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Regional Cerebral Blood Flow in Mood Disorders, V.: Effects of Antidepressant Medication in Late-Life Depression
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Regional Cerebral Blood Flow in Mood Disorders, V. Effects of Antidepressant Medication in Late-Life Depression Mitchell S. Nobler, M.D., Steven P. Roose, M.D. Isak Prohovnik, Ph.D., James R. Moeller, Ph.D. Judy Louie, B.A., Ronald L. Van Heertum, M.D. Harold A. Sackeim, Ph.D.
Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar 133Xenon inhalation technique after a medication washout and following 6– 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this group’s previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action. (Am J Geriatr Psychiatry 2000; 8:289–296)
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everal studies have demonstrated abnormalities in regional cerebral blood flow (rCBF) and regional cerebral metabolic rate (rCMR) in patients during episodes of major depression.1,2 These deficits appear to be especially marked among elderly patients, who are reported to manifest global reductions in resting CBF and CMR.3–6 Regional abnormalities have also been consistently reported in dorsolateral and other prefrontal regions, at times extending to superior temporal and anterior parietal cortices, anterior cingulate, and the caudate nucleus.3–8 In some studies of younger de-
pressed patients, rCBF elevations have been observed in the medial orbital frontal cortex,2 but this has not been reported in late-life depression. Normal aging is also associated with rCBF and rCMR reductions, especially in the frontal cortex.9–11 However, effects of aging and depression are at least additive, given that marked deficits are seen in elderly depressed patients compared with matched-control subjects.4–6 Little is known about the effects of somatic treatment or clinical response on baseline functional abnormalities. Electroconvulsive therapy (ECT) has profound
Received June 3, 1999; revised November 30, 1999; accepted January 17, 2000. From the Department of Biological Psychiatry, New York State Psychiatric Institute, and the Departments of Psychiatry and Radiology, College of Physicians and Surgeons, Columbia University, New York, NY. Address correspondence to Dr. Mitchell S. Nobler, Department of Biological Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY 10032. Copyright 䉷 2000 American Association for Geriatric Psychiatry
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Cerebral Blood Flow and Antidepressants effects on rCBF and rCMR, and most investigators have found reductions in these parameters after a course of treatment.12 Consistent with these findings, we reported on a large sample of predominantly elderly patients undergoing ECT for major depression.13 Despite reduced rCBF at baseline, responders to ECT had further perfusion reductions both globally and in specific frontal cortical regions. The literature on the effects of antidepressant medications is much less consistent, with reports that antidepressants result in increases, decreases, or have no net effect on rCBF and rCMR.2,14 It has been difficult to draw conclusions from this work because of methodological discrepancies. In general, samples have been small and heterogeneous; several medications were given; and time-points of posttreatment imaging have been inconsistent across studies, varying from several weeks to several months. Few studies have focused specifically on elderly samples, even though one might expect more robust effects. We report here on fully quantitative rCBF assessments at baseline and after treatment with antidepressant medication in a sample of older patients with late-life major depression. We hypothesized that, at baseline, patients would differ from matched control subjects in having lower global CBF and specific decreases in prefrontal regions. In line with reports on the effects of ECT on rCBF,12,13 we also hypothesized that responders to medication would manifest reductions in frontal cortical rCBF.
METHODS Subjects Patients were recruited through the Late-Life Depression Research Center at the New York State Psychiatric Institute. Patients were at least 60 years of age, met DSM-IV criteria for major depression episode (unipolar, nonpsychotic) based on SCID–P interviews, and at baseline scored at least 18 on the 24-item Hamilton Rating Scale for Depression (Ham-D).15 Exclusion criteria were a history of schizophrenia, schizoaffective disorder, or other functional psychosis, any other current Axis I disorder, history of neurologic disease or insult, serious or unstable current medical condition, and recent substance abuse or history of substance dependence. Patients were not taking any medications with known effects on rCBF (e.g., insulin, anticoagu-
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lants, or anticholinergics). Six patients were on stable doses of prescription medications (four were on antihypertensives; one patient was taking estrogen replacement; and one was taking pancreatic enzyme replacement). The depressed sample was contrasted with a normal- control group matched for age, sex, and systolic and diastolic blood pressure. Normal-control subjects had Beck Depression Inventory (BDI)16 scores ⬍9 and were free of any current or past history of psychiatric illness, as determined by interviews using the lifetime version of the Schedule for Affective Disorders and Schizophrenia (SADS–L).17 Control subjects had not taken any prescription medication within 3 weeks of assessment. All individuals (patients and controls) were right-handed and scored at least 24 on the Mini-Mental State Exam (MMSE). All participants provided informed consent, and the research procedures were approved by the Institutional Review Board at the New York State Psychiatric Institute. Pharmacotherapy and Assessment Time-Points Patients participated in a minimum 14-day psychotropic medication washout, after which baseline clinical assessments were conducted, including rCBF assessment. Patients were administered the Ham-D by both a research psychiatrist and social worker in independent interviews (intra-class correlation coefficients ⬎0.95) and then received treatment with antidepressant medication. Eleven patients participated in a double-blind, randomized study of nortriptyline (n⳱6) and sertraline (n⳱5), while the remaining nine patients received nortriptyline in an open fashion. Patients treated with nortriptyline achieved therapeutic plasma levels (meanⳲstandard deviation [SD]⳱93Ⳳ34 ng/ml) within 2 weeks. Sertraline oral dosage was progressively increased until clinical response, maximal tolerated dose, or a maximum of 150 mg/day was reached. After 6–9 weeks on medication, rCBF and clinical assessments were repeated. Clinical response was defined as at least a 50% reduction in mean Ham-D score from baseline and a final Ham-D score ⬍10. Control subjects underwent rCBF measurement at only one time-point. rCBF Measurement Procedures The planar 133Xenon inhalation method was used. Assessments were made under resting, supine condi-
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Nobler et al. tions in a quiet, darkened room. Weighted blinders were placed over the eyes. We used a commercial device (Novo Cerebrograph 32C), and head positioning was determined by establishing the orientation of a helmet containing 32 scintillation detectors (16 per hemisphere) in relation to light markers aligned with the canthomeatal line. A mask was placed over the mouth, and adequacy of fit was established. After establishing stable respiratory rate, a mixture of 133Xenon and room air was administered for 1 minute. After this, room air was inhaled for 10 minutes, during which time end-tidal pCO2 was assessed. A technician monitored the adequacy of count rates, movement artifact, mask leak, and stability of respiration. Blood samples for hemoglobin were obtained within 1 week of the procedure. rCBF values were quantified by applying a six-unknown model (M2) to the clearance curves. This model has been shown to be more sensitive under low flow conditions and more accurate in artifact removal than the four-unknown model (M1).18 The major dependent variable was the Initial Slope Index (ISI), a measure dominated by CBF in gray matter (in ml/100g/minute). Global cortical CBF was defined as the mean ISI value across the 32 detectors. Statistical Analyses Baseline characteristics of patients and control subjects were compared, using analyses of variance (ANOVAs), with diagnostic group (depressed vs. control) and gender as between-subject factors. The groups were compared in global CBF, using analysis of covariance (ANCOVA), with diagnostic group and gender as between-subject factors, and pCO2 values as the covariate. To examine group differences in regional CBF, a repeated-measures ANOVA was applied to the 32 detector CBF values, with diagnostic group and gender as between-subject factors.3,19 In addition to this omnibus test for regional differences, a standard regional covariance analysis, the Scaled Subprofile Model (SSM),19,20 was used to identify the regional patterns of control– patient differences that had the largest effect sizes. SSM is a principal-components analysis that was applied to the combined detector data of patients and control subjects. Repeated-measures ANOVA was applied to the subject scores associated with the major principal components to identify regional patterns that revealed significant group differences.
