Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence

SCHRES-06656; No of Pages 10 Schizophrenia Research xxx (2015) xxx–xxx

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Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence Devi Treen a, Santiago Batlle a, Laia Mollà a, Eduard Forcadell a, Jacobo Chamorro a, Antonio Bulbena a,b,c, Victor Perez a,b,c,d a

Institut de Neuropsiquiatria i Addiccions, Hospital del Mar, Barcelona, Spain IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain Autonomous University of Barcelona UAB, Department of Psychiatry and Forensic Medicine, Bellaterra, Spain d Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain b c

a r t i c l e

i n f o

Article history: Received 1 June 2015 Received in revised form 29 November 2015 Accepted 1 January 2016 Available online xxxx Keywords: Glutamate alterations NMDA hypofunction High risk mental state Ultra high risk psychosis H MRS

a b s t r a c t New approaches to underlying alterations in psychosis suggest increasing evidence of glutamatergic abnormalities in schizophrenia and an association between these abnormalities and certain core psychopathological alterations such as cognitive impairment and negative symptoms. Proton magnetic resonance spectroscopy (1H MRS) is an MR-based technique that enables investigators to study glutamate function by measuring in vivo glutamatergic indices in the brain. In this article we review the published studies of 1H MRS in subjects with an atrisk mental state (ARMS) for psychosis. The primary aim was to investigate whether alterations in glutamate function are present before the illness develops in order to expand our understanding of glutamatergic abnormalities in prodromal phases. Three databases were consulted for this review. Titles and abstracts were examined to determine if they fulfilled the inclusion criteria. The reference lists of the included studies were also examined to identify additional trials. Eleven final studies were included in this review. Significant alterations in glutamate metabolites across different cerebral areas (frontal lobe, thalamus, and the associative striatum) in subjects with an ARMS for psychosis are reported in six of the trials. A longitudinal analysis in two of these trials confirmed an association between these abnormalities and worsening of symptoms and final transition to psychosis. Considering that five other studies found no significant differences across these same areas, we can conclude that more research is needed to confirm glutamatergic abnormalities in subjects with an ARMS for psychosis. However, future research must overcome the methodological limitations of existing studies to obtain reliable results. © 2016 Elsevier B.V. All rights reserved.

1. Introduction The first antipsychotic medication was introduced in the 1950s. Although this was the first medical treatment to reduce psychotic symptoms, it was not until 20 years later that the underlying mechanism of action—blockade of the dopamine D2 receptor—was identified. The most consistent and influential theory to date to explain the development of psychosis is that the disease is related to dopaminergic alterations. Although second generation antipsychotics have shown relatively good results in treating (positive) symptoms, schizophrenia remains one of the most disabling mental disorders due to other core features of the illness, including negative symptoms and cognitive and emotional impairment (Carpenter and Gold, 2002; Keefe et al., 2006; Mishara and Goldberg, 2004; Rosenheck et al., 2006). Indeed, cognitive deficits and negative symptoms are a better predictor of social disability than residual positive symptoms (Hyman and Fenton, 2003; Milev et al., 2005; Rosenheck et al., 2006), which explains why the long term prognosis remains poor. Further investigations have suggested a new approach which moves away from the traditional dopamine focus to one that is more closely

related to the glutamatergic hypothesis. This hypothesis presumes disturbances in brain glutamatergic pathways and impairment in signalling at glutamate receptors, including the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR) and metabotropic glutamate receptors (mGluRs) (Chavez-Noriega et al., 2002; Kantrowitz and Javitt, 2010). It has been postulated that NMDA receptor dysfunction may lead to a dopaminergic dysregulation with excess mesolimbic dopamine and reduced mesocortical dopamine being a final common pathway of complex interactions between glutamatergic, dopaminergic, and GABA-ergic mechanisms (Fig. 1) (Schwartz et al., 2012). These findings suggest that abnormalities in dopamine pathways, which are widely-described in schizophrenia patients, could be mediated by the altered glutamatergic neurotransmission. Clinical studies of phencyclidine (PCP) and ketamine abusers also support the NMDAR hypofunction hypothesis of schizophrenia. These substances work as NMDA receptor antagonists and induce hypofunctioning in this receptor. Both clinical and research data show that these subjects present characteristics that resemble the symptoms of schizophrenia, including emotional blunting, thought disorders, auditory hallucinations, and cognitive impairment (Javitt and Zukin, 1991).

http://dx.doi.org/10.1016/j.schres.2016.01.005 0920-9964/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

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Fig. 1. Interactions between glutamatergic, dopaminergic and GABA-ergic mechanisms.

The clinical effects induced by ketamine administration in healthy subjects are thought to most closely mimic schizophrenia (Krystal et al., 2005), as they not only cause perceptual changes but also mimic the negative symptomatology such as anhedonia, emotional blunting, and social retreat, providing a more complete model of psychosis than that obtained by other drug models such as amphetamines, which produce an increase in dopamine and only induce positive symptoms related to thought content, thought disorder, and psychomotor activation. Furthermore, ketamine infusion in schizophrenia patients transiently exacerbates positive symptoms (Lahti et al., 1995a) and is associated with an activation of prefrontal cortex (PFC) and thalamic structures (Lahti et al., 1995b), cerebral regions with impaired functioning in schizophrenia.

