Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine
Introduction
Considerable heterogeneity exists in the functional brain imaging literature as to how Major Depressive Disorder (MDD) is mediated (for reviews, see Ketter et al., 1996, Kennedy et al., 1997, Drevets, 1998). The most commonly reported findings in studies comparing subjects with MDD to normal controls are differences between the groups in prefrontal cortical activity. Specifically, in subjects with MDD, decreased activity in the dorsolateral prefrontal cortex (DLPFC) has been the most commonly reported finding (e.g. Baxter et al., 1989, Dolan et al., 1993, Biver et al., 1994). However, increased activity in the ventral portion of the prefrontal cortex [including the ventrolateral prefrontal cortex (VLPFC), the inferior frontal gyrus (IFG), and orbitofrontal cortex (OFC)] has also been reported (Uytdenhoef et al., 1983, Buchsbaum et al., 1986, Drevets et al., 1992, Biver et al., 1994). In addition to these prefrontal differences, a recent report of a relatively large number of subjects revealed decreased activity (and volume) in the subgenual prefrontal cortex (Drevets et al., 1997), an area more ventral and medial to the prefrontal regions previously described. Other areas commonly reported to have decreased activity in MDD include the anterior cingulate gyrus (AC) (Bench et al., 1992, Mayberg et al., 1994), anterior temporal lobe (Post et al., 1987, Mayberg et al., 1994) and head of the caudate nucleus (Cd) (Baxter et al., 1985, Buchsbaum et al., 1986, Drevets and Raichle, 1992, Mayberg et al., 1994).
Reports of brain metabolic changes from pre- to post-treatment of subjects with MDD have also been heterogeneous (for review, see Rubin et al., 1994, Drevets, 1998). An increase in DLPFC metabolism has been reported with sertraline treatment (Buchsbaum et al., 1997) and with a variety of medications, including tricyclic antidepressants, lithium, and trazodone (Baxter et al., 1989). In contrast, a decrease in ventral prefrontal and limbic activity (including the IFG, the ventral portion of the middle frontal gyrus, and the ventral AC) has been reported in MDD subjects who responded to electroconvulsive therapy (ECT) (Nobler et al., 1994), desipramine (Drevets and Raichle, 1992), fluoxetine (Mayberg et al., 1999), or paroxetine (abstract, Kennedy et al., 1998). In all of these studies, brain activity changes occurred primarily in treatment responders.
Taken together, these findings have led to the hypothesis that MDD is mediated by decreased dorsal prefrontal metabolism and increased ventral prefrontal and paralimbic activity (Drevets, 1998, Mayberg et al., 1999). In the present study, we hypothesized that subjects with MDD who responded to the selective serotonin reuptake inhibitor (SSRI) paroxetine would show increases in dorsal frontal metabolic activity (in the DLPFC) and decreases in ventral frontal metabolic activity (in the VLPFC, IFG and OFC) when compared to non-responders to paroxetine.
In addition to brain metabolic changes reported previously with treatment, one group (Mayberg et al., 1997) recently examined baseline pre-treatment brain metabolic markers of response to antidepressant medication. In that study, higher metabolism in the rostral anterior cingulate gyrus was found to be associated with treatment response. We also sought to determine if pre-treatment regional brain metabolism in any regions associated with MDD would be a baseline marker of response to paroxetine treatment.
Section snippets
Subjects, treatment, and rating scales
Sixteen medication-free outpatients with MDD were recruited through advertisements placed in a local newspaper, flyers, and patient-initiated phone calls to a general psychiatry screening center at the UCLA Neuropsychiatric Institute. Written informed consent was obtained after a complete description of the study to the subjects, using a consent form approved by the UCLA Office for the Protection of Research Subjects. All subjects met DSM-III-R/DSM-IV criteria for MDD. Subjects were screened by
Clinical response
By our criteria, nine of the 16 subjects responded to treatment. Of these, one of the treatment non-responders fell asleep during the second PET scan, so that this subject’s data were excluded from the pre- to post-treatment comparisons but were used for the baseline markers of treatment response analysis.
