REVIEWGlutamate-mediated excitotoxicity in schizophrenia: A review
Introduction
This section provides a comprehensive explanation of topics relevant to the study of glutamate-mediated excitotoxicty in schizophrenia, beginning with a background of the illness and its dopaminergic hypothesis. The limitations of the dopaminergic hypothesis are important in bringing forth the glutamatergic hypothesis of schizophrenia. Subsequently, N-methyl-d-aspartate (NMDA) receptor hypofunction is introduced as a model for schizophrenia, which is followed by an explanation of glutamatergic dysfunction in schizophrenia. Next, glutamate׳s capacity to exert neurotoxic effects is presented. Lastly, common neuroanatomical deficits are noted. This broad introduction provides important background information for the contextualization of current research investigating glutamate-mediated excitotoxicty in schizophrenia.
Schizophrenia is a debilitating illness, present in approximately 1% of the global population and characterized by positive, negative and cognitive symptoms (Sullivan et al., 2003, Weiser et al., 2005). The primary treatment for schizophrenia is dopamine receptor antagonism with antipsychotic medication (Frangou, 2008). The clinical effects of dopamine receptor antagonists have provided the basis for the dopamine hypothesis of schizophrenia (Creese et al., 1976, Seeman and Lee, 1975), which posits that patients with the illness have aberrant functioning of the dopaminergic system (Abi-Dargham et al., 1998, Breier et al., 1997, Hietala et al., 1995, Laruelle et al., 1996). The dopamine hypothesis is limited in that it only addresses positive symptoms (Javitt et al., 2012); antipsychotics have minimal efficacy in the treatment of negative and cognitive symptoms (George et al., 2013, Miyamoto et al., 2012). Another limitation of the dopamine hypothesis is that 20–35% of patients show partial or no response to antipsychotic treatments (Lindenmayer, 2000, Suzuki et al., 2011). In addition, this hypothesis does not appear to adequately explain the neuroanatomical changes in patients with schizophrenia (Stone et al., 2007). Thus, the dopaminergic system does not describe the illness in its entirety (Moghaddam and Javitt, 2012). The glutamatergic hypothesis provides an alternate mechanism to explain the pathophysiology of schizophrenia.
Glutamate antagonists, such as phencyclidine (PCP) and ketamine, are well known to transiently induce symptoms similar to those observed in patients with schizophrenia (Coyle et al., 2003). Glutamate antagonists are unique in that they not only produce psychotomimetic effects, but also elicit negative and cognitive symptoms (Javitt and Zukin, 1991, Vollenweider and Geyer, 2001). Such effects have been reported following the acute administration of glutamate antagonists to healthy volunteers (Adler et al., 1999, Krystal et al., 1994, Krystal et al., 2000, Krystal et al., 2005, Malhotra et al., 1996), while administration of these agents to patients with schizophrenia exacerbates symptoms (Lahti et al., 1995a, Lahti et al., 1995b). The observed symptomatic effects of glutamate antagonists provide the basis for the glutamatergic hypothesis of schizophrenia (Kantrowitz and Javitt, 2012).
Glutamate antagonists induce schizophrenia-like symptoms through modulation of the NMDA receptor. PCP and ketamine are both non-competitive antagonists that exert their physiological effects by binding to the PCP receptor, a specific hydrophobic binding site coupled to the NMDA receptor (Javitt, 2007). Through this binding, PCP and ketamine inhibit the action of glutamate at the NMDA receptor, suggesting that the pathophysiology of schizophrenia may similarly result from dysregulation of the NMDA receptor (Javitt et al., 2012). Current proponents of the glutamatergic hypothesis postulate that hypofunctional NMDA receptors located on gamma-aminobutyric acid (GABA)–ergic inhibitory interneurons disinhibit pyramidal neurons, leading to a paradoxical increase in glutamatergic activity (Moghaddam and Krystal, 2012, Nakazawa et al., 2012, Stone et al., 2007).
The role of the NMDA receptor in increasing glutamate is supported by both preclinical and human studies using NMDA receptor antagonists. Acute treatment of rodents with NMDA receptor antagonists results in increased extracellular glutamate in the striatum and prefrontal cortex (Bustos et al., 1992, Moghaddam et al., 1997), and increased glutamine (the main metabolite of glutamate) in the prefrontal cortex (Iltis et al., 2009). Studies in healthy human participants employing proton magnetic resonance spectroscopy (1H-MRS) report increased glutamate and glutamine in the anterior cingulate after the acute administration of a sub-anaesthetic dose of ketamine (Rowland et al., 2005, Stone et al., 2012). In addition, agents that inhibit glutamate release reverse behavioural, cognitive, and cerebral blood flow changes induced by NMDA receptor antagonists in healthy human volunteers (Anand et al., 2000, Deakin et al., 2008, Doyle et al., 2013).