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Also, regional patterns that had revealed baseline and treatment effects in previous studies of late-life depression were evaluated to determine if they showed comparable effects in the current data. Subject scores for two different a priori patterns were computed and submitted to ANOVA. The first pattern was a frontal/ posterior ratio, consisting of the average of the 10 frontal detectors (5 per hemisphere) divided by the average of the 22 posterior detectors (11 per hemisphere). This pattern highlights the antero–posterior gradient commonly found to be abnormal in major depression.1 Subjects were also scored for the degree of expression of a regional covariance pattern that involved specific prefrontal, temporal, and parietal detectors. In previous studies, this “depression profile” was specifically associated with CBF reductions in predominantly elderly, severely depressed inpatients.3,20 Paired t-tests were used to examine change between the time-points in the total sample. As an omnibus test of differences between Responders and Nonresponders in changes in rCBF, a repeated-measures ANOVA was conducted with response status as a between-subjects factor and region as the repeated-measures factor. An SSM analysis was also conducted on the change in CBF values from pre- to posttreatment, followed by a repeated-measures ANOVA to contrast Responders and Nonresponders in topography scores. Responders and Nonresponders were also contrasted in change for the a priori frontal ratio and “depression profile” scores. Significance values in all repeated-measure ANOVAs were based on the Huynh-Feldt adjustment. All statistical tests were two-tailed, with P set at ⱕ0.05. No correction was made for the number of statistical comparisons. All analyses were performed using SAS Version 6.12.21
RESULTS Comparison of Depressed Patients and Control Subjects Sample characteristics. Table 1 presents sample characteristics for the depressed and normal-control groups. The ANOVAs indicated that depressed patients had lower pCO2 values. There were no other significant differences.
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Cerebral Blood Flow and Antidepressants Comparison of Patients and Control Subjects in Baseline Cerebral Blood Flow Global cortical CBF averaged 46.51Ⳳ8.0 for the patients and 49.27Ⳳ9.5 for control subjects. There was no difference between the depressed and control groups in global CBF; the ANCOVA only yielded a significant effect for the covariate, pCO2, (F[1]⳱8.30; P⬍0.007) and a trend for a main effect of gender (F[1,35]⳱3.91; P⬍0.06). The omnibus repeated-measures ANOVA yielded a significant main effect of detector location (F[31, 1,116]⳱8.09; P⬍0.0001) and an interaction between diagnostic group (depressed vs. normal) and detector location (F[31, 1,116]⳱2.07; P⬍0.007). To characterize the nature of the topographic differences between patients and control subjects, the groups were compared in frontal CBF ratios, and SSM analyses were conducted. The ANOVA on the frontal ratio yielded a significant main effect of diagnostic group (F[1, 36]⳱7.94; P⬍0.008). Compared with control subjects (mean⳱1.03Ⳳ0.04), patients (mean⳱1.00Ⳳ0.03) had lower frontal ratios, indicating relative CBF reductions across the frontal cortex. An ANCOVA indicated that the groups did not differ in the SSM’s estimate of region-independent global CBF. Four topographic patterns were identified by SSM that accounted for 51.3% of the variance in regional CBF. A repeated-measures ANOVA on scores on these four topographic patterns produced a significant interaction between diagnostic group and topography (F[3, 108]⳱4.88; P⳱0.003), indicating that the groups differed in scores on specific topographies. Follow-up ANOVAs indicated that the depressed and control groups differed in manifestation of the first (F[1, 36]⳱4.77; P⬍0.04) and fourth (F[1, 36]⳱8.39; P⳱0.006) topograTABLE 1.
phies. Figure 1 presents the two topographic structures in which patients and control subjects differed at baseline. The difference in expression of the first topography reflected CBF reductions in patients in prefrontal and anterior temporal regions, with CBF preservation in posterior parietal and occipital regions. The difference in expression of the fourth topography was due to a pattern of CBF reductions in patients in selective frontal, superior temporal, and anterior parietal regions, with preservation in the right anterior temporal and left parieto-occipital region. We also contrasted the two groups in their expression of the “depression profile.” The region weights of this profile bore strong similarity to the fourth pattern extracted in the new blinded SSM analysis (r[30]⳱0.70; P⬍0.0001). Not surprisingly, therefore, there was a significant difference between the groups in the expression of this topographic abnormality (F[1, 36]⳱5.88; P⳱0.02), providing independent replication of this pattern of abnormality in an elderly outpatient sample.
Effects of Pharmacotherapy Sample characteristics. After the pharmacological trial, 11 patients were deemed Nonresponders (9 nortriptyline, 2 sertraline) and 9 were Responders (6 nortriptyline, 3 sertraline). There were no significant differences at baseline or after treatment between Responders and Nonresponders in age, gender, blood pressure, hemoglobin, or pCO2 values. Across the sample, there were no changes in these variables across the two time-points. Responders averaged an 80.42%(Ⳳ18.47%) decrease in Ham-D scores, whereas Nonresponders averaged a 20.80%(Ⳳ19.49%) decrease.
Characteristics of the depressed and normal-control sample
Age, years Gender, % female
Depressed Patients (nⴔ20)
Normal-Control Subjects (nⴔ20)
67.8Ⳳ6.1
67.3Ⳳ5.3
70
70
Systolic blood pressure, mm Hg
131.9Ⳳ17.0
131.4Ⳳ15.2 79.8Ⳳ5.8
Diastolic blood pressure, mm Hg
74.5Ⳳ7.9
pCO2, mm Hg*
34.5Ⳳ3.0
37.5Ⳳ2.7
Hemoglobin
14.4Ⳳ1.1
14.7Ⳳ0.6
Ham-D
23.4Ⳳ6.1
—
Note: pCO2⳱End-tidal partial pressure of carbon dioxide; Ham-D⳱Hamilton Rating Scale for Depression. *Groups differed in pCO2 (F[1, 36]⳱9.36; P⳱0.004).
