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Original Article |

Regional Brain Metabolic Changes in Patients With Major Depression Treated With Either Paroxetine or Interpersonal Therapy:  Preliminary Findings FREE

Arthur L. Brody, MD; Sanjaya Saxena, MD; Paula Stoessel, PhD; Laurie A. Gillies, PhD; Lynn A. Fairbanks, PhD; Shervin Alborzian, BS; Michael E. Phelps, PhD; Sung-Cheng Huang, PhD; Hsiao-Ming Wu, PhD; Matthew L. Ho, BS; Mai K. Ho; Scott C. Au, BS; Karron Maidment, RN; Lewis R. Baxter Jr, MD
[+] Author Affiliations

From the Departments of Psychiatry and Biobehavioral Sciences (Drs Brody, Saxena, Stoessel, Fairbanks, and Baxter; Messrs Alborzian, Ho, and Au; and Mss Ho and Maidment) and Medical and Molecular Pharmacology (Drs Phelps, Huang, Wu, and Baxter), University of California–Los Angeles, Los Angeles, Calif; Veterans Affairs Greater Los Angeles Health Care System (Dr Brody); Department of Psychiatry, University of Toronto, Toronto, Ontario (Dr Gillies); and Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham (Dr Baxter).


Arch Gen Psychiatry. 2001;58(7):631-640. doi:10.1001/archpsyc.58.7.631.
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Published online

Background  In functional brain imaging studies of major depressive disorder (MDD), regional abnormalities have been most commonly found in prefrontal cortex, anterior cingulate gyrus, and temporal lobe. We examined baseline regional metabolic abnormalities and metabolic changes from pretreatment to posttreatment in subjects with MDD. We also performed a preliminary comparison of regional changes with 2 distinct forms of treatment (paroxetine and interpersonal psychotherapy).

Methods  Twenty-four subjects with unipolar MDD and 16 normal control subjects underwent resting F 18 (18F) fluorodeoxyglucose positron emission tomography scanning before and after 12 weeks. Between scans, subjects with MDD were treated with either paroxetine or interpersonal psychotherapy (based on patient preference), while controls underwent no treatment.

Results  At baseline, subjects with MDD had higher normalized metabolism than controls in the prefrontal cortex (and caudate and thalamus), and lower metabolism in the temporal lobe. With treatment, subjects with MDD had metabolic changes in the direction of normalization in these regions. After treatment, paroxetine-treated subjects had a greater mean decrease in Hamilton Depression Rating Scale score (61.4%) than did subjects treated with interpersonal psychotherapy (38.0%), but both subgroups showed decreases in normalized prefrontal cortex (paroxetine-treated bilaterally and interpersonal psychotherapy–treated on the right) and left anterior cingulate gyrus metabolism, and increases in normalized left temporal lobe metabolism.

Conclusions  Subjects with MDD had regional brain metabolic abnormalities at baseline that tended to normalize with treatment. Regional metabolic changes appeared similar with the 2 forms of treatment. These results should be interpreted with caution because of study limitations (small sample size, lack of random assignment to treatment groups, and differential treatment response between treatment subgroups).

Figures in this Article

THE REGIONS most commonly found to be abnormal in functional brain imaging studies of major depressive disorder (MDD) are the prefrontal cortex (PFC), anterior cingulate gyrus (AC), and temporal lobe (TEMP).14 Because there are reports of both increased and decreased activity in these structures in MDD, researchers have suspected that subregions of these structures have differentially altered function in MDD. Specifically, it has been hypothesized that dorsal brain structures (eg, dorsolateral prefrontal cortex [DLPFC]) have decreased activity,13,57 while ventral structures (eg, ventrolateral prefrontal cortex [VLPFC] and ventral AC) have increased activity in the symptomatic depressed state.3,5,6,8

Studies examining activity change from before to after short-term medication treatment of MDD have generally found normalization of brain activity in the regions cited above.3,9 The most commonly reported changes are in PFC. An increase in DLPFC metabolism has been reported with fluoxetine hydrochloride,5 sertraline hydrochloride,10 and naturalistic treatment (with a variety of medications, including tricyclic antidepressants, lithium carbonate, benzodiazepines, and trazodone hydrochloride),11,12 whereas a decrease in VLPFC (and anterior paralimbic) activity has been reported with paroxetine hydrochloride,13 venlafaxine hydrochloride,14 desipramine hydrochloride,15 and electroconvulsive therapy.16 Changes in the AC have been reported in a few studies, with dorsal increases and ventral decreases in activity being the most common findings.5

We obtained F 18 fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) scans in subjects with unipolar MDD both before and after treatment with either paroxetine or interpersonal psychotherapy (IPT).17 (Normal control subjects were scanned in a similar time frame for comparison.) This data set was analyzed in 3 parts. First, we compared regional brain metabolism at baseline between the entire group of subjects with MDD and the normal control group, hypothesizing that DLPFC metabolism would be decreased and ventral prefrontal and paralimbic metabolism increased in subjects with MDD compared with normal control subjects, as has been reported previously.16,8 Second, brain metabolic changes from baseline to follow-up in the whole group of subjects with MDD were compared with changes seen in normal control subjects. We hypothesized that, in subjects with MDD, DLPFC metabolism would increase significantly, whereas VLPFC (and other ventral prefrontal and limbic) metabolism would decrease significantly with treatment compared with changes in normal control subjects. Third, we performed a preliminary comparison of brain metabolic changes between the 2 subgroups of subjects with MDD (paroxetine-treated and IPT-treated), hypothesizing that brain metabolic changes found with the 2 forms of treatment would be similar, as has been reported with medication (fluoxetine) and psychotherapy (cognitive behavioral therapy) for obsessive-compulsive disorder.18

SUBJECTS

Forty subjects (24 meeting DSM-IV criteria19 for unipolar MDD and 16 normal controls) were recruited from a general psychiatry screening telephone service at the University of California–Los Angeles Neuropsychiatric Institute, Los Angeles, Calif, and from newspaper advertisements. An additional 3 subjects (1 in each MDD treatment subgroup and 1 normal control subject) underwent an initial scan, but dropped out before completion of other study parts needed for data analysis (eg, magnetic resonance [MR] imaging), so that their data were not used for the present study. The study was described to subjects, and written consent was obtained by means of a form approved by the University of California–Los Angeles Office for Protection of Research Subjects. Subjects were screened twice by a study physician (either A.L.B. or S.S.) before scanning. The Schedule for Affective Disorders and Schizophrenia–Lifetime version20 was administered to confirm the diagnosis made via previous unstructured clinical interviews. Exclusion criteria were comorbid Axis I diagnoses (including substance abuse), concurrent medical conditions affecting brain function (such as neurologic conditions, eg, Parkinson disease), or medications with potential central nervous system side effects (eg, β-blockers). No subjects had taken psychotropic medications for at least 2 weeks (5 weeks for fluoxetine) before starting the study.

