Benzodiazepines in schizophrenia: prefrontal cortex atrophy predicts clinical response to alprazolam augmentation

Benzodiazepines augment clinical responses to neuroleptics in some, but not all, treatment-refractory schizophrenic patients; however the biological predictors of response have remained unclear. Since patients with prefrontal cortex (PFC) volume loss demonstrate exaggerated subcortical dopamine responses to stress, and since benzodiazepines curtail stress-induced subcortical dopamine release in PFC-lesioned animals, we reasoned that patients with PFC volume loss might show preferential clinical responses to benzodiazepine augmentation. Five patients, who were participating in a larger four-week double-blind study of alprazolam augmentation of neuroleptics in treatment-resistant or partially treatment-resistant schizophrenia, had brain MRI scans prior to entry into the study. MRI scans were morphometrically analyzed to yield estimates of PFC grey and white matter volumes and PFC cerebrospinal fluid (CSF) volume, and these were correlated with clinical responses to alprazolam augmentation. PFC grey matter volume (adjusted for overall cranial capacity) was significantly correlated (r = 0.96, p < 0.01), in the predicted direction, with alprazolam-associated changes in total Brief Psychiatric Rating Scale ratings. PFC volume loss may represent a biological marker for benzodiazepine responsivity in schizophrenia, although the present findings are considered preliminary because of the small sample size. Mechanistic considerations and suggestions for future research are discussed.