In animal studies, experimental findings also show that the absence of NMDA-receptor subunits can cause alterations at a molecular and behavioural level, causing schizophrenia-like symptoms (Mohn et al., 1999). Mice with reduced NMDA receptor expression display behaviours related to schizophrenia, and administration of these substances generates cognitive disruption (memory and learning-related tasks) as well as stereotypy, impaired social behaviour, and in rodents and primates, increased locomotor activity (Greenberg and Segal, 1985; Sams-Dodd, 1996; Schlemmer et al., 1978; Steinpreis et al., 1994; Sturgeon et al., 1979). Although the pharmacological effect of NMDA antagonists such as ketamine are well-documented as an increase in extracellular glutamate in the prefrontal cortex (Moghaddam et al., 1997), the neuronal

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

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and cognitive pathways underlying the psychotic-like symptoms are still not clear. Recent approaches suggest the psychotic symptoms can be explained under predictive coding models in a Bayesian framework (Corlett et al., 2009; Corlett et al., 2011). This model assumes that our perception is conditional upon what we expect, leading to inferences about the world, which in turn alter future expectations and modify sensory information to fit it in with our prior beliefs. Any experimental intervention to induce psychotic-like symptoms affects the interaction between a subject's predictions about the world and the sensory inputs, thus originating altered experiences. These models understand that mismatches between expected and actual inputs, known as prediction errors (PE) (Schultz and Dickinson, 2000), are important in learning and experience. Multiple theories about the formation of psychosis propose the existence of aberrant PE processing (Fletcher and Frith, 2009). This is explained by the idea that the brain must infer causes of sensory events. The environment is considered well-predicted when the prediction error is minimised, and this is achieved by integrating new information into pre-existing world models. In this process, hierarchical interactions between topdown and bottom-up processes enable perception and prediction of the world (Friston, 2005). As a connection pathway between the cognitive model and the neurochemical and molecular processes, it has been suggested that the bottom-up information proceeds via forward AMPA signalling and top-down predictions via NMDA signalling, with these two mechanisms responsible for predictions and PE. To understand the altered process in psychosis, this model suggests that the altered mechanism would be mediated by an AMPA upregulation, which causes aberrant perceptions by impairing the filtering of irrelevant information that is consequently understood as salient information requiring an explanation; on the other hand, the NMDA blockade limits the top down process in which prior models could explain these mismatches carried by the upregulated AMPA receptors, these altered processes result in changes in perception and in aberrant explanations (Corlett et al., 2009). The experimental paradigm used to estimate PE signalling is the mismatch negativity (MMN) event related potential (EPR), which consists of an electrophysiological event-related response to unexpected sensory (typically auditory) stimuli. Operationally, it is defined as the difference in waveform obtained by subtracting the ERP of predicted or standard stimuli from unpredicted or unexpected stimuli (Schmidt et al., 2013). Significant reductions in MMN amplitude have been repeatedly reported in schizophrenic patients (Umbricht and Krljes, 2005) and similar results have been found in healthy volunteers after antagonizing NMDA receptors with ketamine infusions (Heekeren et al., 2008). The prefrontal cortex seems to be crucial for PE processing (Umbricht et al., 2002). Schmidt et al. (2012) found that healthy subjects showed a disrupted prefrontal PE processing during the MMN paradigm after ketamine exposure, and this same pattern has been observed in schizophrenia patients compared to healthy controls (Baldeweg et al., 2004). These results can be understood by assuming that ketamine alters short- and long-term NMDAR mediated synaptic plasticity, which is crucial for PE-dependent learning. Thanks to advances in neuroimaging, it is possible to obtain proof of these neurochemical dysfunctions and better understand brain abnormalities in schizophrenia. Proton magnetic resonance spectroscopy (1H MRS) is an MR-based technique that can be used to examine metabolites in vivo in the human brain. MRI scanners with field strengths of 3 T or higher can distinguish most glutamate from its metabolite glutamine. At lower field strengths, glutamate and glutamine are reported in combination, as Glx. Although most of the glutamine synthesis (80%) reflects cycling of the neurotransmitter glutamate (Rothman et al., 2011), meaning that higher levels of this metabolite are usually considered to be an increase in glutamatergic neurotransmission, this could also be due to a deficiency in the conversion from glutamine to glutamate. A limitation of 1H MRS is that the glutamate concentration is not specific to neuronal glutamate and thus changes in concentration levels can be due to metabolic processes other than neurotransmission alterations

