Potential Regional Differences in GABA Levels in Patients With Psychosis Compared With Control Subjects

To the Editor: The study by Marenco et al. (1), published in the May 2016 issue of the Journal, reports GABA levels in the dorsal anterior cingulate cortex of 184 control subjects, 83 treated patients with psychosis, 25 untreated patients, and 31 unaffected siblings. Treated patients and siblings had lower GABA levels than control subjects, siblings had significantly reduced GABA levels compared with treated patients, and untreated patients did not differ significantly from healthy controls. While the GABA results in treated patients are consistent with previous reports in medicated patients with schizophrenia (2–4), how can they be reconciled with two independent studies that found robust increases in GABA levels in unmedicated schizophrenia patients (5) and in antipsychotic-naive subjects at ultra-high risk for psychosis (6)? Both studies found increased GABA levels in the medial prefrontal cortex of unmedicated patients (effect size=0.97) and ultra-high-risk patients (effect size=0.67). Moreover, increased GABA levels in the dorsal caudate of ultra-high-risk individuals (effect size=1.28) were found. Interestingly, and in the same study (5), Kegeles et al. did not find differences between unmedicated patients and controls in the dorsolateral prefrontal cortex (effect size=0.08). Taking all these findings into account, it could be proposed that GABA elevations (as measured by proton magnetic spectroscopy) could be regionally distributed between rostral and subcortical areas; no differences, or even reduced GABA levels, have been reported in dorsal areas, such as the dorsal anterior cingulate cortex (1) and the dorsolateral prefrontal cortex (5), as well as the occipital cortex (7) of unmedicated patients. Further studies measuring GABA in both rostral and dorsal areas within the same subject might shed light on this matter. If this circuitry could be confirmed, as with glutamate (8), pharmacotherapies that are specific to illness phase and that target the GABA system could be proposed.