Symptom severity was measured at the time of both PET scans by a study investigator (A.L.B. or S.S., both psychiatrists trained in standardized assessment) using the 17-item Hamilton Depression Rating Scale (HAM-D),21 Hamilton Anxiety Rating Scale,22 Yale-Brown Obsessive-Compulsive Scale,23 and Global Assessment of Functioning Scale.24 In an attempt to minimize bias, subjects who underwent psychotherapy were not rated by their primary therapist. Percentage changes in rating scales were calculated by subtracting posttreatment scores from pretreatment scores, dividing by pretreatment scores, and multiplying by 100.

TREATMENT

Subjects with MDD were treated during the 12-week period between PET scans with either paroxetine (n = 10) or IPT (n = 14). Treatment type was determined by patient preference to enhance recruitment for this preliminary study, because many study recruits expressed a strong preference for either paroxetine or IPT. Normal control subjects underwent no treatment.

Paroxetine-treated patients initiated drug treatment on the day after the baseline PET scan, with dosage adjusted during 1 to 2 weeks to a target of 40 mg/d. No other psychotropic medications were allowed during the study period. Compliance was monitored by patient report during weekly 20-minute medication visits for the first 2 to 3 weeks and then monthly thereafter. Medication visits consisted of reviews of symptoms and side effects and titration of paroxetine dosage. Subjects received no formal psychotherapy during the medication trial.

Patients treated with IPT had 12 weekly psychotherapy sessions17,25 with a trained IPT therapist (A.L.B. or P.S.), supervised by an experienced IPT supervisor (L.A.G.). Six subjects (3 for each therapist) had all psychotherapy sessions audiotaped and reviewed by the supervisor; these cases were then reviewed during weekly telephone sessions. The remaining cases were supervised as needed. The IPT was initiated during the week after baseline PET scanning. Subjects underwent 3 sessions during the first 2 weeks of treatment to have 12 psychotherapy sessions completed within the study time frame. Subjects treated with IPT who completed the trial were compliant with therapy (by patient report) and received no other psychotherapy and no psychoactive medication during the study. The foci of IPT were improvement of subjects' social networks and reduction of depressive symptoms. The primary problem foci of therapy (within the IPT model) were role transition (n = 6), interpersonal dispute (n = 3), social deficit (n = 4), and grief (n = 1).

MEASUREMENT OF REGIONAL GLUCOSE METABOLISM

Subjects underwent FDG-PET scanning at baseline and after 12 weeks. The FDG-PET method used in this study was similar to the method used in previous reports from our laboratory with separate groups of subjects,13,18 except that all scans in the present study were obtained with a different tomograph (961 ECAT EXACT HR; Siemens-CTI, Knoxville, Tenn) in 2-dimensional mode and consisted of 47 transaxial slices. This technique yielded a resolution of 3.64 mm full-width at half-maximum at the center, with a 3.97-mm slice thickness.26

All subjects were scanned in the awake, resting state. Each subject's head was positioned with a standard head holder to minimize movement and ensure accuracy of placement in the tomograph. Scanning began with a 20-minute transmission scan with the use of 3 rotating germanium 68 rod sources for attenuation correction. Subjects then received an injection of 185 to 370 MBq of 18F fluorodeoxyglucose. After a 40-minute uptake period, emission scanning was performed for 40 minutes. Scans were reconstructed from roughly 100 million counts.

PET DATA ANALYSIS

The PET data were analyzed with both statistical parametric mapping (SPM96)27 and an MR imaging–based analysis of regions of interest (ROIs). Results from both methods were used and compared, given the limitations of each.2730

For PET analysis with SPM96,3134 each subject's pair of images was realigned and coregistered, and all study images were reoriented within the program to the standardized coordinate system of Tailarach and Tournoux.35 Global normalization by proportional scaling was used. To adjust for differences in individual neuroanatomy and to improve the signal-to-noise ratio, a 10-mm full-width at half-maximum 3-dimensional gaussian smoothing filter was applied to all images.

To determine the location of SPM findings, PET scans and MR images of all study subjects were transformed into Tailarach space by means of the SPM program and significant regions were mapped onto group-averaged PET scans and MR images. Voxel coordinates were also located in the standard atlas.35 No differences in anatomic assignment of region location were found between these methods.

For the MR imaging–based ROI analysis, each subject underwent MR imaging of the brain by means of a double-echo sequence (proton density and T2 images; repetition time, 2000-2500 milliseconds; echo time, 25-30 milliseconds and 90-110 milliseconds; 24-cm field of view; 3-mm slices with 0-mm separation). Coregistration of PET to MR images was performed with a 3-dimensional MR-PET image registration program.36 The MR images were segmented into 4 different tissue types; image values were assigned with a relative proportion of 4:1:0:0.5 for gray matter, white matter, cerebrospinal fluid, and muscle, respectively. Segmented images were then smoothed 3-dimensionally to match the measured spatial resolution of PET data. The program then minimized the sum of squares of pixel value differences between PET and MR image sets to align measured FDG-PET images with the reconstructed MR image (the coregistration program used the Powell algorithm for minimization with 10 variable parameters).37 The program then resliced the FDG-PET images to coregister within the 3-dimensional orientation of MR images.

The ROIs selected for analysis (Figure 1) on the basis of the literature cited above were DLPFC, VLPFC, and dorsal and ventral AC. Other ROIs chosen because of documented anatomic circuitry with the PFC and AC were the dorsal and ventral head of the caudate nucleus (Cd) and thalamus.3840 Both supratentorial whole hemispheres were also drawn to calculate ratios of ROI metabolism to overall metabolism in ipsilateral hemisphere. Normalized rather than absolute metabolic values were used for analysis, because absolute metabolic values (calculated from arterialized venous blood samples) were not thought to be adequately reliable. The ROIs were drawn on MR images by raters blind to subject identity (S.A., M.L.H., and M.K.H.) and reviewed at weekly meetings by 2 of us (A.L.B., S.S.) and the team of region drawers.

Place holder to copy figure label and caption
Figure 1.

Regions of interest drawn on a magnetic resonance image of a study subject for transfer onto coregistered positron emission tomography scans. DLPFC indicates dorsolateral prefrontal cortex; AC, anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex; and Cd, head of the caudate nucleus.