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(Merritt et al., 2013). A recent review (Poels et al., 2014) of findings from 1H MRS studies that measured glutamatergic brain indices in individuals with schizophrenia noted that some authors have found regional glutamatergic abnormalities, suggesting elevated levels of glutamatergic indices in the medial prefrontal cortex and basal ganglia (especially associative striatum) in medication-naïve or medicationfree patients and a possible relationship between elevated glutamate/ glutamine in the hippocampus of non-medicated patients and decreased hippocampal volume. Studies that have used 1H MRS at high field strengths in never or minimally-medicated early psychosis have also reported elevated levels of glutamine in the thalamus and the anterior cingulate cortex (ACC) (Théberge et al., 2002), and an elevated ACC glutamine/glutamate ratio (Bustillo et al., 2010), and an elevated glutamate/glutamine ratio in the hippocampus. However, these findings must be taken cautiously due to certain limitations, including the limited spatial resolution of 1H MRS and the differences between studies in the spectral fitting methods and glutamatergic indices analysed. More research is needed to extend and replicate the results in those studies. An interesting question raised by this new explanatory theory is whether the glutamate abnormalities observed during the course of the illness arise after the development of frank psychotic symptoms, or whether they precede such symptoms and are present in the prodromal phase. Detecting individuals with an at-risk mental state for psychosis (ARMS) remains important given that the duration of untreated psychosis is associated with worse outcomes and response to antipsychotic treatment, implying greater severity of global psychopathology, positive and negative symptoms, depression and suicide (Marshall et al., 2005; Perkins et al., 2005; Ruhrmann et al., 2003). Despite all the progress that has been made in recent years, predicting which subjects will eventually develop psychosis remains elusive; however, efforts in this direction have been made to define operationalized ultra-high risk criteria (UHR), which would include young people (age range, 14–30) referred for mental health problems who meet criteria for one of the following groups: 1- Attenuated psychotic symptoms (APS) group: those who have experienced subthreshold positive APS during the past year. 2- The brief limited intermittent psychotic symptoms (BLIPS) group: those who have experienced episodes of frank psychotic symptoms that have not lasted longer than a week and have spontaneously abated (without treatment). 3- The trait and state risk factor group: Those with a first-degree relative with a psychotic disorder or the identified patient has schizotypal personality disorder in addition to a significant decrease in functioning or chronic low functioning during the previous year. Several instruments, such as the Structured Interview for Prodromal Symptoms (SIPS) (Miller et al., 2002), the Comprehensive Assessment of At Risk Mental States (CAARMS) (Yung et al., 2005), the Early Recognition Inventory (ERIraos) (Häfner et al., 2011) and The Bonn Scale for the Assessment of Basic Symptoms (BSABS) (Klosterkötter et al., 2001) have also been developed, but there is no single test that is sensitive and specific enough to justify individual treatment decisions in ARMS subjects. The transition rates range from 13% to 60% within one year depending on the instruments or the criteria used (Miller et al., 2002; Riecher-Rössler et al., 2007; Yung et al., 2005). Nevertheless, identifying ARMS subjects who will progress to psychosis remains a primary challenge. At present, there are no specific clinical features, cognitive impairment, or psychosocial characteristics that can determine the presence of a prodromal state with a predictive power high enough to justify interventions. For this reason, it is essential to ascertain whether the neuroanatomical and neurochemical changes observed during the illness are present before the psychotic disorder becomes established. These changes could act as possible early biomarkers for the illness; however, identifying reliable biomarkers for the emergence and progression of

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

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schizophrenia is a fundamental priority to develop efficient methods of detecting and preventing the transition to psychosis and further progression. Following these lines of investigation, several studies of ARMS subjects have found evidence of dopamine dysfunction in the associative striatum (Howes et al., 2009), a correlation with impaired prefrontal cortical function, and a possible relation between these alterations and the transition to psychosis (Fusar-Poli et al., 2010). Recent research on glutamatergic dysfunction has also been conducted. The aim of the presents study is to review those trials that investigate the presence of glutamatergic abnormalities in subjects with an at-risk mental state for psychosis. Given the recency of this new approach, this is the first review to be carried out on this subject. 2. Method 2.1. Data sources Trials that examined glutamate alterations with 1H MRS in subjects at high risk mental state for psychosis (HR) compared to healthy control subjects (HC) were considered for this review. Three databases were consulted: Pubmed, Tripdatabase, and the Cochrane library. Key words were glutamate alterations; NMDA hypofunction; high risk mental state; ultra-high risk psychosis; and 1H MRS. Titles and abstracts were examined to see if they fulfilled the inclusion criteria. Reference lists of included trials were also examined to identify additional studies. 2.2. Study selection Studies were included if: 1- They used 1H MRS to examine glutamate concentrations in ARMS subjects. 2- They defined the at-risk mental state using: (1) operationalized ultra-high risk criteria, (2) criteria from instruments that have proven to be valid and reliable and (3) a high genetic risk. 3- They compared patients with a healthy control group. 4- They specifically included the following glutamatergic metabolites: glutamate (Glu), the major excitatory neurotransmitter in the nervous system; glutamine (Gln), a glutamate precursor; or the sum of both metabolites (Glx). Studies were excluded: 1- If the subjects did not meet high risk criteria for psychosis. 2- If the samples overlapped with previous studies, only the original study was included. However, an exception was made for two studies that used overlapping samples. In one study, (Egerton et al., 2014), the original sample (Stone et al., 2009) was significantly enlarged. The second exception was made for a study in which the original sample (De la Fuente-Sandoval et al., 2011) was followed for two years to analyse the transition to psychosis (De la FuenteSandoval et al., 2013). Exceptions were made in both cases because these studies were deemed to have contributed new and relevant data to the review. The electronic search produced 478 citations, only 8 of which were relevant to this review. The reference list search yielded an additional 7 citations (Fig. 2). Results from overlapping samples had been published more than once and every effort was made to connect papers to avoid citation bias; four of the studies were eliminated during the full text revision due to this fact (Allen et al., 2015; Fusar-Poli et al., 2011; Stone et al., 2010a, 2010b). 3. Results Eleven articles published between 2004 and 2014 met the selection criteria. These studies used different defining criteria for the at-risk

