87. Glutamate and GABA in Antipsychotic-Naive Schizophrenia and Association With Treatment Outcome

Abstract

Background: Animal models of schizophrenia propose that decreased gamma-Aminobutyric acid (GABA)ergic inhibition of cortical glutamatergic neurons causes dysfunction in cortico-striato-thalamo-cortical networks. Indeed, glutamatergic disturbances are found in anterior cingulate cortex (ACC), thalamus, and striatum of antipsychotic-naive patients with schizophrenia. Additionally, increased levels of glutamate in ACC are associated with poor treatment response in cross-sectional studies. However, GABA studies of first-episode patients are sparse and results inconsistent. Furthermore, it is unknown if levels of glutamate and GABA in antipsychotic-naive schizophrenia patients can predict treatment response.Methods: Longitudinal study in progress of 40 antipsychotic-naive schizophrenia patients and matched healthy controls (HC). Participants are assessed at baseline, after 1.5, and 6 months. Patients are treated with aripiprazole only for the first 1.5 months but can be treated with other antipsychotics hereafter. Glutamate spectra are acquired with magnetic resonance spectroscopy (MRS) in ACC and left thalamus using PRESS, and GABA spectra in ACC using MEGA-PRESS on a 3T scanner. In addition, resting cerebral blood flow (rCBF) is acquired with the pseudo-continuous arterial spin labelling sequence. Clinical outcome is assessed with PANSS.Results: To date, 28 patients and 28 HC have been recruited. In the antipsychotic-naive condition, patients have increased glutamate scaled to creatine (glu/Cr) in thalamus (P = .035), but not ACC, and show a trend toward decreased levels of GABA/Cr in ACC (P = .08) compared to HC. In thalamus glu/Cr decreases after 1.5 (P = .04) and 6 months treatment (P = .004) and in ACC GABA/Cr normalises after 1.5 and 6 months compared to HC. Baseline levels of GABA in ACC correlate positively with reduction in both PANSS total (ρ = .7, P = .007) and positive (ρ = .7, P = .01) after 1.5 months and trend wise with reduction in PANSS positive after 6 month (ρ = .6, P = .06). Furthermore, patients in the antipsychotic-naive state have increased rCBF in left thalamus (P = .037), but not in the frontal lobe, with a decrease in both areas after 1.5 and 6 months of treatment.Conclusion: The results indicate decreased GABA in ACC and increased glutamate in thalamus in the pathophysiology of schizophrenia whereas glutamate in ACC seems unaffected. Blood flow is believed to reflect neural activity, especially glutamatergic, and the rCBF alterations seen in left thalamus but not frontal lobe thereby support the glutamatergic MRS findings. Antipsychotic treatment normalizes GABA in ACC and decreases levels of glutamate in thalamus compared to HC. Interestingly, high levels of GABA in ACC prior to treatment are associated with good treatment response. Inclusion of the entire sample will reveal if nonresponders have decreased GABA and increased glutamate from the beginning of the disease.