Graphic Jump Location

We elected not to delineate temporal lobe regions, because several different ones have been tentatively associated with MDD, and the boundaries of such structures are not reliably identifiable on transaxial MR images obtained.

Regions were drawn on each subject's MR image (Figure 1). The DLPFC and VLPFC were drawn in approximately 6 planes each and consisted of the dorsal and ventral halves of the middle frontal gyrus, respectively. The AC was divided into 6 dorsal and 6 ventral slices. The superior boundary of the AC was the base of the body of the cingulate gyrus, while the inferior boundary was gyrus rectus. The dorsal and ventral Cd regions (roughly 4 slices each) included the entire head of Cd and were drawn excluding the more posterior body of Cd. The entire thalamus was drawn in roughly 6 slices.

STATISTICAL ANALYSES

The data were screened for distributional properties, outliers, and missing values. No data were rejected by this process.

For both the SPM and MR imaging–based ROI analyses, 3 general steps were performed: (1) a comparison of baseline PET scans between the MDD and control groups, (2) a comparison of baseline to follow-up PET changes between the entire MDD and control groups, and (3) a preliminary analysis examining changes seen on PET from baseline to follow-up in the paroxetine-treated and IPT-treated subgroups.

In the SPM analyses, differences between baseline scans in the MDD and control groups were assessed with the Z statistic. Changes from baseline to follow-up were determined with Z values based on each subject's pair of scans within each group (normal control group, MDD group as a whole, paroxetine-treated subgroup, and IPT-treated subgroup). A threshold for significance of P<.01 was used for hypothesized regions. This threshold is similar or identical to that of other published studies using PET in MDD.5,13,4143 Results are presented by means of the voxel of peak significance.

For the MR imaging–based ROI analysis, baseline differences between the entire group of subjects with MDD and normal controls were determined with an overall multivariate analysis of variance with the use of hypothesized ROI (DLPFC, VLPFC, dorsal and ventral AC and Cd, and thalamus) and laterality (left and right) as within-group factors and group (MDD vs normal control) as a between-subject factor (SPSS version 8.0; SPSS Inc, Chicago, Ill). Based on a significant result indicating regional differences between subjects with MDD and control subjects, t tests (2-tailed, uncorrected) were performed to determine which regions accounted for the overall difference between subjects with MDD and normal control subjects. Changes from baseline to follow-up in normalized ROI values were compared between subjects with MDD and normal control subjects by means of change in ROI scores in only regions found to be abnormal at baseline and a t test for independent means (2-tailed). To examine the relationship between symptomatic change and ROI change, Kendall τ correlations (2-tailed) were performed between 17-item HAM-D change and regional metabolic change for the MDD group. Finally, in an exploratory analysis, normalized regional brain metabolic changes for hypothesized ROIs in both subgroups of subjects with MDD (paroxetine-treated and IPT-treated) were compared with brain metabolic change values for normal control subjects by means of a t test for independent means. The α levels were set at P = .05.

CLINICAL FINDINGS

The normal control and MDD groups were similar in age, sex distribution, and time frame between PET scans (Table 1). From before to after treatment, the total MDD group and both MDD subgroups (paroxetine-treated and IPT-treated) had significant mean decreases in the 17-item HAM-D (paired t test, 2-tailed, all P<.001), while control subjects did not have a significant mean change in 17-item HAM-D. Within the MDD group, the paroxetine-treated subgroup was less ill at baseline (lower HAM-D score, fewer previous treatments for depression, less family history, later mean age at onset) and had greater improvement on all symptom rating scales than the IPT-treated subgroup (Table 1).

Table Graphic Jump LocationTable 1. Clinical Variables of Study Population*
COMPARISONS OF BASELINE METABOLISM BETWEEN SUBJECTS WITH MDD AND CONTROL SUBJECTS

At baseline, SPM demonstrated that subjects with MDD had higher relative metabolism than control subjects in left (Z = 3.72; x, y, z coordinates: x = −44, y = 24, z = 30) and right (Z = 3.44; x = 40, y = 38, z = 18) PFC (at the border of DLPFC and VLPFC, roughly corresponding to Brodmann areas 9 and 46), left (Z = 3.04; x = −16, y = 4, z = 16) and right (Z = 2.66; x = 14, y = −4, z = 14) dorsal Cd, and left (Z = 3.35; x = −14, y = −24, z = 8) and right (Z = 3.47; x = 14, y = −24, z = 4) thalamus (Figure 2). This analysis also showed lower relative pretreatment activity in left (Z = 3.21; x = −42, y = 8, z = −16) and right (Z = 3.25; x = 28, y = 18, z = −32) anterior inferior TEMP for subjects with MDD.

Place holder to copy figure label and caption
Figure 2.

Baseline comparison of the major depressive disorder (MDD) (N = 24) and normal control (n = 16) groups, showing regions of elevated normalized metabolism (Z statistic, P<.01) in the MDD group mapped onto a template magnetic resonance image.

Graphic Jump Location

In the ROI-based analysis, the overall multivariate analysis of variance disclosed a significant ROI × laterality × group interaction (F6,33 = 2.46; P<.05), indicating that individual regions differed between the MDD and control groups. In examining individual ROIs at baseline, the group of subjects with MDD had significantly higher normalized metabolism in right DLPFC, left VLPFC, right dorsal Cd, and bilateral thalamus than normal control subjects (Table 2). Baseline differences for other regions did not reach significance.

Table Graphic Jump LocationTable 2. Normalized ROI Values for the Control and MDD Groups*
METABOLIC CHANGES FROM BASELINE TO FOLLOW-UP

From pretreatment to posttreatment, SPM showed decreases in normalized left PFC metabolism in separate regions slightly anterior and posterior to the region found to be elevated at baseline (Table 3 and Figure 3). Statistical parametric mapping also showed decreases in right PFC metabolism, including regions that overlapped with those found elevated at baseline (Table 3). In addition, increases in left insula and bilateral inferior TEMP were found in the total MDD group (Table 3). Normal control subjects did not have these changes other than an increase in normalized right inferior TEMP metabolism.

Table Graphic Jump LocationTable 3. Statistical Parametic Mapping Analysis Showing Regional Changes (P<.01, Uncorrected) in the MDD and Normal Control Groups*
Place holder to copy figure label and caption
Figure 3.

Decreases in relative prefrontal cortical (PFC) metabolism from baseline to follow-up in the total major depressive disorder (MDD) treated group (N = 24) (Z statistic, P<.01). Decreases in activity are transposed onto a template magnetic resonance image and are shown in 2 separate planes.

