Prefrontal GABA levels measured with magnetic resonance spectroscopy in patients with psychosis and unaffected siblings

Objective: The authors sought to compare GABA levels in treated and untreated patients with psychosis with levels in their unaffected siblings and healthy control subjects, and to assess theeffects ofantipsychoticmedicationsonGABAlevels. Method: GABA+ levels (i.e., including signal from unrelated proteins or macromolecules) referenced to creatine or water were studied with J-edited proton spectroscopy in the dorsal anterior cingulate cortex of 289 individuals: 184 healthy control subjects,83treated patients withpsychosis,25untreated patients, 31 unaffected siblings, and 17 patients studied both while off all medications and while on a single antipsychotic. Results: GABA+ levels in the dorsal anterior cingulate did not differ between untreated patients and healthy controls. For treated patients, levels were modestly lower for GABA+/ creatine but did not differ for GABA+/water compared with healthy controls. For both GABA+ measures, unaffected siblings had significantly lower levels compared with controls. GABA+/creatine showed a modest degree of familiality (intraclass correlation=0.36). Antipsychotic dosage was negatively correlated with GABA+ levels, but the on-off medication studies indicated no difference in GABA+ levels on antipsychotics compared with off antipsychotics. Conclusions: GABA+/creatinein the dorsal anterior cingulate may constitute an intermediate phenotype with low effect size for psychosis, but GABA+/water measures do not fully support this conclusion. Low GABA+ levels in unaffected siblings could suggest a genetic association, but the failure to find consistent evidence of this phenotype in the patients themselves weakens genetic inference on risk for psychosis. Replication in independent samples of siblings is warranted to confirm the potential genetic risk association.