The aforementioned findings in rodents and healthy humans following acute treatment with NMDA receptor antagonists are comparable to 1H-MRS studies in patients with schizophrenia, which report increased glutamate levels in antipsychotic-free and naïve subjects during their first episodes of psychosis, as well as in subjects at ultra-high risk for psychosis (de la Fuente-Sandoval et al., 2011, de la Fuente-Sandoval et al., 2013a, Kegeles et al., 2012, Kraguljac et al., 2013, Purdon et al., 2008). 1H-MRS studies have also demonstrated higher glutamine levels in antipsychotic-naïve patients with schizophrenia (Bartha et al., 1997, Theberge et al., 2002). While there is strong evidence to support increased glutamatergic activity in patients with untreated schizophrenia, it should be noted that studies investigating medicated patients with schizophrenia have reported glutamatergic marker decreases or levels similar to healthy controls (Bustillo et al., 2011, de la Fuente-Sandoval et al., 2013, Goto et al., 2012, Kegeles et al., 2012, Ohrmann et al., 2005, Rowland et al., 2013, Theberge et al., 2003). Thus far, two studies have made direct comparisons between unmedicated and medicated patients, both showing elevated glutamate levels in the unmedicated state and normal glutamate levels in the medicated state. Using a longitudinal within-subject comparison, one study in particular administered clinically effective antipsychotic treatment (reduction of at least 30% on the total score of the Positive and Negative Syndrome Scale after 4 weeks) to antipsychotic-naïve patients with first-episode psychosis, significantly decreasing elevated baseline glutamate in the associative striatum, such that levels following treatment did not differ from controls (de la Fuente-Sandoval et al., 2013b). Notably, this study specifically included patients who responded to treatment. Another study utilized a cross-sectional approach to compare unmedicated patients, medicated patients and healthy controls, reporting increased Glx in the medial prefrontal cortex region of unmedicated patients, in comparison to controls, whereas no such difference existed between medicated patients and the control group (Kegeles et al., 2012). To further elucidate the role of treatment in changing glutamatergic activity, a recent review noted that glutamatergic levels are elevated in antipsychotic naïve patients but are similar to those of healthy controls in medicated patients with schizophrenia, independent of stage of illness (Poels et al., 2014a). This is contrasted by a meta-analysis that demonstrated that glutamate and glutamine concentrations decrease at a faster rate with age in patients with schizophrenia, as compared to healthy controls (Marsman et al., 2013).
However, it should be noted that recent research observed higher glutamate levels in the anterior cingulate cortex of antipsychotic-treated first episode patients with unremitted psychotic symptoms and in treatment-resistant patients than in medication responders (Demjaha et al., 2014, Egerton et al., 2012). These findings suggest that an alternative underlying pathophysiology may exist in patients with treatment-resistant schizophrenia than in patients who respond well to antipsychotics – one that similarly involves the glutamatergic system, yet is not modulated by dopaminergic regulation.
Glutamate has the potential to induce neuronal dysfunction and degeneration when present in abnormally high extracellular concentrations (Lahti and Reid, 2011, Lau and Tymianski, 2010, Mehta et al., 2013). This process is referred to as excitotoxicity, a term coined by John Olney (Olney, 1969, Olney and Sharpe, 1969), who posited that excessive stimulation by glutamate has the capacity to vastly increase intracellular calcium, affecting calcium homoeostatic mechanisms and triggering a cascade of events that ultimately result in cell death (Lau and Tymianski, 2010). Though the exact mechanisms of this phenomenon are only partially known, calcium influx is highly implicated (Belousov, 2012, Choi, 1988, Hardingham and Bading, 2010). In schizophrenia, the disruption in glutamatergic signalling may result in an excitotoxic effect secondary to excess stimulation of non-NMDA glutamate receptors (i.e AMPA and Kainate), leading to the structural findings associated with the illness (Abbott and Bustillo, 2006, Deutsch et al., 2001).
Neuroanatomical changes are often reported in patients with schizophrenia; for example, progressive loss of grey matter volume is common in both early and chronic stages of the illness (Arango et al., 2012, Hulshoff Pol and Kahn, 2008, Meyer-Lindenberg, 2011, van Haren et al., 2008). Recent meta-analyses investigating grey matter losses in schizophrenia most commonly identify volumetric reduction within superior temporal, medial temporal, superior prefrontal, medial prefrontal and insular regions, along with the thalamus and basal ganglia (Bora et al., 2011, Chan et al., 2011, Ellison-Wright et al., 2008, Glahn et al., 2008, Honea et al., 2005, Shenton et al., 2001, Steen et al., 2006). Whole brain volume reductions, ventricular enlargement and white-matter alterations are also frequently reported (Colibazzi et al., 2013, Connor et al., 2011, Lawrie and Abukmeil, 1998, Nazeri et al., 2013, Shenton et al., 2001, Voineskos et al., 2013).
In addition, reductions in cortical thickness are common in patients with schizophrenia. Various studies have observed cortical thinning in schizophrenia, particularly within frontal, temporal, parietal and cingulate regions, though insular and occipital areas are also affected (Goldman et al., 2009, Kuperberg et al., 2003, Narr et al., 2005, Rais et al., 2010, Rimol et al., 2010, van Haren et al., 2011, White et al., 2003).
