Abnormal GABAergic function and negative affect in schizophrenia

Abstract

Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated - directly or indirectly - with GABAergic function on a continuum with normal behavior.