Metabolites and First-Episode Psychosis

October 7, 2020
Brian Miller, MD, PhD, MPH

Abnormal glutamate and GABA levels may underlie cognitive deficits. A recent study investigated these associations in a large group of antipsychotic-naïve patients with first-episode psychosis.


Schizophrenia, including first-episode psychosis (FEP), is associated with impaired cognitive function. There is growing evidence that abnormal glutamatergic and gamma-aminobutryic acid (GABA)-ergic neurotransmission is also abnormal in first-episode psychosis, including the anterior cingulate cortex, thalamus, and dorsal striatum, as measured by proton magnetic resonance spectroscopy.1-3 Evidence also suggests that abnormal glutamatergic and GABAeric neurotransmission may also underlie cognitive deficits in schizophrenia.4,5 Given the potential for the effects of treatment on these metabolites, antipsychotic-naïve patients are needed to study the pathophysiology of cognitive deficits.

Bojesen and colleagues6 examined levels of glutamatergic and GABAergic metabolites in the dorsal ACC and thalamus in antipsychotic-naïve patients with schizophrenia and other psychosis.They then tested the hypothesis that glutamate and GABA levels in the dorsal AC were associated with cognitive performance in tests of attention, spatial working memory, and premorbid IQ in these patients, as well as a group of healthy controls.

Study authors recruited 56 antipsychotic-naïve patients and 51 age, sex, and parental SES-matched controls in Denmark. Inclusion criteria were ICD-10 diagnosis of schizophrenia, schizoaffective disorder, or nonorganic psychosis; aged 18 to 45 years; and never prescribed antipsychotics or CNS stimulants. They excluded participants with substance abuse during the past 3 months. Psychopathology was assessed with the PANSS, CGI, GAF, and Personal and Social Performance Scale. Patients also completed a cognitive battery with a priori measures of attention, spatial working memory, and premorbid intelligence.

Patients underwent a 3T MRI scan, and levels of glutamate and other metabolites were acquired with point-resolved spectroscopy. They used multivariate linear regression models to investigate whether glutamate and GABA levels in the dorsal ACC were different in patients with FEP and controls, and whether these levels were associated with cognitive performance, after controlling for potential confounding/moderating factors. Pearson’s correlations were also used to explore associations between glutamate and GAB levels with other metabolites, psychopathology, and level of function.

The mean age was aged 22 years and 43% were male. Forty-three patients had a diagnosis of schizophrenia, and 13 had nonorganic or paranoid psychosis. Patients with FEP had less education, lower functioning, and more smoking than controls. Dorsal ACC levels of glutamate and glutamine and glutamate (only) did not differ between FEP and control groups. Patients with FEP had significantly lower dorsal ACC GABA levels than controls. Left thalamus levels of glutamate and glutamine and glutamate (only) were not significantly different between FEP and control groups.

In the combined patient and control group, there was a positive association between glutamate and glutamine levels and attention, a negative association with spatial working memory, and no association with premorbid intelligence. In exploratory analyses, there were no significant associations between left thalamus glutamate and glutamine levels and cognitive performance. In patients, there were no significant correlations between glutamate and GABA levels and psychopathology or functioning scores.

The authors concluded that dorsal ACC glutamate and glutamine levels in both FEP and controls are significantly associated with spatial working memory. They also found lower dorsal ACC GABA levels and higher thalamic glutamate levels in patients with FEP. Strengths of the study include the antipsychotic-naïve status of patients and comprehensive assessments of cognition and glutamate/GABA. Limitations include the use of single voxel magnetic resonance spectroscopy, and the potential that other macromolecules could have contributed to the GABA signal.

Concluding thoughts

Higher resting dorsal ACC glutamate and glutamine levels are associated with improved cognitive function in FEP and controls. Lower GABA levels in the dorsal ACC and higher thalamic glutamate levels may be involved in the pathophysiology of psychosis.

Dr. Miller is professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.


1. Bustillo JR, Rowland LM, Mullins P, et al. 1H-MRS at 4 tesla in minimally treated early schizophrenia. Mol Psychiatry. 2010;15(6):629-636.

2. Theberge J, Bartha R, Drost DJ, et al. Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry. 2002;159:19441946.

3. Kegeles LS, Mao X, Stanford AD, et al. Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2012;69:449459.

4. Lewis DA, Curley AA, Glausier JR, et al. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:5767.

5. Gonzalez-Burgos G, Fish KN, Lewis DA. GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast.2011:723184.

6. Bojesen KB, Broberg BV, Fagerlund B, et al. Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis. Biol Psychiatry. 2020;Jul 10:S0006-3223(20)31737-6.

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