DEMONSTRATION IN-VIVO OF REDUCED SEROTONIN RESPONSIVITY IN THE BRAIN OF UNTREATED DEPRESSED-PATIENTS

Objective: For over 25 years, it has been hypothesized that major depr ession is due to a deficiency of available serotonin or subsensitivity of key serotonin receptors in relevant brain regions. Direct evidence supporting this hypothesis has been lacking because of the difficulty in studying regional brain serotonergic function. The authors have de veloped a method for visualizing in vivo regional brain responses to s erotonin release by comparing regional brain glucose metabolism after administration of the serotonin-releasing dl-fenfluramine, relative to placebo. Method: Results with healthy subjects (N=6) were compared to those obtained with drug-free inpatients with moderately severe major depression (N=6). Results: Healthy subjects had several areas of stat istically significant increases in metabolism, mostly in the left pref rontal and temporoparietal cortex, and areas of decreased metabolism, such as in the right prefrontal cortex. In contrast, the depressed pat ients had no areas of increase or decrease in metabolism, differing si gnificantly from healthy subjects. Results with patients resembled tho se with healthy subjects (N=10) who were scanned twice without active drug on either occasion. Conclusions: This study provides the first di rect visualization of blunted regional brain responses to serotonin re lease in the brain of patients with major depression, a finding that s upports the hypothesis of impaired serotonergic transmission in depres sion.