1H-MRS brain glutamate levels in schizophrenia; A mega-analysis investigating the association with age, antipsychotic medication and symptom severity

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Abstract

Importance: Proton Magnetic Resonance Spectroscopy (1H-MRS) studies indicate that altered brain glutamate function contributes to the pathophysiology of schizophrenia and the response to antipsychotic treatment. However its relationship to clinical and demographic factors is unclear.

Objective: To determine the effects of age, symptom severity, level of functioning and antipsychotic treatment on brain glutamatergic metabolites.

Data sources:
Authors of 114 1H-MRS studies measuring glutamate in schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.

Study selection: 45 1H-MRS studies contributed brain glutamate metabolites for 1251 patients with schizophrenia and 1197 healthy volunteers.

Data Extraction and Synthesis: Associations of glutamate, Glx or creatine with age, antipsychotic medication, symptom severity and functioning were assessed using linear mixed models, with study as a random factor.

Main Outcomes and Measures: Glutamate (Glu), glutamate+glutamine (Glx) and total creatine plus phosphocreatine (Cr) values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).

Results: 42 studies contributed data for 1251 patients with schizophrenia and 1197 healthy volunteers. MFC Glu and Glx were lower in patients than volunteers (P=0.03), and there was a trend for lower creatine (P=0.06). In both patients and volunteers, MFC Glu was negatively associated with age (0.2 unit reduction per decade). In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC glutamate (estimate=0.10 reduction per 100mg, SE=0.03, n=276) and MFC Glx (est=-0.11, SE=0.04, n=259). MFC Glu/Cr was positively associated with total symptom severity (est=0.01 per 10 points, SE=0.005, n=668), and positive symptom severity (est=0.04, SE=0.02, n=625), and negatively associated with level of global functioning (est=0.04, SE=0.01, n=178). In the MTL, Glx/Cr was positively associated with total symptom severity (est=0.06, SE=0.03, n=132), negative symptoms (est=0.2, SE=0.07, n=132), and worse clinical global impression (est=0.2 per point, SE=0.06, n=76). MFC creatine increased with age (est=0.2, SE=0.05, n=1417), but was not associated with either symptom severity or antipsychotic dose.

Conclusions: These data suggest that lower glutamate in patients may result from antipsychotic exposure rather than greater age-related decline. Higher glutamate levels may act as a biomarker of illness severity.

Original languageEnglish
JournalJAMA Psychiatry
Publication statusAccepted/In press - 11 Feb 2021

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