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 co rrelates of this phenomenon have not been previously characterized Methods: Time course of changes in brain glucose metabolism were measured u sing positron emission tomography in hospitalized unipolar depressed patien ts treated with fluoxetine. Time-specific and response-specific effects wer e examined at 1 and 6 weeks of treatment. Results: Changes were seen over time, and characterized by three distinct p atterns: 1) common changes at I and 6 weeks, 21 reversal of the 1-week patt ern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fl uoxetine responders and nonresponders, similar at 1 week, were differentiat ed by their 6-week pattern. Clinical improvement was uniquely associated wi th limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, pa rietal, anterior, and posterior cingulate). Failed response was associated with a persistent I-week pattern and absence of either subgenual cingulate or prefrontal changes. Conclusions: Chronic treatment and clinical response to fluoxetine was asso ciated with a reciprocal pattern of subcortical and limbic decreases and co rtical increases. Reversal irt the week-1 pattern at 6 weeks suggests a pro cess of adaptation in specific brain regions over time in response to susta ined serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes m ay underlie treatment nonresponse. Biol Psychiatry 2000; 48:830-843 (C) 200 0 Society of Biological Psychiatry.