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Acute and Chronic Effects of Citalopram on Cerebral Glucose Metabolism in Geriatric Depression
Acute and Chronic Effects of Citalopram on Cerebral Glucose Metabolism in Geriatric Depression Gwenn S. Smith, Ph.D., Elisse Kramer, Ph.D. Carol R. Hermann, M.D., Sara Goldberg, B.A. Yilong Ma, Ph.D., Vijay Dhawan, Ph.D. Anna Barnes, Ph.D., Thomas Chaly, Ph.D. Abdel Belakhleff, Ph.D., Fouzia Laghrissi-Thode, M.D. Blaine Greenwald, M.D., David Eidelberg, M.D. Bruce G. Pollock, M.D., Ph.D.
Objective: In vivo studies of serotonin function have been limited by the lack of safe and selective pharmacologic agents and availability of suitable radiotracers. In the present study, the authors evaluated the cerebral metabolic effects of acute and continued administration of the selective serotonin reuptake inhibitor citalopram in patients with geriatric depression as a potential marker of serotonin dysfunction. Methods: Six patients with geriatric depression and five comparison subjects underwent two resting positron emission tomography (PET) studies, performed after administration of a placebo infusion (Day 1) and a citalopram infusion (40 mg, Day 2). The patients were re-scanned after 8 weeks of treatment with the oral medication. Results: The elderly comparison subjects demonstrated greater right-hemisphere cortical decreases than the patients. The depressed patients demonstrated greater left-hemisphere cortical decreases than comparison subjects. The depressed patients demonstrated greater increases in the right putamen and left occipital cortex. After 8 weeks of citalopram treatment, regional decreases and increases in metabolism were observed. Conclusion: These findings suggest regional deficits and also compensatory responses in the acute metabolic response to citalopram in the patients. These preliminary results suggest that the cerebral metabolic response to citalopram may be a useful marker of the pathophysiology of serotonin function in geriatric depression. (Am J Geriatr Psychiatry 2002; 10:715–723)
Received March 27, 2002; revised July 9, 2002; accepted July 30, 2002. From the Departments of Psychiatry Research (GSS), and Geriatric Psychiatry (EK,BG), Hillside Hospital, Glen Oaks, New York, and Center for Neurosciences (GSS,CRH,SG,YM,VD,AB,TC,ABDE) of the North Shore–Long Island Jewish Health System; Hoffman-La Roche Ltd. (FL-T), Basel, Switzerland; Geriatric Psychopharmacology Laboratory, Western Psychiatric Institute and Clinic, Departments of Psychiatry, Pharmacology, and Pharmaceutical Sciences (BGP), University of Pittsburgh School of Medicine, Pittsburgh, PA. Address correspondence to Dr. Smith, Department of Psychiatry Research, Hillside Hospital and the Neuroscience Institute of the North Shore–Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004. e-mail: [email protected] Copyright 䉷 2002 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 10:6, November-December 2002
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Citalopram and Cerebral Glucose Metabolism
T
here is a compelling need to understand the mechanisms that underlie the variability of treatment response in geriatric depression.1 Even though there are effective antidepressant agents available, 25 percent of patients are still refractory to treatment, despite adequate dosing.2 In an effort to understand the pathophysiology of depression, the majority of studies have focused on the evaluation of the serotonin system in midlife depressed patients. The evidence for serotonergic dysfunction in depression has been reviewed extensively.3–6 These investigations have involved neuroimaging and neuroendocrine methods combined with acute pharmacologic interventions directed at the serotonin system.7–11 Specifically, these studies have involved the measurement of the neuroendocrine response (prolactin or cortisol) or the cerebral metabolic response to administration of serotonergic agents such as fenfluramine and mCPP (m-chlorophenylpiperazine). Some of these acute intervention studies have demonstrated serotonin hypofunctioning to a greater extent in patients who respond poorly to antidepressant treatment.8,9,11 These studies are based on the premise that the acute central nervous system (CNS) response to the administration of agents that enhance serotonin activity represents the functional capacity of the serotonin system, which may be related to the pathophysiology of the serotonin system and presumably to the clinical response to antidepressant treatment. Other neurotransmitter systems, including dopamine and acetylcholine, have been evaluated to a more limited extent. Thus far, the studies that have combined either neuroimaging or neurocognitive measures with acute pharmacologic interventions in these systems have not demonstrated differences in response between patients and comparison subjects,12–14 despite the observations that pharmacologic alterations of these systems affect mood.15–17 Since the primary target of antidepressant medications is the serotonin system, a greater understanding of serotonergic dysfunction in patients with geriatric depression may provide insight into a neurobiologic substrate related to treatment response variability. Because the clinical heterogeneity of depressed patients is greater in geriatric depressed patients, factors such as age at onset, treatment history, and medical comorbidity must be considered carefully in designing neurobiological studies. The ability to study serotonin function in vivo has been limited by
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the lack of availability of safe and selective pharmacologic agents, particularly for use in elderly subjects. Also, there have been difficulties in developing suitable radiotracers for the in-vivo imaging of the serotonin system, such as the lack of selective pharmacologic agents for radiolabeling, the low ratios of specific to nonspecific binding of the radiotracers, and the presence of radiolabeled metabolites that hinder quantification of radiotracer binding. The purpose of the current study was to use positron emission tomography (PET) to measure the acute and chronic cerebral metabolic effects of the most selective of the serotonin reuptake inhibitors (SRIs), citalopram (Celexa威), in patients with geriatric depression. The availability of citalopram for intravenous (IV) and oral administration is a unique opportunity to measure the acute effects after administration of a single IV dose, as well as the chronic effects after treatment with the oral medication. Citalopram was also chosen because it is an effective antidepressant medication and is extremely well tolerated across the lifespan. In a recent survey of 50 experienced geriatric psychiatrists, citalopram received the highest ratings for efficacy and tolerability for the treatment of depression in elderly patients.18 The decision to measure cerebral glucose metabolism in this study was based on the current lack of a serotonin-receptor radiotracer to directly measure endogenous serotonin concentrations.19,20 Compared with measures of serotonin transporter or receptor binding, measures of glucose metabolism in the resting state have demonstrated sensitivity in monitoring the effects of antidepressant treatment and also in predicting the outcome of antidepressant treatment on the basis of either pretreatment metabolic rates or changes in metabolism after an acute intervention (e.g., after total sleep deprivation [TSD] or 1 week of antidepressant treatment).21–23 We hypothesized that acute and chronic citalopram administration would be associated with a progressive reduction in cerebral metabolism in cortical areas, including the superior and middle prefrontal and parietal (precuneus) cortices,22,23 which we have found to be hypermetabolic in geriatric depressed patients (before treatment) and to be affected by pharmacologic treatment and TSD. On the basis of previous studies, we also hypothesized that the acute decreases in metabolism would be greater in magnitude, particularly in anterior brain regions, in the comparison subjects than in the patients.
