associations with extrapyramidal side effects, such as akathisia and
ing in patients with schizophrenia who carry these mutations (Stansley dystonia (Heckman et al., 2018).
and Conn, 2018).
Group II mGluRs, which couple to G-protein subunits that inhibit 3.6. α7 nicotinic acetylcholine receptor agonists
adenylate-cyclase activity, consist of mGluR2 and mGluR3 (Stansley
and Conn, 2018). Early studies in rodents with the mGluR2/3 agonist The α7 nicotinic acetylcholine receptor (α7-nAChR) is a cation
LY354740 revealed an improvement in deficits in stereotypy, locomo- channel-linked receptor subtype (Taly et al., 2009). α7-nAChRs are
tion, spatial working memory, and cortical glutamate efflux caused by commonly expressed on the pre- and postsynaptic elements of the hip-
the NMDAR antagonist PCP (Moghaddam and Adams, 1998). Activation pocampus and cerebral cortex where they facilitate release of various
of mGluR2/3 receptors has since been shown to enhance NMDAR key neurotransmitters, including glutamate, dopamine, and GABA

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A. Egerton, A.A. Grace, J. Stone et al. Schizophrenia Research 223 (2020) 59–70

(Beinat et al., 2015; Taly et al., 2009). In preclinical models, low levels of Wassef et al., 2003), although this may be more successful in the ab-
α7-nAChRs correlate with the poor sensory gating associated with inat- sence of previous antipsychotic exposure (Gill et al., 2014). While
tention in schizophrenia (Taly et al., 2009). The PFC of patients with non-selective GABAA modulators such as benzodiazepines may not be
schizophrenia also show low levels of α7-nAChRs, and patients with effective in improving positive symptoms (Volz et al., 2007), com-
schizophrenia show improved sensory gating in response to nicotine pounds with greater subunit selectivity, particularly at α5 could have
or the atypical antipsychotic clozapine, with effects thought to be medi- therapeutic potential (Lodge and Grace, 2011).
ated by α7-nAChRs (Taly et al., 2009). Agonists of α7-nAChRs have been
assessed as adjunct therapy to antipsychotics in clinical trials of patients 4. Conclusions and future perspectives
with schizophrenia. However, results to date have generally been disap-
pointing, with a recent meta-analysis showing no statistically signifi- Since its conception, the NMDAR hypofunction theory of schizophre-
cant effects against cognitive impairment or negative symptoms nia has received intense research interest across the spectrum of pre-
compared with placebo (Jin et al., 2017). On the other hand, α7 modu- clinical to clinical science. While the tenet of NMDAR hypofunction
lators that do not act as direct agonists may show a better remains central, what has emerged is an extreme neurobiological com-
pharmacotherapeutic profile, based on preclinical evidence (Neves plexity and an emphasis on interacting environmental factors and de-
and Grace, 2018). velopmental processes. These studies raise many further questions, as
well as identifying numerous potential targets for intervention. Never-
3.7. N-acetylcysteine theless, the development of glutamatergic drugs for schizophrenia has
proved to be extremely challenging and, as yet, unsuccessful. There
N-acetylcysteine (NAC) is a L-cysteine derivative, which may modu- may be several reasons for this, including a lack of suitable biomarkers
late extracellular glutamate concentrations through the glial cysteine- for target engagement and dose selection (Javitt et al., 2018), indications
glutamate antiporter (Bridges et al., 2012), to reduce presynaptic gluta- of inverted U-shape dose–response relationships for glutamatergic
mate release via mGluR2/3 activation (Baker et al., 2002). NAC also in- compounds (Kinon et al., 2015; Spiros et al., 2014; Umbricht et al.,
creases biosynthesis of the antioxidant glutathione, which may 2014) and factors associated with clinical trial design such as high pla-
increase NMDA receptor activity (Steullet et al., 2006; Willborn et al., cebo response rates. The glutamatergic system is also under tight ho-
2019) NAC has been evaluated for therapeutic efficacy in schizophrenia meostatic control, so pharmacological perturbation is likely to evoke
as well as other psychiatric disorders (Berk et al., 2013). An initial study compensatory mechanisms to restore the healthy or pathophysiological
assessing the efficacy of NAC as an adjunct to standard treatment for ‘state’ of the system.
schizophrenia reported significant improvements in Positive and Nega- One exciting area of research is the identification of biomarkers for
tive Syndrome Scale and the Clinical Global Impression-Severity Scale target engagement in early-stage clinical trials in healthy participants.
