Cerebral Perfusion Response to Successful Treatment of Depression With Different Serotoninergic Agents with antidepressant therapy have been reported in a number of studies.2–4 In contrast, decreases in the ventral anterior cingulate blood flow were found in response to desipramine,5 electroshock therapy,6 and flu-7

1. Cerebral Perfusion Response with antidepressant therapy have been reported in a
number of studies.2–4 In contrast, decreases in the ven-
to Successful Treatment of tral anterior cingulate blood flow were found in re-
Depression With Different sponse to desipramine,5 electroshock therapy,6 and flu-
oxetine.7 The specific effects of the treatment with 5-HT2
Serotoninergic Agents receptor antagonists on CBF in major depressive disor-
der (MDD) have not yet been reported.
Andrei Vlassenko, M.D., Ph.D.
Yvette I. Sheline, M.D. Some of the discrepancies among previous studies
Keith Fischer, M.D. may be related to clinical considerations, including di-
Mark A. Mintun, M.D. agnostic criteria, inclusion of both bipolar and unipolar
subjects, demographic characteristics, illness severity,
and medication status. In a number of studies, one dif-
In 19 patients with major depressive disorder, ef-
ficulty is the alignment of scans from one subject to the
fective treatment with selective serotonin reuptake
next in the absence of anatomical data, which increases
inhibitors (SSRIs) or amesergide (AMSG) was as- the possibility of obscuring significant findings or find-
sociated with increased cerebral perfusion in ante- ing artifacts due to misalignment.
rior cingulate cortex (SSRI and AMSG) and in We used [Tc99m]hexamethylpropyleneamineoxime
medial prefrontal cortex (AMSG). Both selective (HMPAO) single photon emission computed tomogra-
serotonin reuptake inhibitors and AMSG exert phy (SPECT) images of CBF co-registered with anatom-
antidepressant action through the serotonin (5- ical magnetic resonance (MRI) imaging to compare the
HT) system as reuptake inhibitors. Amesergide changes in cerebral perfusion in response to treatment
differs from SSRIs in that it is also a highly selec- with SSRIs or AMSG.
tive 5-HT antagonist, which may in part account
for differences in cerebral blood flow response to
METHOD
treatment.
(The Journal of Neuropsychiatry and Clinical
Nineteen subjects meeting DSM-IV criteria for MDD
Neurosciences 2004; 16:360–363)
were recruited from referrals from other psychiatrists
and also from the community by advertisement. Inclu-
B oth selective serotonin reuptake inhibitors (SSRIs)
and amesergide (AMSG; LY237733) appear to pro-
duce an antidepressant effect through their action upon
sion criteria were a current episode meeting criteria for
MDD, right-handedness, and no other medical illness
potentially affecting the brain. A psychiatrist experi-
the serotonin (5-HT) system. They differ, however, in enced in the use of the Diagnostic Interviews for Genetic
that AMSG is a reuptake inhibitor as well as a highly Studies, a structured interview with high reliability,8 as-
selective antagonist at the 5-HT receptor. AMSG shows sessed all subjects clinically. Exclusion criteria com-
affinity at 5-HT2 receptors similar to that seen for other prised a current or past neurological disorder, head
potent 5-HT2 receptor antagonists such as ketanserin, trauma, uncontrolled hypertension, myocardial infarc-
ritanserin, and setoperone. In contrast to these agents, tion or ischemia, diabetes, Cushing’s disease, steroid
however, AMSG has low to negligible effects at -, b-, use, drug/alcohol abuse, and use of any psychotropic
dopamine, histamine, c-aminobutyric acid, benzodiaz-
epine, and muscarinic receptors.1 Received September 18, 2002; revised December 15, 2002; accepted
January 13, 2003. From the Department of Radiology, Department of
The literature reports contradictory findings for de- Psychiatry, Washington University School of Medicine, St. Louis, Mis-
pression and treatment associated cerebral blood flow souri. Correspondence and reprints: Dr. Sheline, Associate Professor
of Psychiatry and Radiology, Box 8134, WUSM 4940 Childrens Place
(CBF) changes. Increases in dorsal frontal and dorsal an- St. Louis, MO 63110. E-mail: yvette@npg.wustl.edu.
terior cingulate hypoperfusion and hypometabolism Copyright 2004 American Psychiatric Publishing, Inc.
