360 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

Received September 18, 2002; revised December 15, 2002; acceptedJanuary 13, 2003. From the Department of Radiology, Department ofPsychiatry, Washington University School of Medicine, St. Louis, Mis-souri. Correspondence and reprints: Dr. Sheline, Associate Professorof Psychiatry and Radiology, Box 8134, WUSM 4940 Childrens PlaceSt. Louis, MO 63110. E-mail: yvette@npg.wustl.edu.

Copyright � 2004 American Psychiatric Publishing, Inc.

Cerebral Perfusion Responseto Successful Treatment ofDepression With DifferentSerotoninergic AgentsAndrei Vlassenko, M.D., Ph.D.Yvette I. Sheline, M.D.Keith Fischer, M.D.Mark A. Mintun, M.D.

In 19 patients with major depressive disorder, ef-fective treatment with selective serotonin reuptakeinhibitors (SSRIs) or amesergide (AMSG) was as-sociated with increased cerebral perfusion in ante-rior cingulate cortex (SSRI and AMSG) and inmedial prefrontal cortex (AMSG). Both selectiveserotonin reuptake inhibitors and AMSG exertantidepressant action through the serotonin (5-HT) system as reuptake inhibitors. Amesergidediffers from SSRIs in that it is also a highly selec-tive 5-HT antagonist, which may in part accountfor differences in cerebral blood flow response totreatment.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 2004; 16:360–363)

Both selective serotonin reuptake inhibitors (SSRIs)and amesergide (AMSG; LY237733) appear to pro-

duce an antidepressant effect through their action uponthe serotonin (5-HT) system. They differ, however, inthat AMSG is a reuptake inhibitor as well as a highlyselective antagonist at the 5-HT receptor. AMSG showsaffinity at 5-HT2 receptors similar to that seen for otherpotent 5-HT2 receptor antagonists such as ketanserin,ritanserin, and setoperone. In contrast to these agents,however, AMSG has low to negligible effects at �-, b-,dopamine, histamine, c-aminobutyric acid, benzodiaz-epine, and muscarinic receptors.1

The literature reports contradictory findings for de-pression and treatment associated cerebral blood flow(CBF) changes. Increases in dorsal frontal and dorsal an-terior cingulate hypoperfusion and hypometabolism

with antidepressant therapy have been reported in anumber of studies.2–4 In contrast, decreases in the ven-tral anterior cingulate blood flow were found in re-sponse to desipramine,5 electroshock therapy,6 and flu-oxetine.7 The specific effects of the treatment with 5-HT2

receptor antagonists on CBF in major depressive disor-der (MDD) have not yet been reported.

Some of the discrepancies among previous studiesmay be related to clinical considerations, including di-agnostic criteria, inclusion of both bipolar and unipolarsubjects, demographic characteristics, illness severity,and medication status. In a number of studies, one dif-ficulty is the alignment of scans from one subject to thenext in the absence of anatomical data, which increasesthe possibility of obscuring significant findings or find-ing artifacts due to misalignment.

We used [Tc99m]hexamethylpropyleneamineoxime(HMPAO) single photon emission computed tomogra-phy (SPECT) images of CBF co-registered with anatom-ical magnetic resonance (MRI) imaging to compare thechanges in cerebral perfusion in response to treatmentwith SSRIs or AMSG.

METHOD

Nineteen subjects meeting DSM-IV criteria for MDDwere recruited from referrals from other psychiatristsand also from the community by advertisement. Inclu-sion criteria were a current episode meeting criteria forMDD, right-handedness, and no other medical illnesspotentially affecting the brain. A psychiatrist experi-enced in the use of the Diagnostic Interviews for GeneticStudies, a structured interview with high reliability,8 as-sessed all subjects clinically. Exclusion criteria com-prised a current or past neurological disorder, headtrauma, uncontrolled hypertension, myocardial infarc-tion or ischemia, diabetes, Cushing’s disease, steroiduse, drug/alcohol abuse, and use of any psychotropic

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medication within 3 weeks prior to inclusion in thestudy. Depression severity was rated using the Hamil-ton Depression Rating Scale9 (HAMD) on the day of theSPECT study. All patients were then randomized totreatment with AMSG 15–30 mg daily (Eli Lilly, Inc.)(n�10) or SSRI 20 mg daily (n�9) (fluoxetine n�6 orparoxetine n�3). In the case of AMSG this was part ofa double-blinded, placebo-controlled study. In the caseof SSRI it was an open-label study. After 12 weeks, de-pressed subjects were scanned again during their finalweek of antidepressant treatment. Clinical response wasdefined as a posttreatment HAMD score �12 or a 50%decrease compared to the initial HAMD score.