(Berk et al., 2008). NAC was also well tolerated, with no significant ad- A recent study evaluated three potential neuroimaging biomarkers of
verse events reported in the group of patients treated with NAC (Berk functional target engagement using ketamine administration in healthy
et al., 2008). Improvements in negative symptoms were subsequently volunteers, namely the functional MRI (fMRI) blood oxygen level-
reported when NAC was administered as an adjunct to risperidone dependent (pharmaco-BOLD) response, 1H-MRS, and task-based fMRI
(Farokhnia et al., 2013). A recent study evaluated the effect of NAC on (Javitt et al., 2018). The primary objective was to compare both the
symptoms and neurocognition in early psychosis (Conus et al., 2018). magnitude of response and feasibility of implementation of imaging-
Although NAC did not improve negative symptoms, there was some im- based biomarkers for glutamate-targeted drug development (Javitt
provement in neurocognition as well as an increase in brain glutathione et al., 2018), with pharmaco-BOLD showing the most encouraging re-
levels, indicating target engagement (Conus et al., 2018). Recent meta- sults. Such biomarkers will be useful in identifying promising com-
analysis of seven randomized controlled trials of adjunctive NAC in pounds for patient studies, and guiding dose selection. For example,
schizophrenia found improvements in positive, negative symptoms, reductions in the ketamine BOLD-response can be observed following
and working memory, and suggested that these effects may be most ap- single dose administration of the higher, but not lower, tested doses of
parent after longer treatment periods (Yolland et al., 2019). Further- mGluR2/3 and mGluR2 agonist compounds in healthy volunteers, indi-
more, blood glutathione peroxidase activity (as redox peripheral index cating the most pharmacologically active doses (Mehta et al., 2018). A
is associated with glutathione levels), may help identify a subgroup of second question is whether glutamate biomarkers, such as 1H-MRS or
1
patients whose positive symptoms improve with NAC, which could rep- H-fMRS glutamate measures or glutamate genetic/epigenetic markers,
resent a step towards biomarker-guided treatment (Conus et al., 2018). can be used to preselect patients with a ‘greater degree’ of glutamate
A further trial, for which data collection is planned to continue until dysfunction who may be more likely to respond to a glutamate drug,
mid-2019, is underway to determine the clinical value of NAC as an ad- in a stratified approach. Here, glutamate brain imaging approaches
junctive therapy in patients who are only partly responsive to clozapine could also be applied to monitor glutamate function during an interven-
(Rossell et al., 2016). tion trial.
Finally, the question as to ‘when’ in the course of illness glutamate
3.8. GABA agonists manipulation may be most effective may be extremely important. This
is related to the emerging clinical evidence that glutamate levels may
Due concept of functional imbalance between excitatory (gluta- be highest and predictive of outcome at or before the onset of psychosis
matergic) and inhibitory (GABAergic) neurotransmission in schizo- (Bossong et al., 2019; de la Fuente-Sandoval et al., 2013; Egerton et al.,
phrenia, GABA-acting compounds have also been investigated for 2018; Marsman et al., 2013; Merritt et al., 2016). Animal genetic and
therapeutic potential, so far with little clinical success (Xu and Wong, neurodevelopmental models may have utility in providing platforms
2018). As described above, the MAM developmental model indicates against which experimental glutamatergic compounds may be tested
that striatal dopaminergic hyperactivity results from over-active signal- for efficacy during different stages of development and in different envi-
ing between the medial temporal lobe and the striatum (Modinos et al., ronmental contexts.
2015) due to a selective loss of GABAergic PV interneurons in the hippo-
campus and frontal cortex (Zhang and Reynolds, 2002). In turn, this Funding statement
stimulates GABAergic neurons that project from the striatum to the ven-
tral pallidum, thus increasing inhibition of ventral pallidum GABAergic This article is based on a symposium, which was funded by
neurons (Modinos et al., 2015). Potentially, the use of adjunctive Boehringer Ingelheim International GmbH and presented at the 6th
GABA agonists may help to restore this imbalance (Gill et al., 2014; European Conference on Schizophrenia Research. The sponsor was

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A. Egerton, A.A. Grace, J. Stone et al. Schizophrenia Research 223 (2020) 59–70

given the opportunity to review the manuscript for medical and scien- A.I., 2008. N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-
blind, randomized, placebo-controlled trial. Biol. Psychiatry 64 (5), 361–368.
tific accuracy as well as intellectual property considerations. Berk, M., Malhi, G.S., Gray, L.J., Dean, O.M., 2013. The promise of N-acetylcysteine in neu-
ropsychiatry. Trends Pharmacol. Sci. 34 (3), 167–177.