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Nobler et al. FIGURE 1.
Two topographic profiles in which elderly depressed patients differed from normal-control subjects
Global cerebral blood flow. The group as a whole did not evidence change in global CBF over the treatment course. Responders and Nonresponders did not differ in change in global CBF. Topographic CBF: traditional statistics. The omnibus repeated-measures ANOVA yielded a significant interaction between response status and brain region (F[31, 496]⳱1.82; P⳱0.005), indicating that Responders and Nonresponders differed in the topography of CBF change. Although Responders (mean⳱0.014Ⳳ0.034) showed a decrease in the frontal ratio, whereas Nonresponders were unchanged (mean⳱ –0.004Ⳳ0.024), the groups did not differ significantly in this measure.
Note: Purple and blue colors (negative values) reflect areas of rCBF deficit in the depressed sample; colors in the red range (positive values) denote regions of preserved rCBF. The first pattern indicates that the depressed sample had reduced perfusion in selective prefrontal and anterior temporal regions, with CBF preservation in posterior parietal and occipital regions. The fourth topographic pattern reflects rCBF reductions in selective frontal, superior temporal, and anterior parietal regions, with preservation in the right anterior temporal and left parieto-occipital region.
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Topographic CBF: Scaled Subprofile Model (SSM). Four topographic patterns were identified by the blind SSM analysis, accounting for 51% of the variance in CBF regional changes from baseline. An omnibus ANOVA indicated that Responders and Nonresponders differed in scores on these patterns (F[1, 16]⳱12.20; P⳱0.003). Follow-up ANOVAs indicated that Responders and Nonresponders differed significantly only in the expression of the first pattern (F[1, 16]⳱10.31; P⬍0.006; Figure 2). This difference was due principally to Responders’ manifesting CBF reductions in specific prefrontal and anterior temporal regions, a pattern of change not seen in Nonresponders. To further test this association, we correlated scores across the sample for change in this topography with depression severity ratings. Greater expression of this pattern of CBF reduction in selective prefrontal and anterior temporal regions was associated with greater percentage change in Ham-D scores from baseline (r[18]⳱ ⳮ0.47; P⬍0.04) and lower posttreatment absolute Ham-D scores (r[18]⳱0.51; P⬍0.02). We repeated the omnibus repeated-measures ANOVA using medication condition (nortriptyline vs. sertraline) as an additional between-subjects factor. Results were unchanged; type of medication had no impact on the relation with response. Responders to nortriptyline (mean⳱ ⳮ14.57Ⳳ26.35) and sertraline (mean⳱ ⳮ8.54Ⳳ17.12) both had distinctly different mean scores on this topography than Nonresponders to nortriptyline (mean⳱10.77Ⳳ26.58) and sertraline (mean⳱8.06Ⳳ17.81). The sample as a whole did not change in expression of the “depression profile,” and there was no difference between Responders and Nonresponders in change in this measure.
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Cerebral Blood Flow and Antidepressants DISCUSSION The major findings of this study were that elderly outpatients in an episode of major depression did not differ from matched normal-control subjects in resting global cortical CBF, but had significant topographic reductions in CBF, principally involving frontal, temporal, and anterior parietal cortical regions. Furthermore, treatment with antidepressant medications did not result in reversal of baseline deficits. Instead, pharmacotherapy responders showed further CBF reductions in selective frontal and anterior temporal regions. The magnitude of change in this pattern was correlated with the extent of clinical improvement. Several previous studies reported global CBF or CMR deficits in samples of elderly depressed patients.3–6 Much of this work focused on severely depressed inpatients, which may account for the absence of a global deficit in our moderately depressed outpatient sample. We did observe topographic abnormality in the patient sample at baseline. This topographic abnormality was FIGURE 2.
A topographic pattern that distinguished Responders and Nonresponders in change in rCBF
Note: Purple and blue colors (negative values) reflect areas of rCBF decrease in Responders. After antidepressant treatment, Responders had rCBF decreases in selective frontal and anterior temporal regions and right occipital area.
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expressed in reduced values for an a priori frontal ratio in a blind SSM analysis, and when we contrasted scores on a previously obtained “depression profile” in patients and control subjects. The baseline topographic deficit in the depressed sample involved CBF reductions in selective frontal, temporal, and anterior parietal regions. This pattern broadly concurs with the findings of a large number of brain-imaging studies of major depression across diverse age ranges,1,2 and specifically with studies of late-life depression.3–6,11 Since the determination of rCBF by the Xenon-inhalation method is based on the rate of clearance in perfused tissue, it is unlikely that differences between the patient and control groups in cerebral atrophy contributed to the topographic differences in blood flow. Preclinical studies have shown that antidepressant medications, particularly tricyclics, have pronounced effects on capillary permeability, CBF, and CMR,22–25 and chronic treatment often results in reduced functional activity in a regionally distributed fashion. In contrast, studies of changes in CBF and CMR after effective pharmacological treatment of major depression have yielded inconsistent results. Some have argued that functional activity is decreased, particularly in ventrolateral and orbital-frontal cortex.2 However, several studies have shown no change in at least some baseline cortical abnormalities,26–29 whereas other studies have found at least partial reversal of baseline cortical deficits, particularly in dorsolateral prefrontal cortex30,31 or complex patterns of increases and decreases.32 Few of these studies concentrated on late-life depression, and, in general, sample sizes have been small, with heterogeneous imaging and treatment methods. In contrast, findings appear to be more consistent with ECT. With one exception,33 imaging studies have found decreased CBF or CMR in anterior cortical regions acutely and in the short term after ECT.34–36 We showed that during the week after ECT, there was little change in expression of the baseline abnormality (the “depression profile”), but marked CBF reductions in specific frontal regions in patients who responded to ECT.13 These findings regarding response to ECT parallel the findings of this study with pharmacotherapy. The topography of rCBF reductions after response to pharmacotherapy in this study was highly similar to the topography linked with response to ECT. The limitations of this study include relatively small sample size, the baseline difference between the samples in end-tidal pCO2, and the use of a low-resolution
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Nobler et al. imaging technique with restriction to cortical activity. Nonetheless, the findings suggest that, as with ECT, successful pharmacological treatment of late-life major depression may not result in reversal of baseline functional imaging deficits. There are a number of possibilities that might account for this seemingly paradoxical phenomenon. In each case, there is the assumption that the state of depression is characterized by increased activity in specific neural regions—increased activity that is reversed with successful treatment. First, some of the imaging deficits observed at baseline in late-life depression may reflect trait-level abnormalities, perhaps tied to vascular pathology.37 These prominent trait-level deficits would obscure state-related increased activity. Alternatively, the baseline deficits may reflect secondary compensatory changes in reaction to the onset of the state
of depression. Such compensatory reductions in neural activity would similarly obscure the original state-related increases and essentially mimic the more powerful action of effective treatments. Finally, a third alternative is that the pathways involved in the therapeutic action of antidepressant treatments may be distinct from those involved in the pathophysiology of the illness. This work was presented in part at the Annual Meeting of the American Psychiatric Association, Toronto, Canada, May 30–June 4, 1998. The work was supported in part by grants R01 MH55646 (HAS) and K08 MH01244 (MSN) from the National Institute of Mental Health, a Young Investigator Award from the National Association for Research in Schizophrenia and Depression (MSN), and the Paul Beeson Physician Faculty Scholars in Aging Research Award (MSN).