Graphic Jump Location

Of the regions found abnormal at baseline in the ROI analysis, only the right dorsal Cd decreased significantly in the MDD group compared with normal control subjects from baseline to follow-up (Table 2). Change in normalized left thalamic metabolism was significantly correlated with change in HAM-D (τ = 0.30; P = .04).

PRELIMINARY COMPARISON OF METABOLIC CHANGES WITH PAROXETINE AND IPT

The SPM analysis of changes from baseline to follow-up in MDD subgroups treated with either paroxetine or IPT showed several similarities (Table 3 and Figure 4). In the paroxetine-treated subgroup, normalized metabolism decreased in the middle frontal gyrus (including the VLPFC and DLPFC) and left ventral AC, and increased in left TEMP and right insula. In the IPT-treated subgroup, normalized metabolism significantly decreased in right middle frontal gyrus (including both VLPFC and DLPFC) and left middle AC, and increased in left TEMP and anterior insula. Although the insula was not a hypothesized ROI, results are included because they were the most statistically significant result in both subgroups. Normal control subjects had no significant changes in these regions (Table 3).

Place holder to copy figure label and caption
Figure 4.

Comparison of relative brain metabolic decreases (Z statistic, P<.01) from baseline to follow-up in major depressive disorder subgroups treated with either paroxetine (n = 10) or interpersonal psychotherapy (IPT) (n = 14). The paroxetine-treated subgroup showed bilateral prefrontal cortical (PFC) decreases, while the IPT-treated subgroup had changes in right PFC only. Both groups had decreases in left anterior cingulate gyrus (AC).

Graphic Jump Location

In the ROI-based comparison of metabolic changes between subjects with MDD in the 2 treated subgroups and normal control subjects, each treated subgroup showed a significant decrease in right dorsal Cd metabolism compared with control subjects (change in ROI value: paroxetine-treated, −0.03 ± 0.06; IPT-treated, −0.04 ± 0.08; normal control, 0.02 ± 0.05) (2-tailed t test, paroxetine-treated vs normal control, df = 24, P = .03; IPT-treated vs control, df = 28, P = .008). Normalized left VLPFC metabolism also decreased significantly in paroxetine-treated patients compared with control subjects (change in ROI value: paroxetine-treated, −0.04 ± 0.03; normal control, 0.00 ± 0.06) (t test, df = 24, P = .05).

Subjects with MDD had regional brain metabolic abnormalities at baseline that appeared to change in the direction of normalization with treatment. The central findings here of increased relative PFC, Cd, and thalamic metabolism in subjects with MDD at baseline that decreased from pretreatment to posttreatment is consistent with earlier studies having similar findings.3,5,8,13 The portions of VLPFC found to be abnormal here and to decrease with treatment are similar to those found to be abnormal in earlier work (see Drevets,3Table 1) and to change with selective serotonin reuptake inhibitors.13,14 The finding in the present study of increased normalized DLPFC metabolism that decreases with treatment (as opposed to the converse of these findings reported by others)5,1012 may be due to the fact that this study examined ambulatory outpatients with MDD, whereas inpatients with MDD were examined in the majority of previous studies.5,11,12 Such subjects may have had profound differences in symptoms from outpatients studied here (eg, greater suicidality, less mood reactivity, and more psychomotor retardation). A link between decreased DLPFC activity and psychomotor retardation has been reported previously.44

In the preliminary comparison of brain metabolic changes with either paroxetine or IPT, similar regional brain metabolic changes were found in treated patients with MDD that were different from those seen in normal control subjects scanned and rescanned during the same time frame. On SPM, relative PFC and left AC metabolism decreased and relative left TEMP metabolism increased in both treated MDD subgroups. The decrease in middle (IPT-treated subgroup) and ventral (paroxetine-treated subgroup) AC activity (roughly corresponding to slightly different parts of Brodmann area 32 for the 2 subgroups) was similar, but more dorsal, to the subgenual AC decrease (Brodmann area 25) previously found to change from pretreatment to posttreatment with fluoxetine.5 In addition, both subgroups had a regional increase in insular metabolism (right-sided for the paroxetine subgroup and left-sided for the IPT subgroup) as the most statistically significant finding. In contrast, the normal control group did not have these changes. Relative stability of frontal-subcortical brain circuitry from test to retest in normal control subjects undergoing 2 FDG-PET scans has also been demonstrated by others.45,46

In the ROI analysis, normalized right dorsal Cd metabolic rates decreased in both treated subgroups compared with control subjects. These similarities occurred despite there being a difference in HAM-D improvement with the 2 forms of treatment, perhaps indicating that both subgroups had similar changes in symptoms not well measured with the HAM-D (such as improved social functioning). However, only the paroxetine-treated group showed a significant decrease in right VLPFC, which has been found previously to correlate with improvement in HAM-D scores in paroxetine-treated subjects.13 This difference might reflect the more robust improvement in the paroxetine-treated subgroup.

The most important limitation of this study was sample size. A larger, more diverse sample may have improved detection of changes not reaching significance and enhanced power to detect responder-nonresponder differences (the paroxetine-treated subgroup having an unusually high response rate here and the IPT-treated subgroup having an unusually low response rate [likely because of a greater severity of illness]47). A second limitation was the lack of random assignment to treatment subgroups. Because of this limitation, there may have been fundamental differences between subjects who chose one form of therapy vs the other that may have accounted for both clinical (Table 1) and brain metabolic differences. A third limitation was the use of subjects without comorbid Axis I illnesses. While the study population examined herein has the advantage of making the data more clearly interpretable (without confounding illnesses affecting regional glucose metabolism), it limits the degree to which study results are generalizable (given that MDD is a highly comorbid illness).48 Finally, the lack of reliable blood curve data (as might have been obtained from arterial blood samples) meant that absolute glucose metabolic rates could not be determined; global metabolic activity may have an important role in MDD. These limitations require that study results (especially for the comparison of paroxetine vs IPT) be regarded as suggestive and need confirmation in a randomized study with a greater sample size.