360 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

2. VLASSENKO et al.
medication within 3 weeks prior to inclusion in the warped and resliced according to the transformation
study. Depression severity was rated using the Hamil- matrix generated from combining the two types of co-
ton Depression Rating Scale9 (HAMD) on the day of the registration.
SPECT study. All patients were then randomized to
treatment with AMSG 15–30 mg daily (Eli Lilly, Inc.) Statistical Parametric Mapping (SPM) Analysis
(n 10) or SSRI 20 mg daily (n 9) (fluoxetine n 6 or Statistical parametric mapping 96 (Wellcome Depart-
paroxetine n 3). In the case of AMSG this was part of ment of Cognitive Neurology, University College, Lon-
a double-blinded, placebo-controlled study. In the case don) was used to detect significant (P 0.001) regional
of SSRI it was an open-label study. After 12 weeks, de- changes in CBF between the baseline and treatment
pressed subjects were scanned again during their final scans for both AMSG and SSRI groups combined and in
week of antidepressant treatment. Clinical response was contrast to one another. Correction of global differences
defined as a posttreatment HAMD score 12 or a 50% and detection of voxel-by-voxel changes were per-
decrease compared to the initial HAMD score. formed using an analysis of covariance. Single photon
Written informed consent was obtained from all sub- emission computed tomography data was filtered with
jects after the procedures had been fully explained. The a 12 mm full width three-dimensional Gaussian filter at
Human Studies Committee and Radioactive Drug Re- half maximum prior to processing.
search Committee of Washington University School of A chi-square statistic was calculated to determine
Medicine approved the study. whether the gender distribution across the two groups
was significantly different, and a Student’s unpaired t
SPECT test was used to determine differences in age and base-
All SPECT CBF scans were performed on a Prism 3000 line HAMD score.
triple-headed scanner fitted with a high-resolution low-
energy collimator (Picker International, Cleveland) after
the injection of 16 mCi of HMPAO. The imaging proto- RESULTS
col acquired 120 brain images parallel to the orbitomea-
tal line in 40 steps with 360 rotation of the camera. Re- Subjects in SSRI and AMSG groups were similar in gen-
construction of SPECT images used a ramp filter to yield der (male/female ratio was 4/5 and 4/6, respectively;
transverse slices with a matrix of 128 128 128 pixels v2 0.038, P 0.84), age (41.7 11.0 years, and
and voxel size 2.8 2.8 2.8 mm. 45.6 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-
MRI spectively) (t 0.6, df 17, P 0.55). In AMSG group,
MRI scans were performed on a Magnetom SP-4000 1.5- 80% of subjects improved clinically after the treatment
T imaging system (Siemens, Iselin, N.J.). A magnetiza- (posttreatment HAMD was 5.3 3.4, a decrease from
tion prepared rapid gradient echo (MPRAGE) acquisi- initial value was 76% 16%) as compared with 67% in
tion was used to acquire anatomic images, which the SSRI group (posttreatment HAMD score and de-
consisted of 128 contiguous 1.25 mm thick sagittal slices. crease from initial value were 5.8 3.5 and 75% 16%,
Scanning parameters were TR 10 msec, TE 4 msec, respectively.) (Shown in Table 1.)