The occurrence of these neuroanatomical changes is largely unexplained. Though the changes may conceivably result from medication intake and prolonged illness progression (Moncrieff and Leo, 2010, Navari and Dazzan, 2009, Torres et al., 2013, van Haren et al., 2012, Vita et al., 2012), studies utilizing first episode schizophrenia patients have provided evidence that structural changes occur irrespective of continuous antipsychotic treatment and years of illness duration. First episode schizophrenia patients with little or no exposure to antipsychotics exhibit neuroanatomical alterations within a number of brain regions in comparison with healthy controls (Chen et al., 2014, Fornito et al., 2008, Narr et al., 2005, Ren et al., 2013, Schultz et al., 2010, Sprooten et al., 2013, Steen et al., 2006, Venkatasubramanian et al., 2008, Vita et al., 2012). Glutamate-mediated excitotoxicity may contribute to these structural changes present in patients with schizophrenia (Abbott and Bustillo, 2006, Goff and Coyle, 2001, Stone et al., 2007).
The glutamatergic hypothesis offers a mechanism through which neuroanatomical changes may occur: glutamate-mediated excitotoxicity. In short, elevated glutamatergic neurotransmission, which is highly implicated in the pathology of schizophrenia, may have neurotoxic effects. The primary aim of this review was to describe the potential role of glutamate-mediated excitotoxicity as an explanatory mechanism for the neuroanatomical changes observed in patients with schizophrenia. To do so, findings from human studies were reviewed and discussed, followed by a presentation of the evidence from preclinical literature. Limitations of both human and preclinical studies were considered in drawing conclusions and providing future research directions.
Section snippets
Experimental procedures
A Medline® literature search (1946-April Week 3 2014) was performed to identify studies, reviews or case reports relevant to glutamate-mediated excitotoxicity in patients with schizophrenia. The search was conducted using the terms “schizophreni⁎” (Subheadings: schizophrenia, antipsychotic agents and psychotic disorders) and “glutam⁎” (Subheading: magnetic resonance spectroscopy) and ((“MRS” or “MRI” or “magnetic resonance”) or (“computed tomography or “CT”)). Only English language human
Results
The Medline® search yielded 622 publications. All titles and abstracts were read by two of the authors (E.P. and S.N.). Thirteen papers concurrently investigated glutamatergic activity and brain structure, and were thus selected and reviewed. Six articles were excluded because they failed to include statistics regarding the relationship between glutamatergic markers and neuroanatomical measures (Bartha et al., 1999, Duncan et al., 2013, Gruber et al., 2012, Kegeles et al., 2000, Rusch et al.,
Discussion
The overall aim of this review was to explore the evidence in humans for the relationship between glutamate related compounds (glutamate, glutamine and Glx) and structural brain measurements in patients with schizophrenia. A review of existing literature was conducted to elucidate the role of glutamate-mediated excitotoxicity in the structural brain changes associated with schizophrenia. Unexpectedly, the search yielded only seven studies that met inclusion criteria, reflecting the paucity of
Conclusion
The glutamatergic hypothesis of schizophrenia provides an alternate or complementary mechanism to the dopaminergic hypothesis of schizophrenia. Excitotoxic levels of glutamate secondary to NMDA receptor hypofunction on GABAergic inhibitory interneurons may contribute to the structural abnormalities observed in schizophrenia. However, currently available literature from human studies fails to adequately address this topic.
The present review performed a Medline® search to investigate whether
Role of funding source
The work was partially supported by a NARSAD Independent Investigator Grant from the Brain and Behavioural Research Foundation (A.G.), the Canadian Institute of Health Research MOP-114989 (A.G.), the Ontario Graduate Scholarship (E.P.) and the Early Researcher Award, Ministry of Economic Development and Innovation of Ontario (A.G., Y.I.). These sources were not involved in the collection, analysis and interpretation of data, the writing of the report or in the decision to submit the paper for
Contributors
E.P. performed the literature search and analysis, and wrote the draft of the manuscript. S.N. also contributed to the literature search and analysis, participated in the writing of and approved the final draft of the manuscript. C.D. critically reviewed, contributed to and approved the final draft of the manuscript. P.G. was central to the formulation of the idea for the review and critically reviewed, contributed to and approved the final draft of the manuscript. M.C. contributed to the
Conflict of interest
E.P. has received funding from the Ontario Graduate Scholarship. S.N. has received fellowship grant awards from the Centre for Addiction and Mental Health, Japan Society for the Promotion of Science, Canadian Institute of Health Research, and manuscript fees from Dainippon Sumitomo Pharma and Kyowa Hakko Kirin. C.D. has received grant support from Janssen (Johnson & Johnson), and has served as a consultant and/or speaker for AstraZeneca, Eli Lilly and Janssen. P.G. has received fellowship
Acknowledgements
We would like to thank Kristin Vesely for editing the first draft of the manuscript.
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