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Smith et al. METHODS Study Design Patients and comparison subjects underwent two PET scans on two consecutive days to measure the effects of placebo/citalopram administration on cerebral glucose metabolism, as described previously.24 After completion of the first two PET scans, the patients underwent 12 weeks of treatment with oral citalopram and were monitored clinically on a weekly basis. After 8 weeks of treatment, the patients were re-scanned to measure the effects of 8 weeks of citalopram treatment on cerebral metabolism. The decision to re-scan patients at 8 weeks was based on the observation across studies that this is the time when patients will demonstrate significant clinical improvement, if they respond at all.25,26 Subject Screening and Selection Patients and comparison subjects underwent psychiatric evaluation (including a structured clinical interview [SCID27]), laboratory testing (including complete blood count and blood chemistry, including glucose levels and thyroid function tests), toxicology screening, and magnetic resonance imaging (MRI) scans (GE 1.5T) before the PET scans. Depressed patients and comparison subjects were recruited from the Geriatric Psychiatry Outpatient Clinic at Hillside Hospital and also through advertisements in the community. Six patients with depression (one man/five women; mean age 68.8 years, standard deviation [SD]: 5.7 years) who met DSM-IV criteria for current major depressive episode (nonbipolar, nonpsychotic) were enrolled. We enrolled five comparison subjects who did not have a previous or current psychiatric illness (two men/three women; mean age 64.8 years, SD: 4.3 years). The differences in age between the two groups were not statistically significant (t[9]⳱ –1.30; p⬎0.05). Subjects who had a previous or current neurological disorder or substance abuse or who were not medically stable (including a current diagnosis of diabetes not controlled by diet) were excluded from the study. None of the patients or comparison subjects had previous or current cerebrovascular, cardiovascular, or thyroid disease, and none were diabetic, except one patient who was being treated for hypertension with a calcium channel blocker.
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All of the patients had an age at onset of illness (defined as age at first treatment by a mental health professional) of 60 or older. Three patients had never been treated with psychotropic drugs. Of the three patients previously treated, one patient had been treated with fluoxetine and then sertraline until 6 months before enrolling in the study. Another patient had taken sertraline 2 years before entering the study. The third patient had been treated with nortriptyline for 2 years, until 2 weeks before the PET scan (at which time the nortriptyline concentrations in plasma were undetectable). In each case, the onset of depression (including the current episode) in the patients was not associated with the onset of a medical condition. After a complete description of the study to the subjects, we obtained written informed consent according to procedures established by the Institutional Review Board and the Radiation Safety Committee of the North Shore–Long Island Jewish Health System. Acute and Chronic Citalopram Interventions For the acute studies, 40 mg of citalopram was infused over 60 minutes, and the radiotracer was injected 15–30 minutes after the end of the infusion. After administration of the 40 mg intravenous dose of citalopram, steady-state plasma concentrations (up to 3 hours post-infusion) and an increase in cortisol and prolactin concentrations (until 60 minutes post-infusion) were observed.24,27 Two days after the IV administration of citalopram, patients began treatment with citalopram at 10 mg per day for 3 days. The dose was increased to 20 mg on the fourth day. If significant improvement was not observed at the 20-mg dose after 4 weeks of treatment (Clinical Global Impression Scale [CGI28]) improvement rating of 3 or greater), the dose was increased to 30 mg, and then, if necessary, to 40 mg. The mean dose at 8 weeks of treatment, at the time of the PET scan, was 30 mg (SD: 7.0 mg), and after 12 weeks of treatment, the mean dose was 32 mg (SD: 8.0 mg). To measure the effects of acute citalopram administration on mood and anxiety, several items from a visual analog scale (VAS29) were administered before and at the end of the placebo/citalopram infusions and at the end of the PET scans. Patients were seen in the Geriatric Outpatient Clinic of Hillside Hospital on a weekly basis, at which time clinical ratings for depressive and anxiety symptoms were performed (Hamilton Rating Scale for Depression–24 item [Ham-D30], Hamil-
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Citalopram and Cerebral Glucose Metabolism ton Anxiety Rating Scale [Ham-A31], Beck Depression Inventory [BDI32], CGI, and Geriatric Depression Scale [GDS33]). PET Imaging Procedures The PET scans were performed with a GE Advance Tomograph at North Shore University Hospital as described previously.24 Briefly, all PET studies began at the same time of day (10 A.M.). Upon arrival at the laboratory, one catheter was placed in a vein in the left arm for radiotracer and placebo/citalopram infusion, and a second catheter was placed in a vein in the right arm for sampling of citalopram and neuroendocrine levels. The study was single-blinded, in that the subjects were told that they would receive either citalopram or placebo before each study, but the investigator knew the identity of the infusion. The infusions of placebo (250 ml of saline) or citalopram (40 mg of the drug diluted in 250 ml saline) were performed over 60 minutes. Fifteen to 30 minutes after the end of the infusion of placebo/citalopram, 5 mCi of [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) was injected as an intravenous bolus. Subjects were positioned in the GE Advance Tomograph. A 10-minute transmission scan and a 5-minute two-dimensional emission scan were acquired first to perform photon-attenuation correction.34 A threedimensional emission scan began at 35 minutes after radiotracer injection and lasted for 10 minutes. At the end of the PET scan, subjects were removed from the PET scanner, and the intravenous lines were removed after completion of the blood sampling. Subjects were debriefed as to their perception of the study and observed for a minimum of 1 hour after the PET scan was completed. Data and Image Analysis Glucose metabolic rates were calculated on a pixelby-pixel basis as described previously.24,35 Data-processing was performed with the statistical parametric mapping program (SPM99).36 The PET scans for each subject were aligned and nonlinearly warped into Talairach space. The images were smoothed with an isotropic Gaussian kernel (FWHM 8-mm for all planes). The glucose metabolic rates were normalized by scaling to a common mean value across all scans. Differences between treatment conditions (placebo/citalopram) were compared by the paired t-test option in SPM99.