inversion time 300 msec, flip angle 8 , matrix Statistical parametric mapping was used to detect
256 256 pixels, voxel size 1 1 1.25 mm. CBF changes between baseline and posttreatment scans
in the SSRI and AMSG responders. Regions that in-
SPECT-MRI Co-Registration creased significantly following treatment with AMSG or
The MRI images were manually segmented using AN- SSRI included the left anterior cingulate gyrus (coordi-
ALYZE (Mayo Clinic, USA) to remove the scalp, skull, nates: 21, 22, 20), which extended towards the midline
and meninges, then resized to isotropic voxels. The seg- (covering the middle anterior cingulated gyrus [coor-
mented magnetic resonance (MR) brain images and dinates: 5, 45, 20]), the left superior temporal gyrus
SPECT images were co- registered using Automated Im- (coordinates: 57, 17, 6) and the orbital prefrontal cor-
age Alignment (AIR) software.10 The MR images were tex (coordinates: 11, 51, 29) (Figure 1). Regions that
transformed to a reference MRI in Talairach atlas decreased significantly following treatment with AMSG
space.11 SPECT scans were then rotated, translated, or SSRI included the left inferior frontal gyrus (coordi-
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004 361

3. CLINICAL AND RESEARCH REPORTS
nates: 65, 17, 22) and left medial temporal gyrus (coor- participate in autonomic, affective, and motivational be-
dinates: 70, 0, 19). Regions in which AMSG differed haviors (rostral and ventral regions), pain perception,
from SSRI with a significantly higher increase than SSRI attention to action and response selection (dorsal re-
in blood flow following treatment included the medial gions), and they have unique reciprocal connections not
prefrontal cortex (coordinates: 10, 65, 26), precuneus only between their rostral and dorsal parts, but also with
(coordinates: 0, 77, 65) and the right inferior parietal selective dorsal neocortical and ventral paralimbic ar-
cortex (coordinates: 46, 60, 50) (Figure 1). There eas.12 Anterior cingulate regions and their projection sites
were no regions in which SSRIs increased blood flow are the areas where blood flow and metabolic changes
significantly more than AMSG. were seen in previous studies2,12,13 and these changes
were improved in MDD patients who responded to anti-
depressant treatment3,12 or electroconvulsive therapy.14
DISCUSSION We did not analyze the nonresponders group sepa-
rately due to few numbers of patients. However, May-
The primary effect we found in this study was that treat- berg et al.12 demonstrated that the metabolic activity in
ment response to both types of serotoninergic antide- anterior cingulate region discriminated eventual re-
pressants is associated with increased CBF in the left and sponders from nonresponders and suggested that this
mid anterior cingulate, left superior temporal gyrus, and area is necessary for the normal integrative processing
orbital prefrontal cortex. This change in regional neural of mood, motor, autonomic and cognitive behaviors, all
activity may be due to the change in mood state or to a of which are disrupted in depression.
common serotonergic effect. Anterior cingulate regions We found response to AMSG treatment to be associ-
TABLE 1. Clinical Characteristics of the Patients
Treatment Gender (M/F) Age (years) HAMD
Baseline Post-treatment % changes
AMSG (n 10)
Responders (n 8) 3/5 46.4 15.0 22.3 4.4 5.3 3.4* 76.1 15.6
Non-responders (n 2) 1/1 42.5 0.7 17.5 0.7 22.5 3.5** -28.3 15.0**
SSRI (n 9)
Responders (n 6) 2/4 38.8 12.2 24.3 7.1 5.8 3.5* 74.7 17.4
Non-responders (n 3) 2/1 47.3 6.7 19.7 3.2 17.0 7.5** 15.9 26.5**
*, different from baseline, two-tailed paired t-test, p 0.01; **, different from responders, two-tailed unpaired t-test, p 0.01.
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 increased
significantly following treatment with both AMSG and SSRI. B. Regions where AMSG had a significantly higher increase of CBF compared to
SSRI treatment.
362 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

4. VLASSENKO et al.
ated with increased CBF in the medial prefrontal cortex, To our knowledge this study is the first report of me-
which was not seen in the SSRI treated patients. De- dial prefrontal blood flow changes in MDD patients suc-
crease in medial prefrontal CBF associated with the cog- cessfully treated with a 5-HT2 receptor antagonist. Stud-
nitive impairment of depression or so-called depressive ies of other similar drugs (e.g., nefazodone) would be
pseudodementia was demonstrated by Bench et al.,13 informative in determining whether this effect extends
and clinical recovery from depression resulted in CBF to other 5-HT2 antagonists.
increase in these regions.15 Numerous reciprocal con-
nections between anterior cingulate, dorsolateral pre- This study was supported in part by a grant from Eli Lilly,
frontal, and medial prefrontal areas were demonstrated Inc., and NIMH grants MH-01370 and MH-58444 to Dr.
in primate studies,16 and prefrontal areas are considered Sheline, NIMH grant MH-54731 to Dr. Mintun, and grant
to be the sites of convergence for limbic inputs and to RR-00036 from the NIH Division of Research Resources to
serve the function of integration of thought and emo- the General Clinical Research Center at Washington Univer-
tion.17 sity School of Medicine.
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