GABA and the pathophysiology of schizophrenia: a neurodevelopmental perspective

Recent autopsy studies indicate that γ-aminobutyric acid (GABA) function is decreased in brain areas that involve the well-described structural changes observed with CT and MRI in schizophrenia. These structural brain changes have been reported to be associated with negative symptoms, poor premorbid functioning (i.e., a putative neurodevelopmental disorder), and with decreased dopamine and serotonin turnover. A relationship of GABA with each of these clinical and biochemical variables has been observed or can be hypothesized. In 52 drug-free, physically healthy male patients with schizophrenia (DSM-IIIR) (age range 23-49 years) plasma GABA, brain CT scans, CSF monoamine metabolites and clinical assessments were obtained. Plasma GABA was also obtained in 14 carefully screened healthy non-psychiatric male control subjects. Lower plasma GABA levels were independently associated with larger ventricle brain ratios (VBRʹs), lateral prefrontal atrophy, lower CSF HVA or 5HIAA, more affective flattening and poor premorbid school functioning, accounting for 48 to 50% of the variance. The plasma GABA levels of the drug-free schizophrenic patients were not significantly different from the normal controls. Although several reports have indicated that these measures are interrelated, their relationships with plasma GABA were independent from each other. The presence of these relationships without a difference in GABA levels from controls suggests changes in neuronal circuits that include GABA neurons. Our data support the hypothesis that GABA is involved in the pathophysiology of schizophrenia, consistent with a putative neurodevelopmental etiology.