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The between-condition comparisons were considered significant at a t threshold greater than 3.30 (z⳱2.81; p⬍0.005; two-tailed, uncorrected for multiple independent comparisons). Given the small sample sizes for the study, a more stringent probability value was used to correct for the number of comparisons performed.
RESULTS The VAS scores for the drug and placebo conditions for the patients and comparison subjects are shown in Table 1. The patients demonstrated an improvement in the ratings of “Happy” (an increase in scores reflects greater ratings of Happy), “Sad,” and “Anxious” for the citalopram condition, as compared with the placebo condition, whereas the scores for the comparison subjects were not different across conditions. However, the differences between the VAS ratings performed at comparable times between the placebo and citalopram treatment did not reach statistical significance for either group (comparison subjects: pre-infusion: Anxious: t[5]⳱1.4; p⬎0.05; Depressed: t[5]⳱1.0; p⬎0.05; Happy: t[5]⳱ –0.78; p⬎0.05; post-infusion: Anxious: t[5]⳱ –0.39; p⬎0.05; Depressed: t[5]⳱1.0; p⬎0.05; Happy: t[5]⳱ –0.76; p⬎0.05; post-scan: Anxious: t[5]⳱0.38; p⬎0.05; Depressed: t[5]⳱ –1.0; p⬎0.05; Happy: t[5]⳱1.0; p⬎0.05; patients pre-infusion: Anxious: t[5]⳱0.79; p⬎0.05; Depressed: t[5]⳱0.0; p⬎0.05; Happy t[5]⳱2.7; p⬎0.05; post-infusion: Anxious: t[5]⳱ TABLE 1.
Visual analog scale (VAS) ratings, mean (standard deviation)
Elderly comparison subjects Placebo Pre-infusion End of infusion Post-scan Citalopram Pre-infusion End of infusion Post-scan Geriatric depression Placebo Pre-infusion End of infusion Post-scan Citalopram Pre-infusion End of infusion Post-scan
Anxious
Depressed
Happy
2.3 (2.4) 1.6 (2.0) 1.7 (1.5)
0.9 (2.1) 0.4 (0.7) 0.07 (0.3)
6.9 (1.5) 5.9 (2.0) 6.9 (1.9)
1.9 (2.3) 1.3 (2.2) 0.9 (2.1)
0.6 (1.2) 0.4 (0.8) 0.5 (0.9)
6.7 (2.3) 6.7 (2.0) 6.7 (1.9)
5.7 (2.3) 4.2 (3.4) 5.5 (3.1)
4.1 (3.1) 3.5 (3.3) 3.7 (2.7)
3.3 (1.0) 1.8 (1.2) 2.0 (1.9)
4.2 (2.9) 3.7 (2.5) 2.8 (1.9)
4.1 (3.5) 3.5 (2.3) 2.7 (2.9)
1.2 (1.5) 2.2 (2.0) 3.2 (1.9)
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Smith et al. –0.24; p⬎0.05; Depressed: t[5]⳱ –0.13; p⬎0.05; Happy: t[5]⳱0.21; p⬎0.05; post-scan: Anxious: t[5]⳱1.8; p⬎0.05; Depressed: t[5]⳱0.87; p⬎0.05; Happy: t[5]⳱ –0.76; p⬎0.05). The clinical ratings for the patients during 8 weeks of citalopram treatment are shown in Table 2. The baseline Ham-D scores for the six patients were 28, 23, 31, 28, 27, and 25. The patients’ Week 12 scores were 1, 3, 8, 3, 2, and 5, respectively. For the Ham-D, the ratings were significantly reduced from 1 to 12 weeks after initiation of treatment (Week 1: t[5]⳱2.7; p⬍0.05; Week 2: t[5]⳱2.6; p⬍0.05; Week 3: t[5]⳱ 4.1; p⬍0.01; Week 4: t[5]⳱4.0; p⬍0.05; Week 5: t[5]⳱3.2; p⬍0.05; Week 6: t[5]⳱3.7; p⬍0.05; Week 7: t[5]⳱8.7; p⬍0.001; Week 8: t[5]⳱8.1; p⬍0.001; Week 9: t[5]⳱7.6; p⬍0.001; Week 10: t[5]⳱7.9; p⬍0.001; Week 11: t[5]⳱10.6; p⬍0.001; Week 12: t[5]⳱9.7; p⬍0.001). For the Ham-A, the ratings were significantly reduced from baseline on Weeks 1, 3, 4, 6, and thereafter, significant at the p⬍0.05 and p⬍0.01 levels (Week 1: t[5]⳱3.9; p⬍0.05; Week 2: t[5]⳱1.5; p⬎0.05; Week 3: t[5]⳱2.9; p⬍0.05; Week 4: t[5]⳱ 3.1; p⬍0.05; Week 5: t[5]⳱2.1; p⬎0.05; Week 6: t[5]⳱3.3; p⬍0.05; Week 7: t[5]⳱5.7; p⬍0.01; Week 8: t[5]⳱5.0; p⬍0.01; Week 9: t[5]⳱5.2; p⬍0.01; Week 10: t[5]⳱6.3; p⬍0.01; Week 11: t[5]⳱3.9; p⬍0.01; Week 12: t[5]⳱4.6; p⬍0.01). For the BDI, the ratings were significantly reduced from baseline on Weeks 4, 6, 7, 9, and thereafter, but these differences were significant at the p⬍0.05 and
