S. K. Brannan

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

BACKGROUND Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

280. Olanzapine therapy for posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a relatively common condition, for which there is no standard of pharmacological treatment. Preclinical research with the learned helplessness animal model of posttraumatic stress disorder, and prior clinical research with nefazodone, suggests that serotonin 5-HT2 receptor antagonists may successfully treat PTSD, including the “core” or intrusive symptoms. Since the atypical neuroleptic olanzapine (Zyprexa) has antagonist properties at the 5-HT2 receptor, we undertook a multi-site open label study of olanzapine in veterans with combat induced PTSD. Patients are recruited from VA clinics in Dallas, Fort Worth, Waco, Austin, and San Antonio. All procedures have been approved by the relevant ethical review committees, and no procedure is performed without fully informed, signed, witnessed consent. After evaluation and washout, patients are titrated up to a maximum dose of 20 mg per day, as tolerated. Primary outcome measure is the Clinician Administered PTSD Scale (CAPS), and secondary measures are the Hamilton Rating Scales for Anxiety and for Depression (HRSA, HRSD). Patients are seen in clinic weekly. Target enrollment for this ongoing study is 60. We have performed an interim analysis on the first 14 patients who received an “adequate” trial, defined as 4 weeks of therapy. The most significant improvement over baseline was seen in the total CAPS score (F 5 14.1, p 5 0.0001) and in the Cluster B (core symptoms) subscale score (F 5 14.8, p 5 0.0001). Significant improvement was also seen on the other CAPS subcales and on the HRSA and HRSD. If these findings continue in the larger sample, larger scale, randomized, placebo controlled clinical trials should be considered. Also, the efficacy of olanzapine in civilian PTSD should be tested.