Hippocampal glutamate metabolites and glial activation in clinical high risk and first episode psychosis

Abstract

Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy (H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months

“…The opposite association has been found by others with increased levels of glutamate associating to severity of attenuated psychotic symptoms [28], poor functional outcome [26], and transition to psychosis [26]. While some have found no association between metabolite levels and clinical symptoms [22], one study found lower levels of GABA in medial prefrontal cortex to be associated with more severe negative symptoms [30].…”

“…Studies on GABA levels in UHR states are still limited, but meta-analytical studies propose that there is no difference between neither established schizophrenia or UHR and healthy controls [12,16]. Some studies do, however, report differences in glutamate or Glx [7,[17][18][19][20][21][22][23] as well as GABA [21,23,24] levels between UHR and healthy controls, although results are diverging regarding the direction of the differences. This suggests that aberrant metabolite levels may only be present in the subgroup of actual prodromal patients, supported by studies showing that the degree of glutamatergic dysfunction might predict clinical outcome [6,19,25].…”

“…Furthermore, abnormal levels of glutamate (increased as well as decreased) have been found to be associated with the severity of attenuated psychotic symptoms [7,21,28], negative symptoms [29], and poor performance on neurocognitive tests of visuospatial attention [22] and working memory [21]. Similarly, lower levels of GABA have been associated with more severe negative symptoms [30].…”

Neurochemical effects of oxytocin in people at clinical high risk for psychosis

“…To fill this gap in knowledge, we investigated the effects of intranasal oxytocin on several neurochemical metabolites that are thought to be altered in CHR-P individuals in a randomised, double-blind, oxytocin vs placebo single-dose challenge 1 H-MRS study. In line with previous findings in CHR-P individuals, our primary aim was to assess the effects of oxytocin on levels of glutamate, and glutamate plus glutamine (Glx), in the left hippocampus, ACC and left thalamus (Bloemen et al, 2011;Shakory et al, 2018;Tibbo et al, 2004). In view of recent literature suggesting that N-acetylaspartate, myo-inositol and choline may be altered in populations at risk of psychosis (Bossong et al, 2018;Tandon et al, 2013), and that oxytocin's effects may involve several neurochemical pathways (Aoki et al, 2015;Benner et al, 2018;Ninan, 2011;Qi et al, 2012), our secondary aim was to examine the effects of oxytocin on these metabolite levels.…”

“…In humans, metabolite levels can be quantified in vivo using proton magnetic resonance spectroscopy ( 1 H-MRS) (Provencher, 1993). Using this technique, numerous (but not all (Merritt et al, 2016)) studies have reported alterations in glutamate (and/or glutamate plus glutamine (Glx)) levels in people at high risk of psychosis vs controls, particularly in the hippocampus (Bloemen et al, 2011;Shakory et al, 2018), frontal (Merritt et al, 2016) or anterior cingulate cortex (ACC) Tibbo et al, 2004) and thalamus . Moreover, within CHR-P samples, altered metabolite levels at baseline appear related to clinical outcomes; thalamic glutamate is lower at baseline in those who do not remit by follow up (Egerton et al, 2014), and baseline hippocampal glutamate is elevated in those who transition (vs those who do not), and in those with poor (vs good) functional outcomes (Bossong et al, 2018).…”