p⬍0.01 levels only (Week 1: t[5]⳱0.5; p⬎0.05; Week 2: t[5]⳱1.1; p⬎0.05; Week 3: t[5]⳱1.8; p⬎0.05; Week 4: t[5]⳱3.2; p⬍0.05; Week 5: t[5]⳱1.5; p⬎0.05; Week 6: t[5]⳱4.2; p⬍0.01; Week 7: t[5]⳱3.4; p⬍0.05; Week 8: t[5]⳱2.4; p⬎0.05; Week 9: t[5]⳱5.2; p⬍0.01; Week 10: t[5]⳱3.8; p⬍0.05; Week 11: t[5]⳱4.9; p⬍0.01; Week 12: t[5]⳱6.0; p⬍0.01). For the Geriatric Depression Scale (GDS), the ratings were significantly reduced from 6 to 12 weeks after initiation of treatment (Week 6: t[5]⳱3.4; p⬍0.05; Week 7: t[5]⳱8.8; p⬍0.001; Week 8: t[5]⳱19.3; p⬍0.001; Week 9: t[5]⳱16.0; p⬍0.001; Week 10: t[5]⳱8.8; p⬍0.001; Week 11: t[5]⳱13.1; p⬍0.001; Week 12: t[5]⳱21.2; p⬍0.001. All of the six patients would have met the criteria for treatment response used in previous studies: a 50% reduction in Ham-D scores, a HamD score ⱕ10, and a CGI rating of “Much Improved” or “Very Much Improved.”1,25 The between-group comparisons for the acute citalopram effect are shown in Table 3. Topographic maps of the greater and lesser areas of decrease in the patients’ metabolism relative to comparison subjects are shown in Figure 1. The comparison subjects demonstrated greater metabolic decreases than the patients in right (middle frontal, fusiform, inferior parietal, precuneus, and supramarginal) cortices, whereas the patients showed greater decreases than the comparison subjects in left (middle frontal and inferior parietal) cortices. The patients demonstrated greater increases than the comTABLE 3.
TABLE 2. Week of Treatment Baseline 1 2 3 4 5 6 7 8 9 10 11 12
Effects of continued citalopram treatment on depressive symptoms, mean (standard deviation) Ham-D
Ham-A
BDI
GDS
27.0 (2.8) 19.0 (5.3) 19.8 (5.2) 13.7 (6.2) 11.5 (8.8) 11.8 (9.2) 8.8 (8.6) 4.8 (4.5)* 4.6 (4.4)* 4.0 (4.3) 4.2 (4.6)* 3.8 (3.1)* 3.4 (2.7)*
15.0 (5.9) 8.8 (4.5) 10.2 (6.2) 8.7 (6.0) 5.5 (4.6) 7.5 (6.4) 4.6 (4.2) 3.8 (6.8) 4.6 (5.2) 3.0 (2.8) 3.2 (4.5) 5.0 (3.1) 3.4 (2.9)
10.3 (2.4) 9.7 (3.9) 7.8 (4.1) 6.8 (4.8) 6.2 (4.6) 6.0 (7.0) 4.3 (3.6) 1.6 (3.0) 2.0 (4.0) 1.8 (2.2) 2.2 (3.0) 2.4 (2.3) 1.2 (1.8)
22.2 (3.5) 16.7 (4.0) 16.2 (5.9) 16.2 (6.4) 14.2 (8.2) 12.6 (7.1) 11.5 (6.8) 5.6 (4.8)* 4.0 (5.0)* 4.8 (5.1)* 5.2 (6.7)* 4.2 (5.3)* 3.6 (5.1)*
Note: Ham-D: Hamilton Rating Scale for Depression; Ham-A: Hamilton Anxiety Rating Scale; BDI: Beck Depression Inventory; GDS: Geriatric Depression Scale. *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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Cerebral-metabolic effects of acute citalopram administration relative to placebo: comparisons between patients and comparison subjects
Greater decreases in comparison subjects than patients 38, 54, 18 Right-middle-frontal cortex (BA 10) 26, ⳮ40, ⳮ14 Right fusiform cortex 48, ⳮ40, 44 Right inferior parietal lobule (BA 40) 24, ⳮ54, 44 Right parietal cortex (precuneus; BA 07) 56, ⳮ38, 32 Right parietal cortex (supramarginal cortex)
4.16 3.52 3.60 3.18 3.05
Greater decreases in patients than in comparison subjects ⳮ44, 50, ⳮ10 Left-middle-frontal cortex ⳮ48, 34, 18 Left-middle-frontal cortex ⳮ36, ⳮ44, 42 Left inferior-parietal lobule
2.97 3.03 4.37
Greater increases in patients than in comparison subjects 24, 16, 2 Right putamen 24, 2, 10 Right putamen 30, ⳮ66, ⳮ10 Right occipital cortex 26, ⳮ54, ⳮ10 Right occipital cortex (BA 19) ⳮ16, ⳮ64, 4 Left occipital cortex ⳮ14, ⳮ82, ⳮ28 Left cerebellum
3.88 3.59 3.37 3.17 3.47 2.94
Note: Values in first column are Talairach coordinates (mm). *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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Citalopram and Cerebral Glucose Metabolism FIGURE 1.
Changes in cerebral glucose metabolism in geriatric depressed patients compared with elderly control subjects, superimposed on an MRI template
Note: The image on the left shows greater decreases in patients than in control subjects. The image on the right shows greater decreases in control subjects than in patients.
parison subjects in the right putamen, bilaterally in the occipital cortex, and left cerebellum. Comparing 8 weeks of citalopram treatment with baseline (placebo condition, as shown in Table 4 and Figure 2), reductions were observed in the right anterior cingulate cortex, bilaterally in the superior frontal cortices, right inferior frontal cortex, right superior temporal cortex, left middle temporal cortex, right insula, left post-central cortex, right parahippocampal gyrus, and right midbrain. Increases were observed in the
TABLE 4.