Our results are consistent with the putative mechanism of action of selective serotonin reuptake inhibitors. Short-term treatment with selective serotonin reuptake inhibitors has been found to desensitize serotonin autoreceptors (somatodentritic serotonin1a and terminal serotonin1b/d).49,50 This desensitization leads to enhanced serotonin release in the PFC.51,52 Serotonin agonism in the PFC has been linked to increased extracellular γ-aminobutyric acid levels from γ-aminobutyric acid–containing interneurons,53 which may explain the changes seen in this study with short-term paroxetine treatment, as specific γ-aminobutyric acid interneurons exert powerful inhibitory control over excitatory neurons in the PFC.54 Serotonin also has been shown to directly reduce glutamatergic responses in cortex.55 The AC has similarly strong serotonergic innervation.56 Modulation of frontal-subcortical brain circuits could also explain changes seen in Cd (presumably receiving lower levels of excitatory glutamatergic input from PFC and AC38,39,51). Thus, this study supports the hypothesis that selective serotonin reuptake inhibitors lead to an attenuation of PFC (and AC)–basal ganglia–thalamic brain circuit activity that mediates MDD symptomatology.57,58

While less is known about the mechanism of action of IPT, it has been hypothesized that psychotherapy in general (as a learning experience) leads to changes in synaptic plasticity,59,60 through a retraining of implicit memory systems.59,61 Because a focus of IPT is improved socialization, areas of the brain associated with socialization may undergo an attenuation of neuronal connectivity during IPT. For example, increased activity in the cingulate cortex (and related structures) has been associated with distress when an animal is socially isolated.62,63 This model may be analogous to the socially isolated subject with MDD who has a decrease in AC activity as socialization improves with IPT. This change could be the result of enhancement of the serotonergic system, as has been hypothesized for behavioral therapy for obsessive-compulsive disorder.64

Other significant changes seen in subjects with MDD (increases in relative activity in TEMP and insula) may represent either normalization of depression-related baseline dysfunction or compensatory changes related to brain regions found to decrease in activity, given that both TEMP and insula have strong reciprocal connections with PFC and AC regions that decreased in activity with treatment.8,40,65

Accepted for publication July 28, 2000.

This study was supported by the National Alliance for Research in Schizophrenia and Depression, Great Neck, NY (Dr Brody); a Veterans Affairs Advanced Research Career Development Award, Washington, DC (Dr Brody); the Charles A. Dana Foundation Consortium on Neuroimaging Leadership, New York, NY (Dr Saxena); grant R01 MH-53565 from the National Institute of Mental Health, Bethesda, Md (Dr Baxter); and US Department of Energy (Washington) grants AM03-76-SF00012 and DE-FCO3-87-ER 60615 (Drs Phelps, Huang, and Baxter).

Presented in part at the American College of Neuropsychopharmacology Annual Meeting, Acapulco, Mexico, December 14, 1999.

We thank Lori L. Altshuler, MD, Magnus Dahlbom, PhD, and Mark A. Mandelkern, MD, PhD, for their suggestions on the manuscript.

Corresponding author and reprints: Arthur L. Brody, MD, 300 UCLA Medical Plaza, Suite 2340, Los Angeles, CA 90095 (e-mail: abrody@ucla.edu).

