Abstract
Background
Dysfunctional glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmission may be part of the schizophrenia pathophysiology and underlie cognitive deficits. Abnormal levels of glutamate and GABA have been found in patients with first-episode psychosis or schizophrenia, and studies of mainly medicated patients have reported correlations between cortical glutamate and GABA levels and cognitive performance. However, the association between metabolites and cognitive deficits may be altered by treatment. Therefore, we investigated if glutamate and GABA levels in dorsal anterior cingulate cortex were associated with cognitive function in a large group of antipsychotic-naïve patients compared with matched healthy controls and tested the hypothesis that cognitive deficits in patients are related to altered levels of glutamate and GABA.
Methods
We recruited 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy controls matched for age, sex, and parental education. Magnetic resonance spectroscopy was used to measure glutamate and GABA levels in dorsal anterior cingulate cortex (ACC) on a 3T scanner. The cognitive domains attention (outcome was rapid visual information processing A’ (RVP A’)) and working memory (outcome was spatial working memory (SWM) strategy) were assessed with the Cambridge Neuropsychological Test Automated Battery, and premorbid intelligence estimated with the Danish Adult Reading Test (DART) (outcome was number of words correctly pronounced). A multivariate linear regression model was used to evaluate if levels of glutamate and GABA were different in patients compared with healthy controls, and thereafter to test if glutamate and GABA levels were associated with cognitive performance in the two groups (significant main effect) and if the association differed (significant interaction). SWM strategy score were logarithmically transformed because of non-normality.
Results
Levels of GABA in dorsal ACC were lower in the antipsychotic-naïve patients compared with healthy controls (SCZ: 2.24±0.35; HC: 2.40±0.33, p=0.03), but glutamate levels did not differ significantly between patients and healthy controls (SCZ: 10.75±1.45; HC: 10.91±1.17, p=0.54). Patients performed significantly worse than healthy controls in tests of attention (mean RVP A’ score SCZ: 0.89±0.05; HC: 0.94±0.04, p<0.001) and premorbid IQ (mean DART score SCZ: 17.4±6.5; HC: 21.5±5.3, p=0.001), whereas groups did not differ significantly in SWM strategy score (Median score SCZ: 27.0 (22.0–32.0); HC: 23.0 (19.0–30.0), p=0.18). Higher levels of glutamate were associated with better performance in tests of attention (b=0.01, p=0.016) and SWM (b=-0.02, p=0.008, higher score indicates worse performance) in both patients and healthy controls. The association between cognitive performance and glutamate did not differ significantly between the two groups (both interactions insignificant).
There were no significant associations between cognitive function and levels of GABA in dorsal ACC.
Discussion
This is the largest study of antipsychotic-naïve patients to date to investigate the association between cortical glutamate and GABA levels and cognitive function. We found no group differences in levels of glutamate, but lower GABA levels, which indicates reduced GABAergic neurotransmission in dorsal ACC in the pathophysiology of schizophrenia and psychosis.
Higher levels of glutamate in dorsal ACC were associated with better cognitive function. However, glutamate levels did not explain the differences in cognitive performance between patients and healthy controls, indicating that other neurotransmitters are important as well.
Modafinil modulates anterior cingulate function in chronic schizophrenia