Cerebral-metabolic effects of 8 weeks of citalopram treatment relative to baseline in patients
Decreases 4, 42, 6 14, 40, 6 34, 42, ⳮ16 34, 20, ⳮ12 ⳮ22, 44, 16 ⳮ50, ⳮ18, 48 36, ⳮ12, 16 52, ⳮ48, 18 ⳮ40, ⳮ10, ⳮ12 28, 6, ⳮ18 0, ⳮ28, ⳮ20 4, ⳮ14, ⳮ8
Right anterior cingulate (BA 24) Right anterior cingulate Right superior frontal cortex Right inferior frontal cortex Left superior frontal cortex Left post-central cortex (BA 5) Right insula (BA 13) Right superior temporal cortex Left middle-temporal cortex Right parahippocampal gyrus Right brainstem (pons) Right brainstem (midbrain)
4.37 3.41 3.28 3.79 3.92 3.21 4.13 3.16 3.00 2.89 4.23 3.56
Increases 32, ⳮ50, 52 44, ⳮ44, 38 ⳮ34, ⳮ80, ⳮ2 24, ⳮ2, 10 24, 8, 8 20, ⳮ28, 8
Right superior parietal lobule (BA 7) Right inferior parietal lobule Left occipital cortex Right putamen Right putamen Right thalamus (pulvinar)
3.69 3.31 3.26 3.05 2.82 2.82
Note: Values in first column are Talairach coordinates (mm). *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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right superior and inferior parietal lobules, left occipital cortex, right putamen, right thalamus, and left cerebellum. Some homologous regions showed effects that were slightly above the significance threshold used (p⬍0.007); specifically, the left anterior cingulate cortex, left putamen, and right occipital cortex.
DISCUSSION The acute administration of citalopram improved mood and anxiety ratings (below statistical significance) in the patients, but not in the comparison subjects. Since it was not possible to randomize the order of placebo and citalopram administration, it is possible that order effects may have influenced the behavioral (and presumably the neuroimaging) results, despite the fact that baseline levels of anxiety did not differ between the 2 days of study. With respect to the effects of acute citalopram administration on cerebral metabolism, the comparison subjects demonstrated greater relative righthemisphere decreases in cortical metabolism, whereas the patients demonstrated greater relative left- hemisphere decreases in cortical metabolism. Also, the patients demonstrated greater relative increases in the right putamen and left occipital regions. The observations of greater metabolic decreases in the left hemisphere and greater increases in striatal and occipital cortical regions between the patients and comparison subjects may represent compensatory responses to the blunted right-hemisphere cortical response, as reductions in the anterior cingulate have been observed in comparison subjects.29 The spatial normalization in-
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Smith et al. volved in the Statistical Parametric Mapping (SPM) analysis method might introduce noise into the data, especially in a geriatric cohort. However, visual inspection of the MRI scans for the patients and control subjects in the study did not reveal significant levels of atrophy or white-matter hyperintensities that would introduce significant distortion into the data. In the present study, the observation of a blunted right cortical metabolic response to citalopram treatment in patients is consistent with the hypothesis of serotonergic hypofunction in depression and is consistent with some reports in the literature.8 A decreased cortical- metabolic response to fenfluramine in middleaged depressed patients was reported in one study, but a second study reported no differences in response between patients and comparison subjects.9 The two studies differed in methodology (glucose metabolism versus regional cerebral blood flow [rCBF] measurements), preparation and route of administration of fenfluramine (d,l-fenfluramine/oral versus d-fenfluramine/IV), and clinical characteristics (e.g., unipolar/bipolar diagnoses and suicidality), all of which may have contributed to the discrepant results. Another acute intervention that produced a reduction in cortical metabolism is total sleep deprivation (TSD), as observed in middle-aged21 as well as late-life depressed patients.22,37 These early metabolic alterations after TSD (and recovery sleep) have been shown recently to be correlated with the improvement of depressive symptoms after 12 weeks of antidepressant treatment.37,38 With regard to the effects of 8 weeks of citalopram treatment, the patients demonstrated reduced metabolism relative to baseline in the right anterior cingulate cortex and bilateral changes in other cortical regions. FIGURE 2.
Increased metabolism was observed in subcortical structures (right putamen and thalamus), left occipital cortex, and left cerebellum. The cortical metabolic alterations observed after chronic citalopram treatment are similar to the findings reported in two other studies of the effects of antidepressant treatment on rCBF or metabolism in geriatric depressed patients.39,40 The report of the cerebral metabolic effects of antidepressant treatment also observed increased metabolism in the putamen and cerebellum, in addition to the decreases in cortical metabolism.40 Given that all of the six patients studied responded clinically to citalopram treatment, the continued-treatment results may be due to either the euthymic mood state or to the effects of citalopram. In the present study, decreased metabolism in the anterior cingulate cortex in the patients was observed with continued, but not acute, citalopram treatment, perhaps indicative of a blunted acute serotonin response. The cortical effects involve decreased metabolism in cortico–cortical association pathways and reciprocal changes in anterior (decrease) and posterior (increase) cortical regions, as well as cortico-striatal and cortico-thalamic pathways. The chronic treatment effects reported in mid-life depression23,38 also involve reciprocal changes in cortical–subcortical pathways, however, the nature of these interactions is different (increased cortical/decreased subcortical metabolism in mid-life depression and decreased cortical/increased subcortical metabolism in late-life depression). Also, middle-aged depressed patients demonstrate metabolic changes in limbic and paralimbic structures early in the course of treatment, followed later by changes in cortical metabolism.23 In geriatric depressed patients, the
Changes in cerebral metabolism after 8 weeks of citalopram treatment
Note: The image on the left shows decreases in metabolism after 8 weeks of citalopram treatment. The image on the right shows increases in metabolism after 8 weeks of citalopram treatment.