mental state mentioned above. Five studies reported on individuals with high genetic risk for schizophrenia, either children or siblings of individuals with schizophrenia. Seven studies used standardized instruments to determine the presence or not of high risk mental state. A wide range of scales were used across the trials (Table 1). In addition, a wide range of brain regions were analysed in the various studies. The results from all the reviewed trials are presented in Table 2. 3.1. Glutamate and glutamine levels in medial frontal lobes Four studies analysed alterations in this region. Tibbo et al. (2004) found significantly higher levels of glutamate and glutamine in the right medial frontal lobe in the high risk group (HR) compared to the healthy controls (HC), and a significant correlation between these levels and global functioning in the HR group; however, this same analysis was not significant when all subjects were considered. Purdon et al. (2008) found no significant differences in the mean metabolite values (glutamate/glutamine) between HR and HC groups in the same brain region (medial frontal lobes), nor did they find an inverse correlation with the Continuous Performance Test (a sustained attention measure), as they had expected. Similarly, Yoo et al. (2009) found no significant differences in the glutamate/glutamine levels in any of the regions explored (anterior cingulate cortex, left dorsolateral prefrontal cortex, and left thalamus). Natsubori et al. (2014) analysed the medial prefrontal cortex in the following subjects: high risk mental state subjects, first psychotic episode patients, and patients with chronic schizophrenia. The aim was to examine whether glutamate abnormalities in patients with schizophrenia were dependent on the stage. The analysis revealed significant decreases in glutamate/glutamine metabolites only in the chronic schizophrenia group. 3.2. Glutamate and glutamine levels in the thalamus, caudate and anterior cingulate gyrus Three studies analysed alterations in these regions. Tandon et al. (2013) recruited 23 children of individuals with schizophrenia and 24 age-matched healthy controls. Only a subset of subjects (16 HR and 15 HC) were evaluated with the Structured Interview for Prodromal Syndromes (SIPS), the Chapman Schizotypy Scales (Chapman et al., 1978), and the Wisconsin Card Sorting Test (WCST)—a test that measures executive function, which is thought to be impaired in individuals at high genetic risk—(Bhojraj et al., 2010). Glx (Glu + Gln) concentrations were higher in the thalamus and caudate in HR subjects compared to HC; no differences were observed in the anterior cingulate gyrus. In this same subset, thalamic and caudate Glu + Gln levels positively correlated with attenuated psychosis and Schizotypy, while Glu + Gln from the caudate correlated with the perseverative errors from the WCST. No such associations were found in the control group. Grey matter loss has also been detected in the early phase of the illness, although the underlying basis of this volumetric reduction is still unknown. Stone et al. (2009) hypothesised that glutamatergic abnormalities would be present in HR subjects and that these abnormalities would be related to alterations in grey matter. They reported significant lower levels of glutamate in the left thalamus, which was directly correlated with thalamic–acetylaspartate (NAA) levels, which may provide a marker of pyramidal cell integrity. They also found higher levels of glutamine in the anterior cingulate in the HR group. An association between abnormalities in glutamate metabolites and grey matter loss in the medial temporal, lateral temporal, cerebellum, inferior frontal, insula, and cingulate cortex was also confirmed. Another study used data from this same sample, but included an additional 48 HR and 29 HC (Egerton et al., 2014). Those authors examined if regional glutamate levels in HR were predictive of clinical outcome. They reported lower levels of Glu in the thalamus of the HR subjects, but found no significant difference in the ACC. The main findings confirmed the principal

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

D. Treen et al. / Schizophrenia Research xxx (2015) xxx–xxx

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Fig. 2. A study flow diagram of the review Selection procedure.

