Abstract
Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathophysiology of first episode psychosis. We investigated whether first episode psychosis patients free from all pharmacological treatments and illicit substances show cortical glutamatergic alterations. One-hundred and eleven volunteers including 65 healthy volunteers and 46 first episode psychosis patients free from all pharmacological treatments (28 drug naïve) underwent a proton magnetic resonance spectroscopy scan measuring glutamate levels in the bilateral anterior cingulate cortex. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS) and cognition was measured using the Wechsler Adult Intelligence Scale (WAIS) digit symbol test. There were no differences in glutamate levels between patients and controls. These findings remained unchanged when adjusting for the effects of age, sex and ethnicity or when restricting the analyses to patients who were both medication naïve to all pharmacological treatments and illicit substances. Whilst these findings do not preclude glutamatergic alterations in psychosis, methodological advances are needed for us to investigate whether patients show alterations in other aspects of glutamate function, such as pre-synaptic glutamate or release.
Highlights
Schizophrenia and other psychotic disorders have a lifetime prevalence of approximately 0.7%1,2 and are ranked amongst the most disabling health conditions[3], with annual costs ranging from 94 million to 102 billion dollars for each country, worldwide[4]
Glutamate theories of schizophrenia were developed following observations that N-methyl-D-aspartate receptor (NMDAR) antagonists induce positive and negative symptoms and cognitive impairments in healthy volunteers, paralleling symptoms seen in schizophrenia[11,12,13]
Glutamate levels have been investigated in vivo in psychosis using proton magnetic resonance spectroscopy (1H-MRS)
Summary
Schizophrenia and other psychotic disorders have a lifetime prevalence of approximately 0.7%1,2 and are ranked amongst the most disabling health conditions[3], with annual costs ranging from 94 million to 102 billion dollars for each country, worldwide[4]. Pharmacological treatments blocking the D2 dopamine receptor have been shown to reduce psychotic symptoms[5], they are ineffective for approximately 30% of patients[6] and they fail to improve cognitive impairments in the illness[7]. Low doses of ketamine, an NMDAR antagonist, has been shown to induce psychotic symptoms, cognitive impairments and increase in glutamate levels in the anterior cingulate cortex in healthy volunteers[14]. While decreased GLX (glutamate + glutamine) levels have been reported in the medial prefrontal cortex in 16 antipsychotic-naïve patients with first episode psychosis[19], other studies have failed to find evidence of glutamate or GLX alterations in the anterior cingulate cortex in antipyshcotic-free patients with first episode psychosis[20,21,22]. Meta-analyses have come to discrepant conclusions, reporting no differences in glutamate levels in the medial frontal cortex in patients with first episode psychosis or chronic schizophrenia[26] as well as decreased glutamate levels in the medial prefrontal cortex when combining patients with first episode psychosis and chronic schizophrenia[27]
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