Cerebral Perfusion Response                                 with antidepressant therapy have been reported in a

medication within 3 weeks prior to inclusion in the          warped and resliced according to the trans...

nates: 65, 17, 22) and left medial temporal gyrus (coor-                        participat...

ated with increased CBF in the medial prefrontal cortex,                  To our knowledge this study i...
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Serotonin ssri effects


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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

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Serotonin ssri effects

  1. 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. 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. 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. 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. References 1. Cohen ML, Kurz KD, Fuller RW, et al: Comparative 5-HT2-re- Interview for Genetic Studies: rationale, unique features, and ceptor antagonist activity of amesergide and its active metabo- training. Arch Gen Psychiatry 1994; 51:849–859 lite 4-hydroxyamesergide in rats and rabbits. J Pharm Pharmacol 9. Hamilton M: A rating scale for depression. J Neurol Neurosurg 1994; 46:226–229 Psychiatry 1960; 23:56–62 2. Baxter LR, Schwartz JM, Phelps ME, et al: Reduction of prefron- 10. Woods RP, Cherry SR, Mazziotta JC: Rapid automated algorithm tal cortex glucose metabolism common to three types of depres- for aligning and reslicing PET images. J Comput Assist Tomogr sion. Arch Gen Psychiatry 1989; 46:243–250 1992; 16:620–633 3. Goodwin GM, Austin MP, Dougall N, et al: State changes in 11. Talairach J, Tournoux P: Co-Planar Stereotaxic Atlas of the Hu- brain activity shown by the uptake of Tc-99m exametazime with man Brain: Three-Dimensional Proportional System. New York, single photon emission tomography in major depression before Thieme Medical, 1988 and after treatment. J Affect Disord 1993; 29:243–253 12. Mayberg HS, Brannan SK, Mahurin RK, et al: Cingulate function 4. Buchsbaum MS, Delisi LE, Holcomb HH, et al: Anteroposterior in depression: a potential predictor of treatment response. Neu- gradients in cerebral glucose use in schizophrenia and affective roreport 1997; 8:1057–1061 disorders. Arch Gen Psychiatry 1984; 41:1159–1166 13. Bench CJ, Friston KJ, Brown RG, et al: The anatomy of melan- cholia—focal abnormalities of cerebral blood flow in major de- 5. Drevets WC, Raichle ME: Neuroanatomical circuits in depres- pression. Psychol Med 1992; 22:607–615 sion: implications for treatment mechanisms. Psychopharmacol 14. Bonne O, Krausz Y, Shapira B, et al: Increased cerebral blood Bull 1992; 28:261–274 flow in depressed patients responding to electroconvulsive ther- 6. Nobler MS, Sackeim HA, Prohovnik I, et al: Regional cerebral apy. J Nucl Med 1996; 37:1075–1080 blood flow in mood disorders, III: treatment and clinical re- 15. Bench CJ, Frackowiak RSJ, Dolan RJ: Changes in regional blood sponse. Arch Gen Psychiatry 1994; 51:884–897 flow on recovery from depression. Psychol Med 1995; 25:247–251 7. Mayberg HS, Liotti M, Brannan SK, et al: Reciprocal limbic-cor- 16. Pandya DN, Van Hoesen GW, Mesulam MM: Efferent connec- tical function and negative mood: converging PET findings in tions of the cingulate gyrus in the Rhesus monkey. Exp Brain depression and normal sadness. Am J Psychiatry 1999; 156:675– Res 1981; 42:319–330 682 17. Mesulam MM: Frontal cortex and behavior. Ann Neurol 1986; 8. Nurnberger JI Jr, Blehar MC, Kaufmann CA, et al: Diagnostic 19:320–325 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004 363