Ketter  TAGeorge  MSKimbrell  TABenson  BEPost  RM Functional brain imaging, limbic function and affective disorders. Neuroscientist. 1996;255- 65
Kennedy  SHJavanmard  MVaccarino  FJ A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry. 1997;42467- 475
Drevets  WC Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49341- 361
Link to Article
Byrum  CEAhearn  EPKrishan  K A neuroanatomic model for depression. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23175- 193
Link to Article
Mayberg  HSLiotti  MBrannan  SKMcGinnis  SMahurin  RKJerabek  PASilva  JATekell  JLMartin  CCLancaster  JLFox  PT Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156675- 682
Mayberg  HS Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9471- 481
Baxter  LRSaxena  SBrody  ALAckermann  RFColgan  MSchwartz  JMAllen-Martinez  ZFuster  JMPhelps  ME Brain mediation of obsessive-compulsive disorder symptoms: evidence from functional brain imaging studies in the human and non-human primate. Semin Clin Neuropsychiatry. 1996;132- 47
Drevets  WC Prefrontal cortical-amygdalar metabolism in major depression. McGinty  JFed.Advancing from the Ventral Striatum to the Extended Amygdala Implications for Neuropsychiatry and Drug Use: In Honor of Lennart Heimer New York New York Academy of Sciences1999;614- 637
Rubin  ESackeim  HANobler  MSMoeller  JR Brain imaging studies of antidepressant treatment. Psychiatr Ann. 1994;24653- 658
Link to Article
Buchsbaum  MSWu  JSiegel  BVHackett  ETrenary  MAbel  LReynolds  C Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry. 1997;4115- 22
Link to Article
Baxter  LRSchwartz  JMPhelps  MEMazziotta  JCGuze  BHSelin  CEGerner  RHSumida  RM Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46243- 250
Link to Article
Martinot  J-LHardy  PFeline  AHuret  J-DMazoyer  BAttar-Levy  DPappata  SSyrota  A Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry. 1990;1471313- 1317
Brody  ALSaxena  SSilverman  DHSAlborzian  SFairbanks  LAPhelps  MEHuang  S-CWu  H-MMaidment  KBaxter  LR Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res. 1999;91127- 139
Link to Article
Little  JTKetter  TAKimbrell  TADanielson  ABenson  BEWillis  MWDunn  RTFrye  MAPost  RM Anterior paralimbic blood flow decreased after venlafaxine response. Biol Psychiatry. 1997;41(suppl 7)79S- 80S
Link to Article
Drevets  WCRaichle  ME Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull. 1992;28261- 274
Nobler  MSSackheim  HAProhovnik  IMoeller  JRMukherjee  SSchnur  DBPrudic  JDevanand  DP Regional cerebral blood flow in mood disorders, III: treatment and clinical response. Arch Gen Psychiatry. 1994;51884- 897
Link to Article
Klerman  GLWeissman  MMRounsaville  BJChevron  ES Interpersonal Psychotherapy of Depression.  New York, NY Basic Books1984;
Baxter  LRSchwartz  JMBergman  KSSzuba  MPGuze  BHMazziotta  JCAlazraki  ASelin  CEFerng  HKMunford  PPhelps  ME Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49681- 689
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Spitzer  RLEndicott  J Schedule for Affective Disorders and Schizophrenia.  New York New York State Psychiatric Institute1978;
Hamilton  M Development of a rating scale for primary depressive illness. Br J Soc Psychol. 1967;6278- 296
Link to Article
Hamilton  M Diagnosis and rating of anxiety. Br J Psychiatry. 1969;376- 79
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown Obsessive-Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry. 1989;461006- 1011
Link to Article
Endicott  JSpitzer  RLFleiss  JLCohen  J The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976;33766- 771
Link to Article
Weissman  MMMarkowitz  JC Interpersonal psychotherapy: current status. Arch Gen Psychiatry. 1994;51599- 606
Link to Article
Wienhard  KDahlbom  MEriksson  LMichel  CBruckbauer  TPietrzyk  UHeiss  WD The ECAT EXACT HR: performance of a new high-resolution positron scanner. J Comput Assist Tomogr. 1994;18110- 118
Link to Article
Friston  KJWorsley  KJFrackowiak  RSJMazziotta  JCEvans  AC Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994;1214- 220
Nadeau  SECrosson  B A guide to functional imaging of cognitive processes. Neuropsychiatry Neuropsychol Behav Neurol. 1995;8143- 162
Rajkowska  GGoldman-Rakic  PS Cytoarchitectonic definition of prefrontal areas in the normal human cortex, II: variability in locations of areas 9 and 46 and relationship to the Tailarach coordinate system. Cereb Cortex. 1995;5323- 337
Link to Article
Steinmetz  HSeitz  RJ Functional anatomy of language processing: neuroimaging and the problem of individual variability. Neuropsychologia. 1991;291149- 1161
Link to Article
Friston  KFrith  CLiddle  PFrackowiak  R Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991;11690- 699
Link to Article
Friston  KJ Statistical parametric mapping: ontology and current issues. J Cereb Blood Flow Metab. 1995;15361- 370
Link to Article
Friston  KJAshburner  JFrith  CDPoline  JHeather  JDFrackowiak  RSJ Spatial registration and normalisation of images. Hum Brain Mapp. 1995;2165- 189
Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JPFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2189- 210
Link to Article
Tailarach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers Inc1988;
Lin  KPHuang  S-CBaxter  LRPhelps  ME A general technique for inter-study registration of multi-function and multimodality images. IEEE Trans Nucl Sci. 1994;412850- 2855
Link to Article
Press  WHFlannery  BPTeukolsky  SAVetterling  WT Numerical Recipes.  New York, NY Cambridge University Press1986;
Alexander  GEDeLong  MRStrick  PL Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9357- 381
Link to Article
Parent  AHazrati  L-N Functional anatomy of the basal ganglia, I: the cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev. 1995;2091- 127
Link to Article
Devinsky  OMorrell  MJVogt  BA Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118279- 306
Link to Article
Marangell  LBKetter  TAGeorge  MSPazzaglia  PJCallahan  AMParekh  PAndreason  PJHorwitz  BHerscovitch  PPost  RM Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. Am J Psychiatry. 1997;154224- 230