References 1. Sackeim HA, Prohovnik I: Brain imaging studies in depressive disorders, in Biology of Depressive Disorders. Edited by Mann JJ, Kupfer D. New York, Plenum, 1993, pp 205–258 2. Drevets WC: Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 1998; 49:341–361 3. Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders, I: comparison of major depressives and normal controls at rest. Arch Gen Psychiatry 1990; 47:60–70 4. Upadhyaya AK, Abou-Saleh MT, Wilson K, et al: A study of depression in old age using single-photon emission computerised tomography. Br J Psychiatry 1990; 157:76–81 5. Kumar A, Newberg A, Alavi A, et al: Regional cerebral glucose metabolism in late-life depression and Alzheimer’s disease: a preliminary positron-emission tomography study. Proc Natl Acad Sci U S A 1993; 90:7019–7023 6. Lesser IM, Mena I, Boone KB, et al: Reduction of cerebral blood flow in older depressed patients. Arch Gen Psychiatry 1994; 51:677–686 7. Bench CJ, Friston KJ, Brown RG, et al: Regional cerebral blood flow in depression measured by positron-emission tomography: the relationship with clinical dimensions. Psychol Med 1993; 23:579–590 8. Curran SM, Murray CM, Van Beck M, et al: A single photon-emission computerised tomography study of regional brain function in elderly patients with major depression and with Alzheimertype dementia. Br J Psychiatry 1993; 163:155–165 9. Martin AJ, Friston KJ, Colebatch JG, et al: Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 1991; 11:684–689 10. Moeller JR, Ishikawa T, Dhawan V, et al: The metabolic topography of normal aging. J Cereb Blood Flow Metab 1996; 16:385– 398 11. Nobler MS, Mann JJ, Sackeim HA: Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging. Brain Res Brain Res Rev 1999; 30:250–263 12. Nobler MS, Sackeim HA: Mechanisms of action of electroconvulsive therapy: functional brain imaging studies. Psychiatr Ann 1998; 28:23–29
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13. Nobler MS, Sackeim HA, Prohovnik I, et al: Regional cerebral blood flow in mood disorders, III: effects of treatment and clinical response in depression and mania. Arch Gen Psychiatry 1994; 51:884–897 14. Rubin E, Sackeim HA, Nobler MS, et al: Brain imaging studies of antidepressant treatments. Psychiatr Ann 1994; 24:653–658 15. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278–296 16. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–571 17. Endicott J, Spitzer RL: A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978; 35:837–844 18. Prohovnik I, Knudsen E, Risberg J: Accuracy of models and algorithms for determination of fast-compartment flow by non-invasive 133-Xe clearance, in Functional Radionuclide Imaging of the Brain. Edited by Magistretti P. New York, Raven, 1983, pp 87–115 19. Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders, II: comparison of major depression and Alzheimer’s disease. J Nucl Med 1993; 34:1090–1101 20. Moeller J, Strother S, Sidtis J, et al: Scaled Subprofile Model: a statistical approach to the analysis of functional patterns in positron-emission tomographic data. J Cereb Blood Flow Metab 1987; 7:649–658 21. SAS/STAT User’s Guide, Version 6, 4th Edition. Cary, NC, SAS Institute, Inc., 1998 22. Preskorn SH, Raichle ME, Hartman BK: Antidepressants alter cerebrovascular permeability and metabolic rate in primates. Science 1982; 217:250–252 23. Gerber JC, Choki J, Brunswick DJ, et al: The effects of antidepressant drugs on regional cerebral glucose utilization in the rat. Brain Res 1983; 269:319–325 24. Caldecott-Hazard S, Mazziotta J, Phelps M: Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci 1988; 8:1951–1961 25. Freo U, Pietrini P, Dam M, et al: The tricyclic antidepressant clomipramine dose-dependently reduces regional cerebral meta-
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Cerebral Blood Flow and Antidepressants bolic rates for glucose in awake rats. Psychopharmacology 1993; 113:53–59 26. Reischies FM, Hedde JP, Drochner R: Clinical correlates of cerebral blood flow in depression. Psychiatry Res 1989; 29:323–326 27. Hurwitz TA, Clark C, Murphy E, et al: Regional cerebral glucose metabolism in major depressive disorder. Can J Psychiatry 1990; 35:684–688 28. Martinot JL, Hardy P, Feline A, et al: Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry 1990; 147:1313–1317 29. Goodwin GM, Austin MP, Dougall N, et al: State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon-emission tomography in major depression before and after treatment. J Affect Disord 1993; 29:243–253 30. Bench CJ, Frackowiak RS, Dolan RJ: Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995; 25:247–261 31. Passero S, Nardini M, Battistini N: Regional cerebral blood flow changes following chronic administration of antidepressant
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drugs. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19:627–636 32. Buchsbaum M, Wu J, Siegel B, et al: Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 1997; 41:15–22 33. Bonne O, Krausz Y, Shapira B, et al: Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy. J Nucl Med 1996; 37:1075–1080 ¨ ld P, Gustafson L, Risberg J, et al: Acute and late effects 34. Silfverskio of electroconvulsive therapy: clinical outcome, regional cerebral blood flow, and electroencephalogram. Ann NY Acad Sci 1986; 462:236–248 35. Rosenberg R, Vostrup S, Andersen A, et al: Effect of ECT on cerebral blood flow in melancholia assessed with SPECT. Convulsive Therapy 1988; 4:62–73 36. Volkow ND, Bellar S, Mullani N, et al: Effects of electroconvulsive therapy on brain glucose metabolism: a preliminary study. Convulsive Therapy 1988; 4:199–205 37. Alexopoulos GS, Meyers BS, Young RC, et al: “Vascular depression” hypothesis. Arch Gen Psychiatry 1997; 54:915–922
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Regional Cerebral Blood Flow in Mood Disorders, V. Effects of Antidepressant Medication in Late-Life Depression Mitchell S. Nobler, M.D., Steven P. Roose, M.D. Isak Prohovnik, Ph.D., James R. Moeller, Ph.D. Judy Louie, B.A., Ronald L. Van Heertum, M.D. Harold A. Sackeim, Ph.D.
Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar 133Xenon inhalation technique after a medication washout and following 6– 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this group’s previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action. (Am J Geriatr Psychiatry 2000; 8:289–296)
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everal studies have demonstrated abnormalities in regional cerebral blood flow (rCBF) and regional cerebral metabolic rate (rCMR) in patients during episodes of major depression.1,2 These deficits appear to be especially marked among elderly patients, who are reported to manifest global reductions in resting CBF and CMR.3–6 Regional abnormalities have also been consistently reported in dorsolateral and other prefrontal regions, at times extending to superior temporal and anterior parietal cortices, anterior cingulate, and the caudate nucleus.3–8 In some studies of younger de-
pressed patients, rCBF elevations have been observed in the medial orbital frontal cortex,2 but this has not been reported in late-life depression. Normal aging is also associated with rCBF and rCMR reductions, especially in the frontal cortex.9–11 However, effects of aging and depression are at least additive, given that marked deficits are seen in elderly depressed patients compared with matched-control subjects.4–6 Little is known about the effects of somatic treatment or clinical response on baseline functional abnormalities. Electroconvulsive therapy (ECT) has profound
Received June 3, 1999; revised November 30, 1999; accepted January 17, 2000. From the Department of Biological Psychiatry, New York State Psychiatric Institute, and the Departments of Psychiatry and Radiology, College of Physicians and Surgeons, Columbia University, New York, NY. Address correspondence to Dr. Mitchell S. Nobler, Department of Biological Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY 10032. Copyright 䉷 2000 American Association for Geriatric Psychiatry
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Cerebral Blood Flow and Antidepressants effects on rCBF and rCMR, and most investigators have found reductions in these parameters after a course of treatment.12 Consistent with these findings, we reported on a large sample of predominantly elderly patients undergoing ECT for major depression.13 Despite reduced rCBF at baseline, responders to ECT had further perfusion reductions both globally and in specific frontal cortical regions. The literature on the effects of antidepressant medications is much less consistent, with reports that antidepressants result in increases, decreases, or have no net effect on rCBF and rCMR.2,14 It has been difficult to draw conclusions from this work because of methodological discrepancies. In general, samples have been small and heterogeneous; several medications were given; and time-points of posttreatment imaging have been inconsistent across studies, varying from several weeks to several months. Few studies have focused specifically on elderly samples, even though one might expect more robust effects. We report here on fully quantitative rCBF assessments at baseline and after treatment with antidepressant medication in a sample of older patients with late-life major depression. We hypothesized that, at baseline, patients would differ from matched control subjects in having lower global CBF and specific decreases in prefrontal regions. In line with reports on the effects of ECT on rCBF,12,13 we also hypothesized that responders to medication would manifest reductions in frontal cortical rCBF.
METHODS Subjects Patients were recruited through the Late-Life Depression Research Center at the New York State Psychiatric Institute. Patients were at least 60 years of age, met DSM-IV criteria for major depression episode (unipolar, nonpsychotic) based on SCID–P interviews, and at baseline scored at least 18 on the 24-item Hamilton Rating Scale for Depression (Ham-D).15 Exclusion criteria were a history of schizophrenia, schizoaffective disorder, or other functional psychosis, any other current Axis I disorder, history of neurologic disease or insult, serious or unstable current medical condition, and recent substance abuse or history of substance dependence. Patients were not taking any medications with known effects on rCBF (e.g., insulin, anticoagu-
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lants, or anticholinergics). Six patients were on stable doses of prescription medications (four were on antihypertensives; one patient was taking estrogen replacement; and one was taking pancreatic enzyme replacement). The depressed sample was contrasted with a normal- control group matched for age, sex, and systolic and diastolic blood pressure. Normal-control subjects had Beck Depression Inventory (BDI)16 scores ⬍9 and were free of any current or past history of psychiatric illness, as determined by interviews using the lifetime version of the Schedule for Affective Disorders and Schizophrenia (SADS–L).17 Control subjects had not taken any prescription medication within 3 weeks of assessment. All individuals (patients and controls) were right-handed and scored at least 24 on the Mini-Mental State Exam (MMSE). All participants provided informed consent, and the research procedures were approved by the Institutional Review Board at the New York State Psychiatric Institute. Pharmacotherapy and Assessment Time-Points Patients participated in a minimum 14-day psychotropic medication washout, after which baseline clinical assessments were conducted, including rCBF assessment. Patients were administered the Ham-D by both a research psychiatrist and social worker in independent interviews (intra-class correlation coefficients ⬎0.95) and then received treatment with antidepressant medication. Eleven patients participated in a double-blind, randomized study of nortriptyline (n⳱6) and sertraline (n⳱5), while the remaining nine patients received nortriptyline in an open fashion. Patients treated with nortriptyline achieved therapeutic plasma levels (meanⳲstandard deviation [SD]⳱93Ⳳ34 ng/ml) within 2 weeks. Sertraline oral dosage was progressively increased until clinical response, maximal tolerated dose, or a maximum of 150 mg/day was reached. After 6–9 weeks on medication, rCBF and clinical assessments were repeated. Clinical response was defined as at least a 50% reduction in mean Ham-D score from baseline and a final Ham-D score ⬍10. Control subjects underwent rCBF measurement at only one time-point. rCBF Measurement Procedures The planar 133Xenon inhalation method was used. Assessments were made under resting, supine condi-
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Nobler et al. tions in a quiet, darkened room. Weighted blinders were placed over the eyes. We used a commercial device (Novo Cerebrograph 32C), and head positioning was determined by establishing the orientation of a helmet containing 32 scintillation detectors (16 per hemisphere) in relation to light markers aligned with the canthomeatal line. A mask was placed over the mouth, and adequacy of fit was established. After establishing stable respiratory rate, a mixture of 133Xenon and room air was administered for 1 minute. After this, room air was inhaled for 10 minutes, during which time end-tidal pCO2 was assessed. A technician monitored the adequacy of count rates, movement artifact, mask leak, and stability of respiration. Blood samples for hemoglobin were obtained within 1 week of the procedure. rCBF values were quantified by applying a six-unknown model (M2) to the clearance curves. This model has been shown to be more sensitive under low flow conditions and more accurate in artifact removal than the four-unknown model (M1).18 The major dependent variable was the Initial Slope Index (ISI), a measure dominated by CBF in gray matter (in ml/100g/minute). Global cortical CBF was defined as the mean ISI value across the 32 detectors. Statistical Analyses Baseline characteristics of patients and control subjects were compared, using analyses of variance (ANOVAs), with diagnostic group (depressed vs. control) and gender as between-subject factors. The groups were compared in global CBF, using analysis of covariance (ANCOVA), with diagnostic group and gender as between-subject factors, and pCO2 values as the covariate. To examine group differences in regional CBF, a repeated-measures ANOVA was applied to the 32 detector CBF values, with diagnostic group and gender as between-subject factors.3,19 In addition to this omnibus test for regional differences, a standard regional covariance analysis, the Scaled Subprofile Model (SSM),19,20 was used to identify the regional patterns of control– patient differences that had the largest effect sizes. SSM is a principal-components analysis that was applied to the combined detector data of patients and control subjects. Repeated-measures ANOVA was applied to the subject scores associated with the major principal components to identify regional patterns that revealed significant group differences.
