Brain glutamate levels may provide insights into schizophrenia outcomes

Lower brain glutamate levels were linked to antipsychotic exposure rather than to greater age-related decline in people with schizophrenia, according to results of a mega-analysis published in JAMA Psychiatry.

However, higher levels of glutamate may be used as an illness severity biomarker in these individuals.

“Large studies have not yet reached a consensus on the associations of aging with glutamate [Glu] levels in patients with schizophrenia,” Kate Merritt, PhD, of the division of psychiatry at the University College London’s Institute of Mental Health, and colleagues wrote. “An age-related decrease in medial frontal cortex (MFC) Glu level has been observed in both patients and healthy volunteers,16 but these findings were not replicated by another large study. Alternatively, meta-regression analysis has detected accelerated MFC glutamatergic reductions in patients with schizophrenia compared with healthy volunteers, but this finding was not apparent in a more recent analysis.”

The investigators aimed to evaluate links between age, symptom severity, functioning level and antipsychotic treatment with brain glutamatergic metabolites. They searched the MEDLINE database for journal articles published between Jan. 1, 1980, and June 3, 2020, using a variety of search terms, including schizophrenia, psychosis and schizoaffective. Merritt and colleagues contacted authors of 114 proton magnetic resonance spectroscopy (1H-MRS) studies that measured glutamate levels among patients with schizophrenia for individual participant data, which were available for 45 studies. They used linear mixed models, with study as a random factor, to evaluate links between Glu, Glu plus glutamine (Glx) or total creatine plus phosphocreatine (Cr) levels and age, antipsychotic medication dose, symptom severity and functioning. Values of Glu, Glx and Cr in the MFC and the medial temporal lobe (MTL) served as main outcomes and measures.

Merritt and colleagues included 42 studies, which featured data of 1,251 patients with schizophrenia (mean age, 30.3 years) and 1,197 healthy volunteers (mean age, 27.5 years). Results showed lower levels of MFC Glu and FLX among patients compared with healthy volunteers. Despite creatine levels having appeared lower in patients, the researchers noted the difference was insignificant. They observed a negative association among patients and volunteers between MFC Glu level and age that demonstrated a 0.2-unit reduction per decade. Further, they noted a negative association among patients between antipsychotic dose and MFC Glu and MFC Glx levels and a positive association between MFC Glu to Cr ratio and totally symptom severity, as well as positive symptom severity. The MFC Glu to Cr ratio was negatively associated with level of global functioning.

Regarding the MTL, Merritt and colleagues reported a positive association between the Glx to Cr ratio and total symptom severity, negative symptoms and worse Clinical Global Impression score. The level of MFC creatine increased with age; however, it was not linked to either symptom severity or antipsychotic medication dose.

“[These findings] highlight the value of matching or adjusting for age, prioritizing [cerebrospinal fluid]-corrected measures over Cr-scaled metabolite levels and considering antipsychotic dose as an explanatory factor when comparing Glu levels between patients and healthy volunteers,” Merritt and colleagues wrote. “The finding of elevated Glu levels in patients with more severe symptoms provides further support for the use of glutamatergic measures as a potential biomarker of illness severity, alongside other measures, and the development of novel treatments that target brain glutamatergic function.”