hypothesis: low levels of thalamic glutamate at presentation were associated with persistence or worsening of positive symptoms in HR individuals after 18.1 ± 8.5 months follow-up assessments (clinical follow-up measures were available in the 68% of the original sample). 3.3. Glutamate and glutamine levels in left medial temporal areas (hippocampus) Two studies analysed the hippocampal regions. Valli et al. (2011) studied the relation between medial temporal activation during a verbal encoding task and glutamate levels. The results, consistent with previous studies (Allen et al., 2011), showed reduced activation in the HR group in the left parahippocampal gyrus; in the HC, a positive correlation was found between activation in this cluster during encoding and left medial temporal glutamate levels. This relation was not observed in the HR group, suggesting that medial temporal dysfunction in people with prodromal symptoms of psychosis is related to a loss of the normal relationship between function in this region and local glutamate levels. Stone et al. (2009) found no significant differences between groups in the hippocampus area. 3.4. Glutamate and glutamine levels in the associative striatum Four studies reported results on the associative stratum. De la Fuente-Sandoval et al. (2011), based on the widely documented

interaction between glutamate and dopamine, found higher glutamate levels in the dorsal caudate (associative striatum)—a dopamine-rich region of the brain—in patients with prodromal symptoms and in patients with a first psychotic episode compared to healthy controls. In contrast, no such differences were observed in the cerebellum, a region with a minimum quantity of dopamine receptors and without dopamine afferents. This finding suggests that the glutamate alterations may be restricted to dopamine-rich regions. This same research group performed a follow-up study in which they clinically followed the HR group for at least 2 years to determine whether they developed psychosis, finding that 37% of the sample made a transition to psychosis. On a post-hoc test, they found that the transition group had significantly higher glutamate levels in the associative striatum at baseline versus both the non-transition and control groups (De la Fuente-Sandoval et al., 2013). Tandon et al. (2013) also found significantly increased glutamate levels in the dorsal caudate. By contrast, Keshavan et al. (2009) found no significant differences in glutamatergic metabolites between HR and HC subjects overall in the striatal regions. 4. Discussion and future directions Although no single molecular event can completely explain the pathophysiology of schizophrenia, the NMDA receptor hypofunction hypothesis is widely supported by different research areas including imaging, pharmacological, NMDAR antagonist, animal, post-mortem

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

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and genetic studies that enhance NMDAR function in subjects with schizophrenia. It is not clear, for instance, that either dopamine D2 receptors or interneuron NMDA receptors are related to the cause of this disorder, but findings report an important role for glutamate-dopamine interactions within cortico-striato-thalamo-cortico loops that are modulated by hippocampal and amygdala inputs in schizophrenic patients (Gruber et al., 2014). If any alterations are to be found in glutamate concentrations, it will be in these areas where Glu-Gaba-Dopamine interactions take place. These hypothesised specific impairments in the cortico-thalamic circuitry would explain why alterations in glutamate and glutamine are regional and not generalized across all brain areas in the reviewed studies. The loss of the usual GLU tone may be a standalone cause of schizophrenia or may lead to a downstream increase in DA system activity, leading back to and supporting the original DA hypothesis. It is clear that both alterations might be related processes and it is important to clarify the nature of their interactions in order to distinguish primary dysfunction from secondary dysfunction. One approach that could separate cause from effect is genetics. Altered circuits may be hyperfunctioning or hypofunctioning as a result of subtle molecular abnormalities in gene products. It is well-documented that the aetiology of schizophrenia involves a strong genetic component with heritability estimates ranging from 60% to 80% (Szulk et al., 2013), but family studies and lack of concordance between monozygotic twins suggest that schizophrenia is likely caused by complex interactions between multiple genes and their interaction with environmental and epigenetic factors (Cardno and Gottesman, 2000; Harrison and Weinberger, 2005; Sullivan et al., 2003; Tandon et al., 2008; Van Os et al., 2008). The search for genetic lesions has not yet identified any clear targets, but efforts have been made to calculate polygenic risk scores (PGRS) that better capture the polygenic nature of complex disorders. A PGRS can be estimated based on a few significant hits from genome-wide association

Table 1 Genetic and clinical measures of the included studies. Reference

Genetic risk

Measures

Tibbo et al. (2004)

One parent with schizophrenia Two relatives with schizophrenia

SCID-I, DICA, GAF, modified premorbid adjustment scale CAARMS, PANSS, BPRS, HAM-D, HAM-A, GAF CAARMS, PANSS, Premorbid IQ: Wide Range Achievement Test-Revised SCID, K-SADS, SIPS, Chapman Schizotypy Scales and WCST

Yoo et al. (2009) Valli et al. (2011) Tandon et al. (2013) Purdon et al. (2008) Stone et al. (2009) De la Fuente-Sandoval et al. (2011) Natsubori et al. (2014) Egerton et al. (2014) De la Fuente-Sandoval et al. (2013) Keshavan et al. (2009)

Offspring of individuals with schizophrenia Sibling with schizophrenia

SCID, CPT, MIS, SAS CAARMS, PANSS, HAM-D, HAM-A SCID, SIPS

SIPS, PANSS, Hollingshead scale, Premorbid IQ (Japanese version of the National Adult Reading Test) CAARMS, PANSS, GAF SCID, SIPS