Written informed consent was obtained from all sub-jects after the procedures had been fully explained. TheHuman Studies Committee and Radioactive Drug Re-search Committee of Washington University School ofMedicine approved the study.

SPECTAll SPECT CBF scans were performed on a Prism 3000triple-headed scanner fitted with a high-resolution low-energy collimator (Picker International, Cleveland) afterthe injection of 16 mCi of HMPAO. The imaging proto-col acquired 120 brain images parallel to the orbitomea-tal line in 40 steps with 360� rotation of the camera. Re-construction of SPECT images used a ramp filter to yieldtransverse slices with a matrix of 128�128�128 pixelsand voxel size�2.8�2.8�2.8 mm.

MRIMRI scans were performed on a Magnetom SP-4000 1.5-T imaging system (Siemens, Iselin, N.J.). A magnetiza-tion prepared rapid gradient echo (MPRAGE) acquisi-tion was used to acquire anatomic images, whichconsisted of 128 contiguous 1.25 mm thick sagittal slices.Scanning parameters were TR�10 msec, TE�4 msec,inversion time�300 msec, flip angle�8�, matrix�

256�256 pixels, voxel size�1�1�1.25 mm.

SPECT-MRI Co-RegistrationThe MRI images were manually segmented using AN-ALYZE (Mayo Clinic, USA) to remove the scalp, skull,and meninges, then resized to isotropic voxels. The seg-mented magnetic resonance (MR) brain images andSPECT images were co- registered using Automated Im-age Alignment (AIR) software.10 The MR images weretransformed to a reference MRI in Talairach atlasspace.11 SPECT scans were then rotated, translated,

warped and resliced according to the transformationmatrix generated from combining the two types of co-registration.

Statistical Parametric Mapping (SPM) AnalysisStatistical parametric mapping 96 (Wellcome Depart-ment of Cognitive Neurology, University College, Lon-don) was used to detect significant (P�0.001) regionalchanges in CBF between the baseline and treatmentscans for both AMSG and SSRI groups combined and incontrast to one another. Correction of global differencesand detection of voxel-by-voxel changes were per-formed using an analysis of covariance. Single photonemission computed tomography data was filtered witha 12 mm full width three-dimensional Gaussian filter athalf maximum prior to processing.

A chi-square statistic was calculated to determinewhether the gender distribution across the two groupswas significantly different, and a Student’s unpaired ttest was used to determine differences in age and base-line HAMD score.

RESULTS

Subjects in SSRI and AMSG groups were similar in gen-der (male/female ratio was 4/5 and 4/6, respectively;v2�0.038, P�0.84), age (41.7�11.0 years, and45.6�13.4 years, respectively) (t�0.7, df�17, P�0.49)and baseline HAMD scores (22.8�6.3 and 21.3�4.4, re-spectively) (t�0.6, df�17, P�0.55). In AMSG group,80% of subjects improved clinically after the treatment(posttreatment HAMD was 5.3�3.4, a decrease frominitial value was 76%�16%) as compared with 67% inthe SSRI group (posttreatment HAMD score and de-crease from initial value were 5.8�3.5 and 75%�16%,respectively.) (Shown in Table 1.)

Statistical parametric mapping was used to detectCBF changes between baseline and posttreatment scansin the SSRI and AMSG responders. Regions that in-creased significantly following treatment with AMSG orSSRI included the left anterior cingulate gyrus (coordi-nates: �21, 22, 20), which extended towards the midline(covering the middle anterior cingulated gyrus [coor-dinates:�5, 45, 20]), the left superior temporal gyrus(coordinates:�57, �17, 6) and the orbital prefrontal cor-tex (coordinates: 11, 51, �29) (Figure 1). Regions thatdecreased significantly following treatment with AMSGor SSRI included the left inferior frontal gyrus (coordi-

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CLINICAL AND RESEARCH REPORTS

FIGURE 1. A Statistical Parametric Map Derived From a HMPAO SPECT Study

Regions that show statistically significant changes (p � 0.001) after successful treatment are displayed in black. A. Regions that increasedsignificantly following treatment with both AMSG and SSRI. B. Regions where AMSG had a significantly higher increase of CBF compared toSSRI treatment.