Ketter  TAAndreason  PJGeorge  MSLee  CGill  DSParekh  PIWillis  MWHerscovitch  PPost  RM Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences. Arch Gen Psychiatry. 1996;5359- 69
Link to Article
Sargent  PAKjaer  KHBench  CJRabiner  EAMessa  CMeyer  JGunn  RNGrasby  PMCowen  PJ Brain serotonin1A receptor binding measured by positron emission tomography with [11C] WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57174- 180
Link to Article
Dolan  RJBench  CJLiddle  PFFriston  KJFrith  CDGrasby  PMFrackowiak  RS Dorsolateral prefrontal cortex dysfunction in the major psychoses: symptom or disease specificity? J Neurol Neurosurg Psychiatry. 1993;561290- 1294
Link to Article
Goldman  SDethy  SLotstra  FBiver  FStanus  EWikler  DHildebrand  JMendlewicz  JLuxen  A Basal ganglia and frontal lobe glucose metabolism: a reproducibility positron emission tomography study. J Neuroimaging. 1995;5219- 226
Stapleton  JMMorgan  MJLiu  XYung  BCPhillips  RLWong  DFShaya  EKDannals  RFLondon  ED Cerebral glucose utilization is reduced in second test session. J Cereb Blood Flow Metab. 1997;17704- 712
Link to Article
Elkin  IGibbons  RDShea  MTSotsky  SMWatkins  JTPilkonis  PAHedeker  D Initial severity and differential treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psychol. 1995;63841- 847
Link to Article
Blazer  DGKessler  RCMcGonagle  KASwartz  MS The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry. 1994;151979- 986
Blier  PPineyro  GEl Mansari  MBergeron  RDe Montigny  D Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Martin  GREglen  RMHoyer  DHamblin  MWYocca  Feds.Advances in Serotonin Receptor Research Molecular Biology, Signal Transduction, and Therapeutics New York New York Academy of Sciences1998;204- 216
Bergqvist  PBFBouchard  CBlier  P Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive-compulsive disorder. Biol Psychiatry. 1999;45164- 174
Link to Article
el Mansari  MBouchard  CBlier  P Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors: relevance to treatment of obsessive-compulsive disorder. Neuropsychopharmacology. 1995;13117- 127
Link to Article
Blier  Pde Montigny  C Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999;21(suppl 2)91S- 98S
Link to Article
Abi-Saab  WMBubser  MRoth  RHDeutch  AY 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology. 1999;2092- 96
Link to Article
Lewis  DAPierri  JNVolk  DWMelchitzky  DSWoo  TW Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry. 1999;46616- 626
Link to Article
Sizer  ARKilpatrick  GJRoberts  MH A post-synaptic depressant modulatory action of 5-hydroxytryptamine on excitatory amino acid responses in rat entorhinal cortex in vitro. Neuropharmacology. 1992;31531- 539
Link to Article
Crino  PBMorrison  JHHof  PR Monoaminergic innervation of cingulate cortex. Vogt  BAGabriel  Meds.Neurobiology of Cingulate Cortex and Limbic Thalamus A Comprehensive Handbook Boston, Mass Birkhaeuser1993;285- 310
Swerdlow  NR Serotonin, obsessive-compulsive disorder and the basal ganglia. Int Rev Psychiatry. 1995;7115- 129
Link to Article
Feifel  D Neurotransmitters and neuromodulators in frontal-subcortical circuits. Miller  BLCummings  JLeds.The Human Frontal Lobes Functions and Disorders New York, NY Guilford Press1999;174- 186
Liggan  DYKay  J Some neurobiological aspects of psychotherapy: a review. J Psychother Pract Res. 1999;8103- 114
Post  RMWeiss  SR Emergent properties of neural systems: how focal molecular neurobiological alterations can affect behavior. Dev Psychopathol. 1997;9907- 929
Link to Article
Amini  FLewis  TLannon  RLouie  ABaumbacher  GMcGuinness  TSchiff  EZ Affect, attachment, memory: contributions toward psychobiologic integration. Psychiatry. 1996;59213- 239
Panksepp  JNelson  EBekkedal  M Brain systems for the mediation of social separation-distress and social-reward: evolutionary antecedents and neuropeptide intermediaries. Carter  CSLederhendler  IIKirkpatrick  Beds.The Integrative Neurobiology of Affiliation New York New York Academy of Sciences1997;78- 100
Kyuhou  SGemba  H Two vocalization-related subregions in the midbrain periaqueductal gray of the guinea pig. Neuroreport. 1998;91607- 1610
Link to Article
Baer  L Behavior therapy: endogenous serotonin therapy? J Clin Psychiatry. 1996;57(suppl 6)33- 35
Augustine  JR Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev. 1996;22229- 244
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Regions of interest drawn on a magnetic resonance image of a study subject for transfer onto coregistered positron emission tomography scans. DLPFC indicates dorsolateral prefrontal cortex; AC, anterior cingulate gyrus; VLPFC, ventrolateral prefrontal cortex; and Cd, head of the caudate nucleus.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Baseline comparison of the major depressive disorder (MDD) (N = 24) and normal control (n = 16) groups, showing regions of elevated normalized metabolism (Z statistic, P<.01) in the MDD group mapped onto a template magnetic resonance image.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Decreases in relative prefrontal cortical (PFC) metabolism from baseline to follow-up in the total major depressive disorder (MDD) treated group (N = 24) (Z statistic, P<.01). Decreases in activity are transposed onto a template magnetic resonance image and are shown in 2 separate planes.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Comparison of relative brain metabolic decreases (Z statistic, P<.01) from baseline to follow-up in major depressive disorder subgroups treated with either paroxetine (n = 10) or interpersonal psychotherapy (IPT) (n = 14). The paroxetine-treated subgroup showed bilateral prefrontal cortical (PFC) decreases, while the IPT-treated subgroup had changes in right PFC only. Both groups had decreases in left anterior cingulate gyrus (AC).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Variables of Study Population*
Table Graphic Jump LocationTable 2. Normalized ROI Values for the Control and MDD Groups*
Table Graphic Jump LocationTable 3. Statistical Parametic Mapping Analysis Showing Regional Changes (P<.01, Uncorrected) in the MDD and Normal Control Groups*