First-degree relatives of schizophrenia

SCID-I, K-SADS, Chapman perceptual aberration and magical ideation scales

DICA: Diagnostic Interview for Children and Adolecents. CAARMS: Comprehensive Assessment At-Risk Mental States. SIPS: Structured Interview for Prodromal Symptoms. MIS: Magical Ideation Scale. SAS: Social Anhedonia Scale. SCID: Structured Clinical Interview for DSM-IV. GAF: Global Assessment of Functioning scale. PANSS: Positive and Negative Syndrome Scale. BPRS: Brief Psychiatric Rating Scale. HAM-D: Hamilton Rating Scale for Depression. HAM-A: Hamilton Rating Scale for Anxiety. K-SADS: Kiddie-Schedule for Affective Disorders & Schizophrenia. WCST: Wisconsin Card Sorting Test.

studies (GWAS) as well as on a large number of single nucleotide polymorphism (SNPs) throughout the whole genome (Ripke et al., 2011; Purcell et al., 2009). Recent international consortia (Insel, 2010) combining SNP data from several independent studies have found replicable associations with genes of the major histocompatibility complex (MHC) region on various chromosomes while other studies have reported SNPs in candidate genes associated either with schizophrenia or a phenotype of psychosis. There are now several genes in which polymorphisms have been reproducibly associated with schizophrenia and it has been emphasized that many of these genes converge glutamatergic neurotransmission (Moghaddam, 2003; Lisman et al., 2008; Harrison and Weinberger, 2005; Collier and Li, 2003; Greenwood et al., 2011; Harrison and Owen, 2003; Jia et al., 2010; Harrison and West, 2006). Advances in genetic studies are crucial and will provide decisive information to ascertain the causes and interactions of these molecular alterations. To the best of our knowledge, this is the first review of glutamate alterations in high risk mental state subjects. Of the eleven studies evaluated, six reported significant alterations in glutamate levels in high risk mental state subjects compared to age- and gender-matched controls. Significantly increased glutamate/glutamine levels have been described in the frontal lobe (Tibbo et al., 2004), results that are largely consistent with the NMDA receptor hypofunction hypothesis. This line of investigation seems to merit more attention considering that 1H MRS studies at higher field strengths (4 T) reveal increased frontal glutamine/glutamate in early psychotic stages in minimally or nevertreated patients (Bustillo et al., 2010; Théberge et al., 2002). These findings could also explain the impaired frontal executive functions in schizophrenia, as they are strongly dependent on NMDA receptors (Lisman et al., 1998; Krystal et al., 1994). A recent study has also shown that elevated frontal Glx at baseline was associated with poor response to treatment at 4-weeks of follow-up (Szulc et al., 2013) in chronic schizophrenia. Although three other studies did not find significant differences in the frontal lobes, this might be explained by differences in sample selection criteria. Significantly higher glutamate rates were found in children at a high genetic risk with at least one parent with schizophrenia. Nonsignificant results were found in siblings of schizophrenia patients; since these siblings were healthy adults, it seems probable that they had passed the risk period for developing psychosis (Purdon et al., 2008). Natsubori et al. (2014) used subjects at UHR according to the SIPS criteria, but only one of the subjects had high risk genetics. The third and final study (Yoo et al., 2009) did select subjects with a high genetic risk, but that study had a technical limitation: only parts of the frontal lobe were examined, not the whole region as in the other studies. When the thalamus is analysed, contradictory findings have also been described. Although Tandon et al. (2013) found increased glutamate levels in this specific area, Stone et al. (2009) found the opposite: significantly reduced glutamate levels in the thalamus and an association between these lower levels and a decrease in grey matter. This finding by Stone et al., may suggest that glutamatergic dysfunction in the thalamus of HR individuals may lead to structural abnormalities. This same sample was expanded in a subsequent study (Egerton et al., 2014) and the results were replicated; in addition, Egerton and colleagues found a significant correlation between lower levels of glutamate in the thalamus and subsequent persistence or worsening of symptoms. A possible explanation for these opposing results might be the difference in the resolution strength of the H-MRI., Tandon et al. (2013) used a 1′5 T resolution, at which glutamate and glutamine levels can hardly be distinguished from each other (Rothman et al., 2011); as a result, these elevated levels could be explained by high levels of glutamine and not glutamate. Three other studies (Yoo et al., 2009; Valli et al., 2011; Keshavan et al., 2009) found no significant differences in thalamic regions.

