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

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Abstract

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 at-risk 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.

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).

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 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 top-down 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 (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 medication-free 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 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.

Section snippets

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

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

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 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

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

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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