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Citalopram and Cerebral Glucose Metabolism cortical changes in metabolism occur early and persist with continued treatment, as was observed in both the citalopram and TSD studies, and alterations in limbic and paralimbic regions are not as prominent. The possibility cannot be eliminated that alterations in limbic and paralimbic regions may be observed with a larger sample size. It is also possible that the lack of a response in these regions may be due to age-related changes in response. A greater anterior-cortical response to acute citalopram administration has also been observed in the normal aging process (Goldberg S et al., unpublished, 2002), and, in geriatric depression, there is evidence of greater cortical responses, as well. The enhanced cortical responses may reflect a compensation for diminished limbic and paralimbic function. This preliminary study describes the differences in the cerebral-metabolic response to acute citalopram treatment between geriatric depressed patients and comparison subjects as well as the progressive alterations in glucose metabolism that occur with 8 weeks of citalopram treatment in the patients. The results are not only consistent with the hypothesis of serotonin hypofunction in geriatric depression, but indicate potential compensatory responses for the blunted cerebralmetabolic response in the right hemisphere. The data
indicate altered cortico–cortical interactions in the acute response to citalopram and additional alterations in cortico–striatal and cortico–thalamic pathways after 8 weeks of antidepressant treatment in geriatric depression. Subsequent studies will be conducted in a larger sample of patients and comparison subjects to determine whether the acute and chronic effects of serotonin reuptake inhibition on cerebral glucose metabolism represent a biological marker of serotonergic function that relates to treatment outcome. These data were presented in preliminary form at the American Association of Geriatric Psychiatry Annual Meeting 2002. We gratefully acknowledge David Bjelke, CNMT, and Claude Margouleff, B.S., for their contribution to the conduct of the PET studies. We gratefully acknowledge also Ann Hourihane, N.P., C.C.R.C., and Pam O’Byrne R.N., C.C.R.C., for nursing oversight. This work was supported in part by National Institute of Health grants MH49936, MH57078, MH01621, MH 01509, and MH 60575, the General Clinical Research Center of the North Shore–Long Island Jewish Research Institute, and an unrestricted educational grant from Forest Laboratories.
References 1. Dew MA, Reynolds CF III, Houck PR, et al: Temporal profiles of the course of depression during treatment: predictors of pathways toward recovery in the elderly. Arch Gen Psychiatry 1997; 54:1016–1024 2. Little JT, Reynolds CF III, Dew MA, et al: How common is resistance to treatment in recurrent, nonpsychotic geriatric depression? Am J Psychiatry 1998; 155:1035–1038 3. Maes M, Meltzer H: The serotonin hypothesis of major depression, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom F, Kupfer D. New York, Raven, 1995, pp 933–944 4. Owens MJ, Nemeroff CB: The serotonin transporter and depression. Depress Anxiety 1998, 8(suppl1):5–12 5. Mann JJ: Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology 1999; 21(suppl2):99S–105S 6. Meltzer C, Smith G, DeKosky S, et al: Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 1998; 18:407–430 7. Mann JJ, McBride PA, Malone KM, et al: Blunted serotonergic responsivity in depressed inpatients. Neuropsychopharmacology 1995; 13:53–64 8. Mann JJ, Malone KM, Diehl DJ, et al: Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients. Am J Psychiatry 1996; 153:174–182 9. Meyer JH, Kennedy S, Brown GM: No effect of depression on [(15)O]H2O PET response to intravenous d-fenfluramine. Am J Psychiatry 1998; 155:1241–1246
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10. Malone KM, Thase ME, Mieczkowski T, et al: Fenfluramine challenge test as a predictor of outcome in major depression. Psychopharmacol Bull 1993; 29:155–161 11. Kapitany T, Schindl M, Schindler S, et al: The citalopram challenge test in patients with major depression and in healthy controls. Psychiatry Res 1999; 88:75–88 12. Parsey RV, Oquendo MA, Zea-Ponce Y, et al: Dopamine D2 receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001; 50:313–322 13. Anand A, Verhoeff P, Seneca N, et al: Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. Am J Psychiatry 2000; 157:1108–1114 14. Newhouse PA, Sunderland T, Tariot PN, et al: The effects of acute scopolamine in geriatric depression. Arch Gen Psychiatry 1988; 45:906–912 15. Kapur S, Mann JJ: Role of the dopaminergic system in depression. Biol Psychiatry 1992; 32:1–17 16. Brown AS, Gershon S: Dopamine and depression. J Neural Trans 1993; General Section 91(2–3):75–109 17. Janowsky DS, Overstreet DH: The role of acetylcholine mechanisms in mood disorders, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 945–956 18. Alexopoulos G, Katz IR, Reynolds CF III, et al: Pharmacotherapy of Depressive Disorders in Older Patients. Postgrad Med Special Report 2001, 1–88 19. Meyer JH, Cho R, Kennedy S, et al: The effects of single-dose nefazodone and paroxetine upon 5-HT2A binding potential in hu-
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Smith et al. mans using [18F]-setoperone PET. Psychopharmacology 1999; 144:279–281 20. Smith G, Kirschner MA, Soriso D, et al: Evaluation of citalopram as a pharmacologic intervention of the serotonin system (abstract). Biol Psychiatry 200; 47(suppl1):99 21. Wu J, Buchsbaum MS, Gillin JC, et al: Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry 1999; 156:1149–1158 22. Smith G, Reynolds CF III, Houck P, et al: The glucose metabolic response to total sleep deprivation, recovery sleep, and acute antidepressant treatment as functional neuroanatomic correlates of treatment outcome in geriatric depression. Am J Geriatr Psychiatry 2002; 10:561–567 23. Mayberg HS, Brannan SK, Tekell JL, et al: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48:830–843 24. Smith G, Ma Y, Dhawan V, et al: Serotonin modulation of cerebral glucose metabolism measured with positron emission tomography (PET) in human subjects. Synapse 2002; 45:105–112 25. Mulsant B, Houck P, Gildengers A, et al: What is the optimal duration of an acute antidepressant trial when treating geriatric depression? (abstract) Am J Geriatr Psychiatry 2002; 10(suppl1):75 26. Sackeim H: How long should antidepressant trials be in geriatric depression? (abstract) Am J Geriatr Psychiatry 2002; 10(suppl1):42 27. First M, Spitzer R, Gibbon M, et al: Structured Clinical Interview for DSM-IV Axis I Disorders: Patient Edition (SCID-I/P). New York, New York Psychiatric Institute, 1995 28. National Institute of Mental Health: Clinical Global Impressions, in Manual for the ECDEU Assessment Battery, 2nd Edition. Edited by Guy W, Bonato RR. Rockville, MD, National Institute of Mental Health, 1976, p 12 29. Guy W: ECDEU: An Assessment Manual for Psychopharmacology.