CRediT authorship contribution statement Berry, S.C., Lodge, D., 1984. Benz(f)isoquinolines as excitatory amino acid antagonists: an
indication of their mechanism of action? Biochem. Pharmacol. 33 (23), 3829–3832.
Boerner, T., Bygrave, A.M., Chen, J., Fernando, A., Jackson, S., Barkus, C., Sprengel, R.,
Alice Egerton: Writing - original draft, Validation. Anthony A. Seeburg, P.H., Harrison, P.J., Gilmour, G., Bannerman, D.M., Sanderson, D.J., 2017.
Grace: Writing - original draft, Validation. James Stone: Writing - orig- The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor
antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial
inal draft, Validation. Matthijs G. Bossong: Writing - original draft, Val-
working memory in GluA1 knockout mice. Eur. J. Neurosci. 45 (7), 912–921.
idation. Michael Sand: Writing - original draft, Validation. Philip Bojesen, K.B., Andersen, K.A., Rasmussen, S.N., Baandrup, L., Madsen, L.M., Glenthoj, B.Y.,
McGuire: Writing - original draft, Validation. Rostrup, E., Broberg, B.V., 2018. Glutamate levels and resting cerebral blood flow in
anterior cingulate cortex are associated at rest and immediately following infusion
Declaration of competing interest of S-ketamine in healthy volunteers. Front Psychiat. 9, 22.
Born, G., Grayton, H.M., Langhorst, H., Dudanova, I., Rohlmann, A., Woodward, B.W.,
Collier, D.A., Fernandes, C., Missler, M., 2015. Genetic targeting of NRXN2 in mice un-
The authors met the criteria for authorship as recommended by the International
veils role in excitatory cortical synapse function and social behaviors. Front Synapt.
Committee of Medical Journal Editors. AE has previously received funding from Hoffman
Neurosci. 7, 3.
la Roche and a study-related consultancy payment from Heptares Therapeutics Ltd. AAG
Bossong, M., Allen, P., Azis, M., Samson, C., Quinn, B., Bonoldi, I., Modinos, G., Howes, O.,
has previously received consultancy payment from Lundbeck, Pfizer, Otsuka, Takeda, Stone, J., McGuire, P., 2016. Elevated hippocampal glutamate levels predict the later
Newron, Alkermes, and Janssen and has also received honoraria from Lilly, Roche, Asubio, onset of psychosis (abstract). NPJ Schizophr. 16011.
Abbott and Autofony. JS has previously received honoraria from Roche and Janssen and Bossong, M.G., Wilson, R., Appiah-Kusi, E., McGuire, P., Bhattacharyya, S., 2018. Human
has received a study-related consultancy payment from Takeda. MGB has nothing to dis- striatal response to reward anticipation linked to hippocampal glutamate levels. Int.
close. MS is an employee of Boehringer Ingelheim, but received no direct compensation re- J. Neuropsychopharmacol. 21 (7), 623–630.
lated to the development of this manuscript. PM has previously received research funding Bossong, M.G., Antoniades, M., Azis, M., Samson, C., Quinn, B., Bonoldi, I., Modinos, G.,
from GW Pharmaceuticals and attended advisory boards with Boehringer Ingelheim. Perez, J., Howes, O.D., Stone, J.M., Allen, P., McGuire, P., 2019. Association of hippo-
campal glutamate levels with adverse outcomes in individuals at clinical high risk
for psychosis. JAMA Psychiat. 76 (2), 199–207.
Acknowledgments
Breier, A., Adler, C.M., Weisenfeld, N., Su, T.-P., Elman, I., Picken, L., Malhotra, A.K., Pickar,
Editorial support was provided by Lisa Auker, PhD, of Fishawack Communications Ltd.,
D., 1998. Effects of NMDA antagonism on striatal dopamine release in healthy sub-
and was funded by Boehringer Ingelheim International GmbH.
jects: application of a novel PET approach. Synapse 29 (2), 142–147.
Bridges, R., Lutgen, V., Lobner, D., Baker, D.A., 2012. Thinking outside the cleft to under-
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