References

Ketter  TAGeorge  MSKimbrell  TABenson  BEPost  RM Functional brain imaging, limbic function and affective disorders. Neuroscientist. 1996;255- 65
Kennedy  SHJavanmard  MVaccarino  FJ A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry. 1997;42467- 475
Drevets  WC Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49341- 361
Link to Article
Byrum  CEAhearn  EPKrishan  K A neuroanatomic model for depression. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23175- 193
Link to Article
Mayberg  HSLiotti  MBrannan  SKMcGinnis  SMahurin  RKJerabek  PASilva  JATekell  JLMartin  CCLancaster  JLFox  PT Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156675- 682
Mayberg  HS Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9471- 481
Baxter  LRSaxena  SBrody  ALAckermann  RFColgan  MSchwartz  JMAllen-Martinez  ZFuster  JMPhelps  ME Brain mediation of obsessive-compulsive disorder symptoms: evidence from functional brain imaging studies in the human and non-human primate. Semin Clin Neuropsychiatry. 1996;132- 47
Drevets  WC Prefrontal cortical-amygdalar metabolism in major depression. McGinty  JFed.Advancing from the Ventral Striatum to the Extended Amygdala Implications for Neuropsychiatry and Drug Use: In Honor of Lennart Heimer New York New York Academy of Sciences1999;614- 637
Rubin  ESackeim  HANobler  MSMoeller  JR Brain imaging studies of antidepressant treatment. Psychiatr Ann. 1994;24653- 658
Link to Article
Buchsbaum  MSWu  JSiegel  BVHackett  ETrenary  MAbel  LReynolds  C Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry. 1997;4115- 22
Link to Article
Baxter  LRSchwartz  JMPhelps  MEMazziotta  JCGuze  BHSelin  CEGerner  RHSumida  RM Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46243- 250
Link to Article
Martinot  J-LHardy  PFeline  AHuret  J-DMazoyer  BAttar-Levy  DPappata  SSyrota  A Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry. 1990;1471313- 1317
Brody  ALSaxena  SSilverman  DHSAlborzian  SFairbanks  LAPhelps  MEHuang  S-CWu  H-MMaidment  KBaxter  LR Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res. 1999;91127- 139
Link to Article
Little  JTKetter  TAKimbrell  TADanielson  ABenson  BEWillis  MWDunn  RTFrye  MAPost  RM Anterior paralimbic blood flow decreased after venlafaxine response. Biol Psychiatry. 1997;41(suppl 7)79S- 80S
Link to Article
Drevets  WCRaichle  ME Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull. 1992;28261- 274
Nobler  MSSackheim  HAProhovnik  IMoeller  JRMukherjee  SSchnur  DBPrudic  JDevanand  DP Regional cerebral blood flow in mood disorders, III: treatment and clinical response. Arch Gen Psychiatry. 1994;51884- 897
Link to Article
Klerman  GLWeissman  MMRounsaville  BJChevron  ES Interpersonal Psychotherapy of Depression.  New York, NY Basic Books1984;
Baxter  LRSchwartz  JMBergman  KSSzuba  MPGuze  BHMazziotta  JCAlazraki  ASelin  CEFerng  HKMunford  PPhelps  ME Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49681- 689
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Spitzer  RLEndicott  J Schedule for Affective Disorders and Schizophrenia.  New York New York State Psychiatric Institute1978;
Hamilton  M Development of a rating scale for primary depressive illness. Br J Soc Psychol. 1967;6278- 296
Link to Article
Hamilton  M Diagnosis and rating of anxiety. Br J Psychiatry. 1969;376- 79
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown Obsessive-Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry. 1989;461006- 1011
Link to Article
Endicott  JSpitzer  RLFleiss  JLCohen  J The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976;33766- 771
Link to Article
Weissman  MMMarkowitz  JC Interpersonal psychotherapy: current status. Arch Gen Psychiatry. 1994;51599- 606
Link to Article
Wienhard  KDahlbom  MEriksson  LMichel  CBruckbauer  TPietrzyk  UHeiss  WD The ECAT EXACT HR: performance of a new high-resolution positron scanner. J Comput Assist Tomogr. 1994;18110- 118
Link to Article
Friston  KJWorsley  KJFrackowiak  RSJMazziotta  JCEvans  AC Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994;1214- 220
Nadeau  SECrosson  B A guide to functional imaging of cognitive processes. Neuropsychiatry Neuropsychol Behav Neurol. 1995;8143- 162
Rajkowska  GGoldman-Rakic  PS Cytoarchitectonic definition of prefrontal areas in the normal human cortex, II: variability in locations of areas 9 and 46 and relationship to the Tailarach coordinate system. Cereb Cortex. 1995;5323- 337
Link to Article
Steinmetz  HSeitz  RJ Functional anatomy of language processing: neuroimaging and the problem of individual variability. Neuropsychologia. 1991;291149- 1161
Link to Article
Friston  KFrith  CLiddle  PFrackowiak  R Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991;11690- 699
Link to Article
Friston  KJ Statistical parametric mapping: ontology and current issues. J Cereb Blood Flow Metab. 1995;15361- 370
Link to Article
Friston  KJAshburner  JFrith  CDPoline  JHeather  JDFrackowiak  RSJ Spatial registration and normalisation of images. Hum Brain Mapp. 1995;2165- 189
Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JPFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2189- 210
Link to Article
Tailarach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers Inc1988;
Lin  KPHuang  S-CBaxter  LRPhelps  ME A general technique for inter-study registration of multi-function and multimodality images. IEEE Trans Nucl Sci. 1994;412850- 2855
Link to Article
Press  WHFlannery  BPTeukolsky  SAVetterling  WT Numerical Recipes.  New York, NY Cambridge University Press1986;
Alexander  GEDeLong  MRStrick  PL Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9357- 381
Link to Article
Parent  AHazrati  L-N Functional anatomy of the basal ganglia, I: the cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev. 1995;2091- 127
Link to Article
Devinsky  OMorrell  MJVogt  BA Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118279- 306
Link to Article
Marangell  LBKetter  TAGeorge  MSPazzaglia  PJCallahan  AMParekh  PAndreason  PJHorwitz  BHerscovitch  PPost  RM Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. Am J Psychiatry. 1997;154224- 230
Ketter  TAAndreason  PJGeorge  MSLee  CGill  DSParekh  PIWillis  MWHerscovitch  PPost  RM Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences. Arch Gen Psychiatry. 1996;5359- 69
Link to Article
Sargent  PAKjaer  KHBench  CJRabiner  EAMessa  CMeyer  JGunn  RNGrasby  PMCowen  PJ Brain serotonin1A receptor binding measured by positron emission tomography with [11C] WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57174- 180
Link to Article
Dolan  RJBench  CJLiddle  PFFriston  KJFrith  CDGrasby  PMFrackowiak  RS Dorsolateral prefrontal cortex dysfunction in the major psychoses: symptom or disease specificity? J Neurol Neurosurg Psychiatry. 1993;561290- 1294
Link to Article
Goldman  SDethy  SLotstra  FBiver  FStanus  EWikler  DHildebrand  JMendlewicz  JLuxen  A Basal ganglia and frontal lobe glucose metabolism: a reproducibility positron emission tomography study. J Neuroimaging. 1995;5219- 226
Stapleton  JMMorgan  MJLiu  XYung  BCPhillips  RLWong  DFShaya  EKDannals  RFLondon  ED Cerebral glucose utilization is reduced in second test session. J Cereb Blood Flow Metab. 1997;17704- 712
Link to Article
Elkin  IGibbons  RDShea  MTSotsky  SMWatkins  JTPilkonis  PAHedeker  D Initial severity and differential treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J Consult Clin Psychol. 1995;63841- 847
Link to Article
Blazer  DGKessler  RCMcGonagle  KASwartz  MS The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry. 1994;151979- 986
Blier  PPineyro  GEl Mansari  MBergeron  RDe Montigny  D Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Martin  GREglen  RMHoyer  DHamblin  MWYocca  Feds.Advances in Serotonin Receptor Research Molecular Biology, Signal Transduction, and Therapeutics New York New York Academy of Sciences1998;204- 216
Bergqvist  PBFBouchard  CBlier  P Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive-compulsive disorder. Biol Psychiatry. 1999;45164- 174
Link to Article
el Mansari  MBouchard  CBlier  P Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors: relevance to treatment of obsessive-compulsive disorder. Neuropsychopharmacology. 1995;13117- 127
Link to Article
Blier  Pde Montigny  C Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999;21(suppl 2)91S- 98S
Link to Article
Abi-Saab  WMBubser  MRoth  RHDeutch  AY 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology. 1999;2092- 96
Link to Article
Lewis  DAPierri  JNVolk  DWMelchitzky  DSWoo  TW Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry. 1999;46616- 626
Link to Article
Sizer  ARKilpatrick  GJRoberts  MH A post-synaptic depressant modulatory action of 5-hydroxytryptamine on excitatory amino acid responses in rat entorhinal cortex in vitro. Neuropharmacology. 1992;31531- 539
Link to Article
Crino  PBMorrison  JHHof  PR Monoaminergic innervation of cingulate cortex. Vogt  BAGabriel  Meds.Neurobiology of Cingulate Cortex and Limbic Thalamus A Comprehensive Handbook Boston, Mass Birkhaeuser1993;285- 310
Swerdlow  NR Serotonin, obsessive-compulsive disorder and the basal ganglia. Int Rev Psychiatry. 1995;7115- 129
Link to Article
Feifel  D Neurotransmitters and neuromodulators in frontal-subcortical circuits. Miller  BLCummings  JLeds.The Human Frontal Lobes Functions and Disorders New York, NY Guilford Press1999;174- 186
Liggan  DYKay  J Some neurobiological aspects of psychotherapy: a review. J Psychother Pract Res. 1999;8103- 114
Post  RMWeiss  SR Emergent properties of neural systems: how focal molecular neurobiological alterations can affect behavior. Dev Psychopathol. 1997;9907- 929
Link to Article
Amini  FLewis  TLannon  RLouie  ABaumbacher  GMcGuinness  TSchiff  EZ Affect, attachment, memory: contributions toward psychobiologic integration. Psychiatry. 1996;59213- 239
Panksepp  JNelson  EBekkedal  M Brain systems for the mediation of social separation-distress and social-reward: evolutionary antecedents and neuropeptide intermediaries. Carter  CSLederhendler  IIKirkpatrick  Beds.The Integrative Neurobiology of Affiliation New York New York Academy of Sciences1997;78- 100
Kyuhou  SGemba  H Two vocalization-related subregions in the midbrain periaqueductal gray of the guinea pig. Neuroreport. 1998;91607- 1610
Link to Article
Baer  L Behavior therapy: endogenous serotonin therapy? J Clin Psychiatry. 1996;57(suppl 6)33- 35
Augustine  JR Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev. 1996;22229- 244
Link to Article

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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