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Also, regional patterns that had revealed baseline and treatment effects in previous studies of late-life depression were evaluated to determine if they showed comparable effects in the current data. Subject scores for two different a priori patterns were computed and submitted to ANOVA. The first pattern was a frontal/ posterior ratio, consisting of the average of the 10 frontal detectors (5 per hemisphere) divided by the average of the 22 posterior detectors (11 per hemisphere). This pattern highlights the antero–posterior gradient commonly found to be abnormal in major depression.1 Subjects were also scored for the degree of expression of a regional covariance pattern that involved specific prefrontal, temporal, and parietal detectors. In previous studies, this “depression profile” was specifically associated with CBF reductions in predominantly elderly, severely depressed inpatients.3,20 Paired t-tests were used to examine change between the time-points in the total sample. As an omnibus test of differences between Responders and Nonresponders in changes in rCBF, a repeated-measures ANOVA was conducted with response status as a between-subjects factor and region as the repeated-measures factor. An SSM analysis was also conducted on the change in CBF values from pre- to posttreatment, followed by a repeated-measures ANOVA to contrast Responders and Nonresponders in topography scores. Responders and Nonresponders were also contrasted in change for the a priori frontal ratio and “depression profile” scores. Significance values in all repeated-measure ANOVAs were based on the Huynh-Feldt adjustment. All statistical tests were two-tailed, with P set at ⱕ0.05. No correction was made for the number of statistical comparisons. All analyses were performed using SAS Version 6.12.21
RESULTS Comparison of Depressed Patients and Control Subjects Sample characteristics. Table 1 presents sample characteristics for the depressed and normal-control groups. The ANOVAs indicated that depressed patients had lower pCO2 values. There were no other significant differences.
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Cerebral Blood Flow and Antidepressants Comparison of Patients and Control Subjects in Baseline Cerebral Blood Flow Global cortical CBF averaged 46.51Ⳳ8.0 for the patients and 49.27Ⳳ9.5 for control subjects. There was no difference between the depressed and control groups in global CBF; the ANCOVA only yielded a significant effect for the covariate, pCO2, (F[1]⳱8.30; P⬍0.007) and a trend for a main effect of gender (F[1,35]⳱3.91; P⬍0.06). The omnibus repeated-measures ANOVA yielded a significant main effect of detector location (F[31, 1,116]⳱8.09; P⬍0.0001) and an interaction between diagnostic group (depressed vs. normal) and detector location (F[31, 1,116]⳱2.07; P⬍0.007). To characterize the nature of the topographic differences between patients and control subjects, the groups were compared in frontal CBF ratios, and SSM analyses were conducted. The ANOVA on the frontal ratio yielded a significant main effect of diagnostic group (F[1, 36]⳱7.94; P⬍0.008). Compared with control subjects (mean⳱1.03Ⳳ0.04), patients (mean⳱1.00Ⳳ0.03) had lower frontal ratios, indicating relative CBF reductions across the frontal cortex. An ANCOVA indicated that the groups did not differ in the SSM’s estimate of region-independent global CBF. Four topographic patterns were identified by SSM that accounted for 51.3% of the variance in regional CBF. A repeated-measures ANOVA on scores on these four topographic patterns produced a significant interaction between diagnostic group and topography (F[3, 108]⳱4.88; P⳱0.003), indicating that the groups differed in scores on specific topographies. Follow-up ANOVAs indicated that the depressed and control groups differed in manifestation of the first (F[1, 36]⳱4.77; P⬍0.04) and fourth (F[1, 36]⳱8.39; P⳱0.006) topograTABLE 1.
phies. Figure 1 presents the two topographic structures in which patients and control subjects differed at baseline. The difference in expression of the first topography reflected CBF reductions in patients in prefrontal and anterior temporal regions, with CBF preservation in posterior parietal and occipital regions. The difference in expression of the fourth topography was due to a pattern of CBF reductions in patients in selective frontal, superior temporal, and anterior parietal regions, with preservation in the right anterior temporal and left parieto-occipital region. We also contrasted the two groups in their expression of the “depression profile.” The region weights of this profile bore strong similarity to the fourth pattern extracted in the new blinded SSM analysis (r[30]⳱0.70; P⬍0.0001). Not surprisingly, therefore, there was a significant difference between the groups in the expression of this topographic abnormality (F[1, 36]⳱5.88; P⳱0.02), providing independent replication of this pattern of abnormality in an elderly outpatient sample.
Effects of Pharmacotherapy Sample characteristics. After the pharmacological trial, 11 patients were deemed Nonresponders (9 nortriptyline, 2 sertraline) and 9 were Responders (6 nortriptyline, 3 sertraline). There were no significant differences at baseline or after treatment between Responders and Nonresponders in age, gender, blood pressure, hemoglobin, or pCO2 values. Across the sample, there were no changes in these variables across the two time-points. Responders averaged an 80.42%(Ⳳ18.47%) decrease in Ham-D scores, whereas Nonresponders averaged a 20.80%(Ⳳ19.49%) decrease.
Characteristics of the depressed and normal-control sample
Age, years Gender, % female
Depressed Patients (nⴔ20)
Normal-Control Subjects (nⴔ20)
67.8Ⳳ6.1
67.3Ⳳ5.3
70
70
Systolic blood pressure, mm Hg
131.9Ⳳ17.0
131.4Ⳳ15.2 79.8Ⳳ5.8
Diastolic blood pressure, mm Hg
74.5Ⳳ7.9
pCO2, mm Hg*
34.5Ⳳ3.0
37.5Ⳳ2.7
Hemoglobin
14.4Ⳳ1.1
14.7Ⳳ0.6
Ham-D
23.4Ⳳ6.1
—
Note: pCO2⳱End-tidal partial pressure of carbon dioxide; Ham-D⳱Hamilton Rating Scale for Depression. *Groups differed in pCO2 (F[1, 36]⳱9.36; P⳱0.004).
