Elsevier

Biological Psychiatry

Volume 48, Issue 8, 15 October 2000, Pages 830-843
Biological Psychiatry

Dysfunction in neural circuits involved in the pathophysiology of mood disorders
Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

https://doi.org/10.1016/S0006-3223(00)01036-2Get rights and content

Abstract

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.

Introduction

It is well recognized that all of the major classes of antidepressant medications are associated with a several-week minimum delay in onset of clinical effectiveness Hickie et al 1999, Nurenberg et al 1999. Converging preclinical evidence suggests that mechanisms underlying this response timeline involve a variety of adaptive neurochemical changes including aminergic reuptake inhibition and associated presynaptic autoregulatory desensitization, up- and downregulation of multiple postsynaptic receptor sites, and receptor-mediated second messengers and neurotrophic effects Blier and de Montigny 1999, Duman et al 1999, Hyman and Nestler 1996. Requisite brain regions mediating these events remain generally uncharacterized, although putative sites of action in the dorsal raphe and locus coeruleus as well as in the hippocampus, hypothalamus, and frontal cortex are suggested from maps of normal human chemoarchitecture; postmortem receptor studies in depressed suicide victims; animal models of reward, stress, and learned helplessness; and in vivo and ex vivo pharmacologic studies Arango et al 1995, Arango et al 1999, Azmitia and Gannon 1986, Blier and de Montigny 1985, Duman et al 1999, Fraser and Hensler 1990, Haddjeri et al 1998, Mann et al 2000, Petty et al 1997. Supporting evidence of critical target sites in the brain mediating antidepressant effects is further provided by functional imaging studies of depressed patients studied before and after various forms of antidepressant treatment. However, there is considerable variability in both site and direction of changes across studies Baxter et al 1989, Bench et al 1995, Brody et al 1999, Buchsbaum et al 1997, Goodwin et al 1993, Malizia 1997, Martinot et al 1990, Mayberg et al 1999, Nobler et al 1994, Passero et al 1995, Smith et al 1999, Teneback et al 1999, Wu et al 1992, and reported findings are not necessarily in regions targeted by preclinical or autopsy studies. The time course of regional changes has not been characterized.

This study examines the time course of changes in regional brain glucose metabolism associated with 6 weeks of fluoxetine treatment in unipolar depressed patients. Three hypotheses are tested: 1) distinctive patterns of change in specific cortical, subcortical, and limbic regions will be seen at 1 week and 6 weeks of fluoxetine treatment, as indexed by 18 fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism; 2) the time course of metabolic changes will reflect the temporal delay in clinical response; and 3) variability in the 6-week metabolic change pattern will differentiate treatment responders from nonresponders.

Section snippets

Patient selection

Unmedicated depressed men with symptoms requiring hospitalization and treatment were recruited from the inpatient psychiatry unit at the Audie L. Murphy Memorial Veterans Administration Hospital (San Antonio). The clinical diagnosis of a major depressive episode, unipolar type, was confirmed by two independent psychiatrists using DSM-IV criteria and a structured psychiatric interview (Spitzer et al 1988). Patients with cerebrovascular risk factors or a previous stroke, documented head trauma or

Results

Fifteen of the 17 enrolled patients completed all three scans. Mechanical problems with the PET scanner precluded the timely scanning of two subjects, both of whom remained clinically symptomatic at 6 weeks, and later proved to have been treated with a placebo. Breaking the blind also revealed that 10 of the remaining 15 patients had received active fluoxetine; the other five, a placebo. Only scan data from the 10 active fluoxetine-treated patients were used to assess the 1- and 6-week

Discussion

There are three principle findings from this study. The first is that fluoxetine effects on regional brain glucose metabolism are not static over time. The second is that late-occurring changes mirror clinical response, with failure to modify early-occurring changes characterizing treatment nonresponse. The third is that the metabolic change pattern seen in responders is not merely the correction of pretreatment abnormalities, but rather a more complex combination of effects involving both

Acknowledgements

This research was supported by National Institute of Mental Health Grant No. MH49553, an Independent Investigator Award from the National Alliance for Research in Schizophrenia and Depression, and a physician-initiated grant from Eli Lilly and Company.

The authors thank Betty Heyl, Ralph Evans, and Sergio Leal for their expert technical assistance.

Aspects of this work were presented at the 1999 annual meeting of the Society of Biological Psychiatry in Washington, District of Columbia and at the

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