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U.S. Department of Health, Education, and Welfare Publication (ADM) 1976, 76:336 30. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62 31. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50–55 32. Beck AT, Steer RA, Ball R, et al: Comparison of Beck Depression Inventories –IA and –II in psychiatric outpatients. J Pers Assess 1996; 67:588–597 33. Yesavage JA: Geriatric Depression Scale. Psychopharmacol Bull 1988; 24:709–711 34. Dhawan V, Kazumata K, Robeson W, et al: Quantitative brain PET: comparison of 2-D and 3-D acquisition on the GE Advance Scanner. Clinical Positron Imaging 1998; 1:135–144 35. Takikawa S, Dhawan V, Spetsieris P, et al: Noninvasive quantitative fluorodeoxyglucose PET studies with an estimated input function derived from a population-based arterial blood curve. Radiology 1993; 188:131–136 36. Friston KJ, Holmes AP, Worsley, KJ, et al: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2:189–210 37. Smith G, Reynolds C, Pollock, B, et al: Acceleration of the cerebral glucose metabolic response to antidepressant treatment by total sleep deprivation in geriatric depression. Am J Psychiatry 1999; 156:683–689 38. Buchsbaum MS, Wu J, Siegel BV, et al: Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 1997; 41:15–22 39. Nobler MS, Roose SP, Prohovnik I, et al: Regional cerebral blood flow in mood disorders, V: effects of antidepressant medication in late-life depression. Am J Geriatr Psychiatry 2000; 8:289–296 40. Little J, Smith G, Meltzer C, et al: Cerebral metabolic changes with paroxetine treatment in geriatric depression. Am J Geriatr Psychiatry 2002; 10(suppl1):73
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Objective: In vivo studies of serotonin function have been limited by the lack of safe and selective pharmacologic agents and availability of suitable radiotracers. In the present study, the authors evaluated the cerebral metabolic effects of acute and continued administration of the selective serotonin reuptake inhibitor citalopram in patients with geriatric depression as a potential marker of serotonin dysfunction. Methods: Six patients with geriatric depression and five comparison subjects underwent two resting positron emission tomography (PET) studies, performed after administration of a placebo infusion (Day 1) and a citalopram infusion (40 mg, Day 2). The patients were re-scanned after 8 weeks of treatment with the oral medication. Results: The elderly comparison subjects demonstrated greater right-hemisphere cortical decreases than the patients. The depressed patients demonstrated greater left-hemisphere cortical decreases than comparison subjects. The depressed patients demonstrated greater increases in the right putamen and left occipital cortex. After 8 weeks of citalopram treatment, regional decreases and increases in metabolism were observed. Conclusion: These findings suggest regional deficits and also compensatory responses in the acute metabolic response to citalopram in the patients. These preliminary results suggest that the cerebral metabolic response to citalopram may be a useful marker of the pathophysiology of serotonin function in geriatric depression. (Am J Geriatr Psychiatry 2002; 10:715–723)
Received March 27, 2002; revised July 9, 2002; accepted July 30, 2002. From the Departments of Psychiatry Research (GSS), and Geriatric Psychiatry (EK,BG), Hillside Hospital, Glen Oaks, New York, and Center for Neurosciences (GSS,CRH,SG,YM,VD,AB,TC,ABDE) of the North Shore–Long Island Jewish Health System; Hoffman-La Roche Ltd. (FL-T), Basel, Switzerland; Geriatric Psychopharmacology Laboratory, Western Psychiatric Institute and Clinic, Departments of Psychiatry, Pharmacology, and Pharmaceutical Sciences (BGP), University of Pittsburgh School of Medicine, Pittsburgh, PA. Address correspondence to Dr. Smith, Department of Psychiatry Research, Hillside Hospital and the Neuroscience Institute of the North Shore–Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004. e-mail: [email protected] Copyright 䉷 2002 American Association for Geriatric Psychiatry
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Citalopram and Cerebral Glucose Metabolism
T
here is a compelling need to understand the mechanisms that underlie the variability of treatment response in geriatric depression.1 Even though there are effective antidepressant agents available, 25 percent of patients are still refractory to treatment, despite adequate dosing.2 In an effort to understand the pathophysiology of depression, the majority of studies have focused on the evaluation of the serotonin system in midlife depressed patients. The evidence for serotonergic dysfunction in depression has been reviewed extensively.3–6 These investigations have involved neuroimaging and neuroendocrine methods combined with acute pharmacologic interventions directed at the serotonin system.7–11 Specifically, these studies have involved the measurement of the neuroendocrine response (prolactin or cortisol) or the cerebral metabolic response to administration of serotonergic agents such as fenfluramine and mCPP (m-chlorophenylpiperazine). Some of these acute intervention studies have demonstrated serotonin hypofunctioning to a greater extent in patients who respond poorly to antidepressant treatment.8,9,11 These studies are based on the premise that the acute central nervous system (CNS) response to the administration of agents that enhance serotonin activity represents the functional capacity of the serotonin system, which may be related to the pathophysiology of the serotonin system and presumably to the clinical response to antidepressant treatment. Other neurotransmitter systems, including dopamine and acetylcholine, have been evaluated to a more limited extent. Thus far, the studies that have combined either neuroimaging or neurocognitive measures with acute pharmacologic interventions in these systems have not demonstrated differences in response between patients and comparison subjects,12–14 despite the observations that pharmacologic alterations of these systems affect mood.15–17 Since the primary target of antidepressant medications is the serotonin system, a greater understanding of serotonergic dysfunction in patients with geriatric depression may provide insight into a neurobiologic substrate related to treatment response variability. Because the clinical heterogeneity of depressed patients is greater in geriatric depressed patients, factors such as age at onset, treatment history, and medical comorbidity must be considered carefully in designing neurobiological studies. The ability to study serotonin function in vivo has been limited by