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Nobler et al. FIGURE 1.
Two topographic profiles in which elderly depressed patients differed from normal-control subjects
Global cerebral blood flow. The group as a whole did not evidence change in global CBF over the treatment course. Responders and Nonresponders did not differ in change in global CBF. Topographic CBF: traditional statistics. The omnibus repeated-measures ANOVA yielded a significant interaction between response status and brain region (F[31, 496]⳱1.82; P⳱0.005), indicating that Responders and Nonresponders differed in the topography of CBF change. Although Responders (mean⳱0.014Ⳳ0.034) showed a decrease in the frontal ratio, whereas Nonresponders were unchanged (mean⳱ –0.004Ⳳ0.024), the groups did not differ significantly in this measure.
Note: Purple and blue colors (negative values) reflect areas of rCBF deficit in the depressed sample; colors in the red range (positive values) denote regions of preserved rCBF. The first pattern indicates that the depressed sample had reduced perfusion in selective prefrontal and anterior temporal regions, with CBF preservation in posterior parietal and occipital regions. The fourth topographic pattern reflects rCBF reductions in selective frontal, superior temporal, and anterior parietal regions, with preservation in the right anterior temporal and left parieto-occipital region.
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Topographic CBF: Scaled Subprofile Model (SSM). Four topographic patterns were identified by the blind SSM analysis, accounting for 51% of the variance in CBF regional changes from baseline. An omnibus ANOVA indicated that Responders and Nonresponders differed in scores on these patterns (F[1, 16]⳱12.20; P⳱0.003). Follow-up ANOVAs indicated that Responders and Nonresponders differed significantly only in the expression of the first pattern (F[1, 16]⳱10.31; P⬍0.006; Figure 2). This difference was due principally to Responders’ manifesting CBF reductions in specific prefrontal and anterior temporal regions, a pattern of change not seen in Nonresponders. To further test this association, we correlated scores across the sample for change in this topography with depression severity ratings. Greater expression of this pattern of CBF reduction in selective prefrontal and anterior temporal regions was associated with greater percentage change in Ham-D scores from baseline (r[18]⳱ ⳮ0.47; P⬍0.04) and lower posttreatment absolute Ham-D scores (r[18]⳱0.51; P⬍0.02). We repeated the omnibus repeated-measures ANOVA using medication condition (nortriptyline vs. sertraline) as an additional between-subjects factor. Results were unchanged; type of medication had no impact on the relation with response. Responders to nortriptyline (mean⳱ ⳮ14.57Ⳳ26.35) and sertraline (mean⳱ ⳮ8.54Ⳳ17.12) both had distinctly different mean scores on this topography than Nonresponders to nortriptyline (mean⳱10.77Ⳳ26.58) and sertraline (mean⳱8.06Ⳳ17.81). The sample as a whole did not change in expression of the “depression profile,” and there was no difference between Responders and Nonresponders in change in this measure.
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Cerebral Blood Flow and Antidepressants DISCUSSION The major findings of this study were that elderly outpatients in an episode of major depression did not differ from matched normal-control subjects in resting global cortical CBF, but had significant topographic reductions in CBF, principally involving frontal, temporal, and anterior parietal cortical regions. Furthermore, treatment with antidepressant medications did not result in reversal of baseline deficits. Instead, pharmacotherapy responders showed further CBF reductions in selective frontal and anterior temporal regions. The magnitude of change in this pattern was correlated with the extent of clinical improvement. Several previous studies reported global CBF or CMR deficits in samples of elderly depressed patients.3–6 Much of this work focused on severely depressed inpatients, which may account for the absence of a global deficit in our moderately depressed outpatient sample. We did observe topographic abnormality in the patient sample at baseline. This topographic abnormality was FIGURE 2.
A topographic pattern that distinguished Responders and Nonresponders in change in rCBF
Note: Purple and blue colors (negative values) reflect areas of rCBF decrease in Responders. After antidepressant treatment, Responders had rCBF decreases in selective frontal and anterior temporal regions and right occipital area.
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expressed in reduced values for an a priori frontal ratio in a blind SSM analysis, and when we contrasted scores on a previously obtained “depression profile” in patients and control subjects. The baseline topographic deficit in the depressed sample involved CBF reductions in selective frontal, temporal, and anterior parietal regions. This pattern broadly concurs with the findings of a large number of brain-imaging studies of major depression across diverse age ranges,1,2 and specifically with studies of late-life depression.3–6,11 Since the determination of rCBF by the Xenon-inhalation method is based on the rate of clearance in perfused tissue, it is unlikely that differences between the patient and control groups in cerebral atrophy contributed to the topographic differences in blood flow. Preclinical studies have shown that antidepressant medications, particularly tricyclics, have pronounced effects on capillary permeability, CBF, and CMR,22–25 and chronic treatment often results in reduced functional activity in a regionally distributed fashion. In contrast, studies of changes in CBF and CMR after effective pharmacological treatment of major depression have yielded inconsistent results. Some have argued that functional activity is decreased, particularly in ventrolateral and orbital-frontal cortex.2 However, several studies have shown no change in at least some baseline cortical abnormalities,26–29 whereas other studies have found at least partial reversal of baseline cortical deficits, particularly in dorsolateral prefrontal cortex30,31 or complex patterns of increases and decreases.32 Few of these studies concentrated on late-life depression, and, in general, sample sizes have been small, with heterogeneous imaging and treatment methods. In contrast, findings appear to be more consistent with ECT. With one exception,33 imaging studies have found decreased CBF or CMR in anterior cortical regions acutely and in the short term after ECT.34–36 We showed that during the week after ECT, there was little change in expression of the baseline abnormality (the “depression profile”), but marked CBF reductions in specific frontal regions in patients who responded to ECT.13 These findings regarding response to ECT parallel the findings of this study with pharmacotherapy. The topography of rCBF reductions after response to pharmacotherapy in this study was highly similar to the topography linked with response to ECT. The limitations of this study include relatively small sample size, the baseline difference between the samples in end-tidal pCO2, and the use of a low-resolution
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Nobler et al. imaging technique with restriction to cortical activity. Nonetheless, the findings suggest that, as with ECT, successful pharmacological treatment of late-life major depression may not result in reversal of baseline functional imaging deficits. There are a number of possibilities that might account for this seemingly paradoxical phenomenon. In each case, there is the assumption that the state of depression is characterized by increased activity in specific neural regions—increased activity that is reversed with successful treatment. First, some of the imaging deficits observed at baseline in late-life depression may reflect trait-level abnormalities, perhaps tied to vascular pathology.37 These prominent trait-level deficits would obscure state-related increased activity. Alternatively, the baseline deficits may reflect secondary compensatory changes in reaction to the onset of the state
of depression. Such compensatory reductions in neural activity would similarly obscure the original state-related increases and essentially mimic the more powerful action of effective treatments. Finally, a third alternative is that the pathways involved in the therapeutic action of antidepressant treatments may be distinct from those involved in the pathophysiology of the illness. This work was presented in part at the Annual Meeting of the American Psychiatric Association, Toronto, Canada, May 30–June 4, 1998. The work was supported in part by grants R01 MH55646 (HAS) and K08 MH01244 (MSN) from the National Institute of Mental Health, a Young Investigator Award from the National Association for Research in Schizophrenia and Depression (MSN), and the Paul Beeson Physician Faculty Scholars in Aging Research Award (MSN).
