Progressive changes in glutamate concentration in early stages of schizophrenia: A longitudinal 7-Tesla MRS study

Abstract

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Healthy controls were also scanned at two time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, p = 0.03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, p = 0.50), and the group by time interaction was not significant (F(1,27) = 0.86, p = 0.36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/year increase, while healthy controls showed a 0.06 mM/year reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset glutamate loss in schizophrenia. Interestingly, it provides evidence in favour of a lack of progressive glutamate change in our schizophrenia sample indicating that the glutamatergic level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamatergic dynamics in schizophrenia.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level

“…This result suggests that findings of reduced Glu levels in patients compared with healthy volunteers are not associated with accelerated aging in patients but may be explained by greater antipsychotic exposure, although lower Glu levels have been reported in minimally treated patients with first-episode psychosis. 80,81 This finding may explain reports of reduced anterior cingulate cortex Glu levels in patients with chronic schizophrenia compared with healthy volunteers. 9-14 Indeed, a large longitudinal study reports a decrease in Cr-scaled Glu levels with treatment.…”

The impact of spectral basis set composition on estimated levels of cingulate glutamate and its associations with different personality traits

“…One study reported higher levels 28 , whereas others found reductions [29][30][31] or no significant differences 32,33 in first-episode psychosis or schizophrenic patients in the ACC. The same irregularity can be found for subjects at risk for psychosis, in the ACC higher 4,11,[34][35][36] and lower 10 glutamate levels, or even no significant results [37][38][39] have been described.…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…To our knowledge, only 2 studies report on longitudinal GSH measurements in psychosis to date. In a sample of 21 subjects with first episode schizophrenia scanned at baseline with <3 days of lifetime antipsychotic exposure and followed after 6 months of antipsychotic treatment, GSH levels were highly stable (Mean(SD) at baseline =1.71 (0.36), at 6-months = 1.75 (0.23)) [84]. The same stability in GSH levels was also seen in the 10 demographically healthy controls scanned at 2 time points (Mean(SD) at baseline =1.64 (0.25), at 6-months = 1.63 (0.32)) [84].…”

“…In a sample of 21 subjects with first episode schizophrenia scanned at baseline with <3 days of lifetime antipsychotic exposure and followed after 6 months of antipsychotic treatment, GSH levels were highly stable (Mean(SD) at baseline =1.71 (0.36), at 6-months = 1.75 (0.23)) [84]. The same stability in GSH levels was also seen in the 10 demographically healthy controls scanned at 2 time points (Mean(SD) at baseline =1.64 (0.25), at 6-months = 1.63 (0.32)) [84]. In a larger sample of 38 patients with first episode psychosis (onset within 2 years) and 48 healthy controls followed up over 4 years [85], GSH levels was found to have a near zero change in all 5 studied brain regions (ACC, thalamus, DLPFC, centrum semiovale and orbitofrontal cortex) over time, strongly arguing for a 'trait-like' stability of GSH levels compared to other metabolites.…”

“…In schizophrenia, while the exact nature of glutamate dysfunction in schizophrenia is yet to be clarified, meta-and mega-analyses of MRS data demonstrate a glutamatergic deficit state, at least in the prefrontal cortex [66,130,131]. Emerging observations implicate antipsychotics in progressive glutamate reduction in schizophrenia [130] but evidence in this regard is still inconclusive (see [84] and [131]). Interestingly, lower GSH levels cooccur with reduced glutamate in the chronic stage [65,68], especially in ultra-treatmentresistant patients [71].…”