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

D. Treen et al. / Schizophrenia Research xxx (2015) xxx–xxx

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Table 2 Characteristics and results of the included studies. Reference

Sample

Field Cerebral area strength

Tibbo et al. (2004)

20 HR 22HC 19 HR (4 excluded) 16HC (2 excluded) 24 HR 19 FE 25ChSz 22 HR 22 HC 22 HR 16 HC (2 excluded) 23HR (4 excluded) 24HC (2 excluded) 27HR 27 HC

3.0 T

Purdon et al. (2008)

Natsubori et al. (2014) Yoo et al. (2009) Valli et al. (2011)

Tandon et al. (2013)

Stone et al. (2009)

Egerton et al. (2014) De la Fuente-Sandoval et al. (2011) De la Fuente-Sandoval et al. (2013) Keshavan et al. (2009)

75HR 56 HC 18 HR 18FE 40 HC 19HR 26 HC 40HR 48 HC

Glutamate Medication Synthesis of results metabolites

Right medial frontal lobe Glutamate Glutamine Medial frontal lobes Glutamate Glutamine

None

Significant increased glutamate and glutamine in HR

None

No significant differences between groups

3.0 T

Medial prefrontal cortex

Glutamate Glutamine

10 HR: AA

No significant alterations in HR group, only in the chronic schizophrenia group

1.5 T

ACC, left DL-PFC and left thalamus Medial temporal cortex, ACC and thalamus

Glutamate Glutamine Glutamate Glutamine

None

No significant differences between groups

3 HR: SSRI

1.5 T

Left and right thalamus, ACC and caudate

Glutamate Glutamine

None

No group differences in regional glutamate levels Loss of the normal relationship between parahippocampal gyrus and left medial temporal glutamate levels in HR Significant increased glutamate in thalamus and caudate, not in the anterior cingulate in the HR

3.0 T

ACC, left hippocampus, and left thalamus

Glutamate Glutamine

2HR: AA 2HR: SSRI

3.0 T

Left thalamus and Glutamate anterior cingulate cortex Glutamine Associative striatum and Glutamate the cerebellar cortex

3 HR: AA 6 HR: SSRI 4 HR: SSRI

3.0 T

Associative striatum

Glutamate Glutamine

None

Transition group had higher glutamate levels in the associative striatum than both the nontransition and control groups

1.5 T

Corticostriatal and thalamic brain regions

Glutamate Glutamine

None

No significant differences between groups

3.0 T

3.0 T

3.0 T

Significant reduced thalamic glutamate in HR group and directly correlated with grey matter volume in the medial temporal cortex and insula. Significant high glutamine in the anterior cingulate in HR Low levels of thalamic glutamate at presentation associated with persistence or worsening of positive symptoms in HR Significant higher glutamate in the dorsal caudate in HR group No significant differences in the cerebellum

HR: high risk group. HC: healthy control. FE: first episode. ChSz: chronic schizophrenia. ACC: anterior cingulate cortex. DL-PFC: dorsolateral prefrontal cortex. AA: antipsychotics. SSRI: selective serotonin reuptake inhibitors.

The associative striatum is a major integration area involved in multiple functions such as reward cognition, motivational salience, executive functions, and stimulus response learning, all of which are important functions that are impaired in schizophrenia. A wide variety of inputs affect this region, include cholinergic afferents from striatal interneurons, GABAergic inputs from striatal interneurons (Dautan et al., 2014), dopaminergic inputs from the ventral tegmental area (VTA) and the substantia nigra (SNr), and glutamatergic inputs from several areas, including the cortex, amygdala, hippocampus, and thalamus (Yager et al., 2015). Significant abnormalities in the striatum have been described across the studies evaluated in this review. Two of the studies (Tandon et al., 2013; De la Fuente-Sandoval et al., 2011) found significantly higher glutamate levels in the caudate and dorsal caudate. Marked increases in presynaptic dopamine function have been described in this area (associative striatum) in ARMS subjects (Howes et al., 2009). This raises the possibility that dopaminergic increases in this area may be associated with increased glutamatergic input from frontal cortical areas. De la Fuente-Sandoval et al. (2013) performed a follow-up study of the original sample (two additional years), finding that subjects who transitioned to psychosis presented significantly higher levels of glutamate in the caudate at the baseline measure in comparison to the non-transition group, a finding that suggests that these differences may predict the development of psychosis in high risk individuals; however, the small number of the subjects who developed psychosis (n = 7) makes these results underpowered, so no definitive conclusions can be made. Nevertheless, these results are consistent with abnormalities found in medication-naïve psychotic patients, where high glutamate levels in the striatum have also been described (Poels et al., 2014). Only one study (Stone et al., 2009) found alterations (high glutamine levels) in the ACC. This same finding has also been reported in minimally medicated early psychosis patients (Théberge et al., 2002). Nonetheless, results were not significant in three other studies that