TABLE 1. Clinical Characteristics of the Patients

Treatment Gender (M/F) Age (years) HAMD

Baseline Post-treatment % changes

AMSG (n � 10)Responders (n � 8)Non-responders (n � 2)

3/51/1

46.4�15.042.5�0.7

22.3�4.417.5�0.7

5.3�3.4*22.5�3.5**

76.1�15.6-28.3�15.0**

SSRI (n � 9)Responders (n � 6)Non-responders (n � 3)

2/42/1

38.8�12.247.3�6.7

24.3�7.119.7�3.2

5.8�3.5*17.0�7.5**

74.7�17.415.9�26.5**

*, different from baseline, two-tailed paired t-test, p � 0.01; **, different from responders, two-tailed unpaired t-test, p � 0.01.

nates: 65, 17, 22) and left medial temporal gyrus (coor-dinates: 70, 0, �19). Regions in which AMSG differedfrom SSRI with a significantly higher increase than SSRIin blood flow following treatment included the medialprefrontal cortex (coordinates: �10, 65, 26), precuneus(coordinates: 0, �77, 65) and the right inferior parietalcortex (coordinates: �46, �60, 50) (Figure 1). Therewere no regions in which SSRIs increased blood flowsignificantly more than AMSG.

DISCUSSION

The primary effect we found in this study was that treat-ment response to both types of serotoninergic antide-pressants is associated with increased CBF in the left andmid anterior cingulate, left superior temporal gyrus, andorbital prefrontal cortex. This change in regional neuralactivity may be due to the change in mood state or to acommon serotonergic effect. Anterior cingulate regions

participate in autonomic, affective, and motivational be-haviors (rostral and ventral regions), pain perception,attention to action and response selection (dorsal re-gions), and they have unique reciprocal connections notonly between their rostral and dorsal parts, but also withselective dorsal neocortical and ventral paralimbic ar-eas.12 Anterior cingulate regions and their projection sitesare the areas where blood flow and metabolic changeswere seen in previous studies2,12,13 and these changeswere improved in MDD patients who responded to anti-depressant treatment3,12 or electroconvulsive therapy.14

We did not analyze the nonresponders group sepa-rately due to few numbers of patients. However, May-berg et al.12 demonstrated that the metabolic activity inanterior cingulate region discriminated eventual re-sponders from nonresponders and suggested that thisarea is necessary for the normal integrative processingof mood, motor, autonomic and cognitive behaviors, allof which are disrupted in depression.

We found response to AMSG treatment to be associ-

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ated with increased CBF in the medial prefrontal cortex,which was not seen in the SSRI treated patients. De-crease in medial prefrontal CBF associated with the cog-nitive impairment of depression or so-called depressivepseudodementia was demonstrated by Bench et al.,13

and clinical recovery from depression resulted in CBFincrease in these regions.15 Numerous reciprocal con-nections between anterior cingulate, dorsolateral pre-frontal, and medial prefrontal areas were demonstratedin primate studies,16 and prefrontal areas are consideredto be the sites of convergence for limbic inputs and toserve the function of integration of thought and emo-tion.17

To our knowledge this study is the first report of me-dial prefrontal blood flow changes in MDD patients suc-cessfully treated with a 5-HT2 receptor antagonist. Stud-ies of other similar drugs (e.g., nefazodone) would beinformative in determining whether this effect extendsto other 5-HT2 antagonists.

This study was supported in part by a grant from Eli Lilly,Inc., and NIMH grants MH-01370 and MH-58444 to Dr.Sheline, NIMH grant MH-54731 to Dr. Mintun, and grantRR-00036 from the NIH Division of Research Resources tothe General Clinical Research Center at Washington Univer-sity School of Medicine.

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