References 1. Sackeim HA, Prohovnik I: Brain imaging studies in depressive disorders, in Biology of Depressive Disorders. Edited by Mann JJ, Kupfer D. New York, Plenum, 1993, pp 205–258 2. Drevets WC: Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 1998; 49:341–361 3. Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders, I: comparison of major depressives and normal controls at rest. Arch Gen Psychiatry 1990; 47:60–70 4. Upadhyaya AK, Abou-Saleh MT, Wilson K, et al: A study of depression in old age using single-photon emission computerised tomography. Br J Psychiatry 1990; 157:76–81 5. Kumar A, Newberg A, Alavi A, et al: Regional cerebral glucose metabolism in late-life depression and Alzheimer’s disease: a preliminary positron-emission tomography study. Proc Natl Acad Sci U S A 1993; 90:7019–7023 6. Lesser IM, Mena I, Boone KB, et al: Reduction of cerebral blood flow in older depressed patients. Arch Gen Psychiatry 1994; 51:677–686 7. Bench CJ, Friston KJ, Brown RG, et al: Regional cerebral blood flow in depression measured by positron-emission tomography: the relationship with clinical dimensions. Psychol Med 1993; 23:579–590 8. Curran SM, Murray CM, Van Beck M, et al: A single photon-emission computerised tomography study of regional brain function in elderly patients with major depression and with Alzheimertype dementia. Br J Psychiatry 1993; 163:155–165 9. Martin AJ, Friston KJ, Colebatch JG, et al: Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 1991; 11:684–689 10. Moeller JR, Ishikawa T, Dhawan V, et al: The metabolic topography of normal aging. J Cereb Blood Flow Metab 1996; 16:385– 398 11. Nobler MS, Mann JJ, Sackeim HA: Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging. Brain Res Brain Res Rev 1999; 30:250–263 12. Nobler MS, Sackeim HA: Mechanisms of action of electroconvulsive therapy: functional brain imaging studies. Psychiatr Ann 1998; 28:23–29
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13. Nobler MS, Sackeim HA, Prohovnik I, et al: Regional cerebral blood flow in mood disorders, III: effects of treatment and clinical response in depression and mania. Arch Gen Psychiatry 1994; 51:884–897 14. Rubin E, Sackeim HA, Nobler MS, et al: Brain imaging studies of antidepressant treatments. Psychiatr Ann 1994; 24:653–658 15. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278–296 16. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–571 17. Endicott J, Spitzer RL: A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978; 35:837–844 18. Prohovnik I, Knudsen E, Risberg J: Accuracy of models and algorithms for determination of fast-compartment flow by non-invasive 133-Xe clearance, in Functional Radionuclide Imaging of the Brain. Edited by Magistretti P. New York, Raven, 1983, pp 87–115 19. Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders, II: comparison of major depression and Alzheimer’s disease. J Nucl Med 1993; 34:1090–1101 20. Moeller J, Strother S, Sidtis J, et al: Scaled Subprofile Model: a statistical approach to the analysis of functional patterns in positron-emission tomographic data. J Cereb Blood Flow Metab 1987; 7:649–658 21. SAS/STAT User’s Guide, Version 6, 4th Edition. Cary, NC, SAS Institute, Inc., 1998 22. Preskorn SH, Raichle ME, Hartman BK: Antidepressants alter cerebrovascular permeability and metabolic rate in primates. Science 1982; 217:250–252 23. Gerber JC, Choki J, Brunswick DJ, et al: The effects of antidepressant drugs on regional cerebral glucose utilization in the rat. Brain Res 1983; 269:319–325 24. Caldecott-Hazard S, Mazziotta J, Phelps M: Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci 1988; 8:1951–1961 25. Freo U, Pietrini P, Dam M, et al: The tricyclic antidepressant clomipramine dose-dependently reduces regional cerebral meta-
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Cerebral Blood Flow and Antidepressants bolic rates for glucose in awake rats. Psychopharmacology 1993; 113:53–59 26. Reischies FM, Hedde JP, Drochner R: Clinical correlates of cerebral blood flow in depression. Psychiatry Res 1989; 29:323–326 27. Hurwitz TA, Clark C, Murphy E, et al: Regional cerebral glucose metabolism in major depressive disorder. Can J Psychiatry 1990; 35:684–688 28. Martinot JL, Hardy P, Feline A, et al: Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am J Psychiatry 1990; 147:1313–1317 29. Goodwin GM, Austin MP, Dougall N, et al: State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon-emission tomography in major depression before and after treatment. J Affect Disord 1993; 29:243–253 30. Bench CJ, Frackowiak RS, Dolan RJ: Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995; 25:247–261 31. Passero S, Nardini M, Battistini N: Regional cerebral blood flow changes following chronic administration of antidepressant
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drugs. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19:627–636 32. Buchsbaum M, Wu J, Siegel B, et al: Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 1997; 41:15–22 33. Bonne O, Krausz Y, Shapira B, et al: Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy. J Nucl Med 1996; 37:1075–1080 ¨ ld P, Gustafson L, Risberg J, et al: Acute and late effects 34. Silfverskio of electroconvulsive therapy: clinical outcome, regional cerebral blood flow, and electroencephalogram. Ann NY Acad Sci 1986; 462:236–248 35. Rosenberg R, Vostrup S, Andersen A, et al: Effect of ECT on cerebral blood flow in melancholia assessed with SPECT. Convulsive Therapy 1988; 4:62–73 36. Volkow ND, Bellar S, Mullani N, et al: Effects of electroconvulsive therapy on brain glucose metabolism: a preliminary study. Convulsive Therapy 1988; 4:199–205 37. Alexopoulos GS, Meyers BS, Young RC, et al: “Vascular depression” hypothesis. Arch Gen Psychiatry 1997; 54:915–922
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