Regional metabolic changes with paroxetine treatment
The overall MANOVA of the effects of treatment response on change in metabolism across the four regions (DLPFC, VLPFC, IFG, OFC) and two hemispheres revealed a significant interaction between
Discussion
This study is, to our knowledge, the first reported pre- to post-treatment study of MDD using an MRI-based ROI analysis of FDG-PET scans. The use of anatomical information from MRIs to localize cortical brain regions decreases the intersubject variability in ROIs associated with regions drawn directly on functional brain images, as well as the potential confounding factor of anatomical standardization across subjects with SPM. Both variations in region placement on functional images and
Acknowledgements
Supported by the National Alliance for Research in Schizophrenia and Depression (NARSAD) (A.L.B. and D.H.S.S.); the Charles A. Dana Foundation Consortium on Neuroimaging Leadership (S.S.); and R01 MH-53565 (L.R.B.). The authors thank Edythe D. London, John Matochik, and Peter C. Whybrow, for their suggestions on the manuscript.
References (47)
- et al.
Frontal and parietal metabolic disturbances in unipolar depression
Biological Psychiatry
(1994) - et al.
Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [18F]2-deoxyglucose in affective illness
Journal of Affective Disorders
(1986) - et al.
Effect of sertraline on regional metabolic rate in patients with affective disorder
Biological Psychiatry
(1997) - et al.
Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Research:
Brain Research Reviews
(1995) - et al.
Functional anatomy of the basal ganglia. II. The place of the subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Research:
Brain Research Reviews
(1995) - et al.
Glucose utilization in the temporal cortex of affectively ill patients: positron emission tomography
Biological Psychiatry
(1987) - et al.
Functional anatomy of language processing: neuroimaging and the problem of individual variability
Neuropsychologia
(1991) - et al.
Parallel organization of functionally segregated circuits linking basal ganglia and cortex
Annual Review of Neuroscience
(1986) - et al.
Stereotactic transformation of PET scans by nonlinear least squares
- et al.
Cerebral metabolic rates for glucose in mood disorders
Archives of General Psychiatry
(1985)
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Archives of General Psychiatry
Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive–compulsive disorder
Archives of General Psychiatry
The anatomy of melancholia — focal abnormalities of cerebral blood flow in major depression
Psychological Medicine
3D PET using a conventional multislice tomograph without septa
Journal of Computer Assisted Tomography
Contributions of the anterior cingulate cortex to behaviour
Brain
Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity?
Journal of Neurology, Neurosurgery and Psychiatry
Functional neuroimaging studies of depression: the anatomy of melancholia
Annual Review of Medicine
Neuroanatomical circuits in depression: implications for treatment mechanisms
Psychopharmacology Bulletin
A functional anatomical study of unipolar depression
Journal of Neuroscience
Subgenual prefrontal cortex abnormalities in mood disorders
Nature
The Global Assessment Scale. A procedure for measuring overall severity of psychiatric disturbance
Archives of General Psychiatry
A double-blind, placebo-controlled trial of nefazodone in the treatment of patients hospitalized for major depression
Journal of Clinical Psychiatry
Statistical parametric mapping: ontology and current issues
Journal of Cerebral Blood Flow and Metabolism
Cited by (246)
Persistent Ventral Anterior Cingulate Cortex and Resolved Amygdala Hyper-responses to Negative Outcomes After Depression Remission: A Combined Cross-sectional and Longitudinal Study
2023, Biological PsychiatryCitation Excerpt :There is strong evidence that individuals with depression exhibit enhanced memory for negative information (92–95). The hippocampus is tightly connected to the amygdala and plays a key role in memory formation and recall of negative events in individuals with MDD (16,96,97). Previous studies have demonstrated that neural activity in the hippocampus was increased in patients with MDD (16,98), a finding that was replicated in our study.
Effects of pharmacological treatments on neuroimaging findings in borderline personality disorder: A review of FDG-PET and fNIRS studies
2022, Journal of Affective DisordersfMRI and Other Neuroimaging Methods
2022, Comprehensive Clinical Psychology, Second Edition