analysed the same region (Yoo et al., 2009; Valli et al., 2011; Tandon et al., 2013). A possible explanation for the non-significant results reported in some of the studies might be the considerable variability in the methodologies applied to the relatively novel quantification of glutamate levels. 1 H MRS is a difficult imaging method to apply, with a potential for erroneous results if poor-quality spectra are included in the analysis. The spectrum quality for exclusion varied across the included studies. Higher field strengths (≥3.0 T) offer sufficient resolutions to exclude most of the glutamine and N-acetyl-aspartate spectra from the glutamate estimate, but the current procedures are not entirely free of contamination. In this review, all the analysed studies used a field strength ≤ 3.0 T as glutamine levels were mixed with the glutamate levels and included in most of the results. Another important factor to keep in mind is that existing methods to detect ARMS subjects are not 100% reliable, and that only 13% to 60% of these at-risk patients transition to psychosis; this implies that an important proportion of subjects included in the HR groups might not have had a predisposition to develop psychosis; as a result, the results may have been underestimated. Another issue to consider is that symptom severity might contribute to variability in glutamatergic metabolites between patients considered at risk for psychosis; as we mentioned before, there are strong reasons to suspect that negative symptoms and cognitive impairment, resistant to actual antipsychotic medications, may be more fully explained by aberrant glutamatergic transmission (Javitt, 2010; Coyle and Tsai, 2004; Moghaddam, 2003). Clinical evidence supports the possibility that what we have historically labelled as “schizophrenia” may actually be many different disorders with different outcomes (Kirkpatrick et al., 2001), and future research could lead to the identification of specific diseases based on different clinical features, course, treatment response, and biological correlates. It has been proposed that deficit psychopathology (i.e., enduring, idiopathic, negative symptoms) defines a group of patients with a disease that differs

Please cite this article as: Treen, D., et al., Are there glutamate abnormalities in subjects at high risk mental state for psychosis? A review of the evidence, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2016.01.005

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from schizophrenia without deficit features; this notion would be congruent with the fact that differences in clinical presentations (i.e., presence of deficit features and major symptom severity) might be associated with different glutamatergic alterations in different brain regions, depending on the type of patient. Future, more specific classifications would provide more homogenous samples and could help answer this question: Are glutamate abnormalities higher and present in specific areas when deficit symptoms are more prominent? A limitation of the cross-sectional nature of the studies included in this review is that no evidence of temporal relationship can be assumed between the glutamatergic alterations and the posterior transition to psychosis. Only two of the studies performed a longitudinal follow-up, finding significant associations between glutamate alterations and worsening of the positive symptoms or transition to psychosis. As we pointed out earlier, many ARMS subjects will either not develop any psychopathology or they will develop other forms of psychopathology (but not schizophrenia). It is for these reasons that longitudinal studies in larger samples are essential to better understand the relation between abnormalities in glutamatergic neurotransmission and symptom severity and the final transition to psychosis. Future research will also benefit from the standardization of procedures and publication of accepted reference ranges for glutamate in certain brain regions. A limitation of this review is that some relevant studies, including unpublished ones, may have been overlooked. It should also be noted that only studies from open access databases have been reviewed. Another limitation is the marked heterogeneity of the articles included in relation to the criteria used for the determination of ARMS, the brain regions analysed, the mean age of the patients, and the sample sizes.

5. Conclusions Abnormal glutamate neurotransmission has been associated with the prodromal phase of schizophrenia, early psychotic episodes, and with the frequently treatment refractory processes of negative and cognitive symptoms—which are strongly related to a poorer long-term outcomes. In this brief review we have reported recent findings from studies that assessed alterations in glutamatergic neurotransmission in subjects with an at risk mental state for psychosis. These findings indicate that these abnormalities might be present before the transition to psychosis occurs, and their presence might contribute to the onset of a psychotic disorder. These findings are important because they contribute to an expanded definition of a full architecture of individual risk. Numerous factors must be taken into account—genetic and epigenetic biomarkers, biomolecular abnormalities, cognitive indicators, and physiological predictors of vulnerability to the disorder—to monitor ARMS subjects and to reduce, to the extent possible, the duration of untreated psychosis and to develop plausible early interventions that would delay onset or prevent the final transition to psychosis. One-third of patients with schizophrenia do not respond to dopaminergic antipsychotics, and a substantial proportion of patients receive suboptimal treatment of negative and cognitive symptoms. Considering that some studies have suggested that symptoms that respond poorly to antipsychotic treatment (negative symptoms and cognitive impairment) might have a glutamatergic basis (Egerton et al., 2014), the development of novel treatments that target the glutamatergic mechanism would be an interesting approach in future clinical trials. However, advances in this area of research must be made in parallel with genetic studies, as this is the only way to trace back the primary altered processes to explain these molecular abnormalities. Future clinical, genetic, animal and H-MRS studies should contribute and amplify the investigation of the underlying causes of the NMDA hypofunction. Further research in this area will lead to a better understanding of the primary cause of glutamatergic alterations, the relation and influence in dopamine neurotransmission and how these abnormalities contribute to the development of the illness.

After our review of these studies, we believe that longitudinal studies in larger, more homogenous samples are essential to confirm whether or not the presence of abnormal glutamate levels is an important marker of ARMS and if variations in these levels contribute to symptom severity and final transition to psychosis. Conflict of interest There are no relevant conflicts of interest from any of the authors. Role of funding source None. Acknowledgement None.

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