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the lack of availability of safe and selective pharmacologic agents, particularly for use in elderly subjects. Also, there have been difficulties in developing suitable radiotracers for the in-vivo imaging of the serotonin system, such as the lack of selective pharmacologic agents for radiolabeling, the low ratios of specific to nonspecific binding of the radiotracers, and the presence of radiolabeled metabolites that hinder quantification of radiotracer binding. The purpose of the current study was to use positron emission tomography (PET) to measure the acute and chronic cerebral metabolic effects of the most selective of the serotonin reuptake inhibitors (SRIs), citalopram (Celexa威), in patients with geriatric depression. The availability of citalopram for intravenous (IV) and oral administration is a unique opportunity to measure the acute effects after administration of a single IV dose, as well as the chronic effects after treatment with the oral medication. Citalopram was also chosen because it is an effective antidepressant medication and is extremely well tolerated across the lifespan. In a recent survey of 50 experienced geriatric psychiatrists, citalopram received the highest ratings for efficacy and tolerability for the treatment of depression in elderly patients.18 The decision to measure cerebral glucose metabolism in this study was based on the current lack of a serotonin-receptor radiotracer to directly measure endogenous serotonin concentrations.19,20 Compared with measures of serotonin transporter or receptor binding, measures of glucose metabolism in the resting state have demonstrated sensitivity in monitoring the effects of antidepressant treatment and also in predicting the outcome of antidepressant treatment on the basis of either pretreatment metabolic rates or changes in metabolism after an acute intervention (e.g., after total sleep deprivation [TSD] or 1 week of antidepressant treatment).21–23 We hypothesized that acute and chronic citalopram administration would be associated with a progressive reduction in cerebral metabolism in cortical areas, including the superior and middle prefrontal and parietal (precuneus) cortices,22,23 which we have found to be hypermetabolic in geriatric depressed patients (before treatment) and to be affected by pharmacologic treatment and TSD. On the basis of previous studies, we also hypothesized that the acute decreases in metabolism would be greater in magnitude, particularly in anterior brain regions, in the comparison subjects than in the patients.
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Smith et al. METHODS Study Design Patients and comparison subjects underwent two PET scans on two consecutive days to measure the effects of placebo/citalopram administration on cerebral glucose metabolism, as described previously.24 After completion of the first two PET scans, the patients underwent 12 weeks of treatment with oral citalopram and were monitored clinically on a weekly basis. After 8 weeks of treatment, the patients were re-scanned to measure the effects of 8 weeks of citalopram treatment on cerebral metabolism. The decision to re-scan patients at 8 weeks was based on the observation across studies that this is the time when patients will demonstrate significant clinical improvement, if they respond at all.25,26 Subject Screening and Selection Patients and comparison subjects underwent psychiatric evaluation (including a structured clinical interview [SCID27]), laboratory testing (including complete blood count and blood chemistry, including glucose levels and thyroid function tests), toxicology screening, and magnetic resonance imaging (MRI) scans (GE 1.5T) before the PET scans. Depressed patients and comparison subjects were recruited from the Geriatric Psychiatry Outpatient Clinic at Hillside Hospital and also through advertisements in the community. Six patients with depression (one man/five women; mean age 68.8 years, standard deviation [SD]: 5.7 years) who met DSM-IV criteria for current major depressive episode (nonbipolar, nonpsychotic) were enrolled. We enrolled five comparison subjects who did not have a previous or current psychiatric illness (two men/three women; mean age 64.8 years, SD: 4.3 years). The differences in age between the two groups were not statistically significant (t[9]⳱ –1.30; p⬎0.05). Subjects who had a previous or current neurological disorder or substance abuse or who were not medically stable (including a current diagnosis of diabetes not controlled by diet) were excluded from the study. None of the patients or comparison subjects had previous or current cerebrovascular, cardiovascular, or thyroid disease, and none were diabetic, except one patient who was being treated for hypertension with a calcium channel blocker.
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All of the patients had an age at onset of illness (defined as age at first treatment by a mental health professional) of 60 or older. Three patients had never been treated with psychotropic drugs. Of the three patients previously treated, one patient had been treated with fluoxetine and then sertraline until 6 months before enrolling in the study. Another patient had taken sertraline 2 years before entering the study. The third patient had been treated with nortriptyline for 2 years, until 2 weeks before the PET scan (at which time the nortriptyline concentrations in plasma were undetectable). In each case, the onset of depression (including the current episode) in the patients was not associated with the onset of a medical condition. After a complete description of the study to the subjects, we obtained written informed consent according to procedures established by the Institutional Review Board and the Radiation Safety Committee of the North Shore–Long Island Jewish Health System. Acute and Chronic Citalopram Interventions For the acute studies, 40 mg of citalopram was infused over 60 minutes, and the radiotracer was injected 15–30 minutes after the end of the infusion. After administration of the 40 mg intravenous dose of citalopram, steady-state plasma concentrations (up to 3 hours post-infusion) and an increase in cortisol and prolactin concentrations (until 60 minutes post-infusion) were observed.24,27 Two days after the IV administration of citalopram, patients began treatment with citalopram at 10 mg per day for 3 days. The dose was increased to 20 mg on the fourth day. If significant improvement was not observed at the 20-mg dose after 4 weeks of treatment (Clinical Global Impression Scale [CGI28]) improvement rating of 3 or greater), the dose was increased to 30 mg, and then, if necessary, to 40 mg. The mean dose at 8 weeks of treatment, at the time of the PET scan, was 30 mg (SD: 7.0 mg), and after 12 weeks of treatment, the mean dose was 32 mg (SD: 8.0 mg). To measure the effects of acute citalopram administration on mood and anxiety, several items from a visual analog scale (VAS29) were administered before and at the end of the placebo/citalopram infusions and at the end of the PET scans. Patients were seen in the Geriatric Outpatient Clinic of Hillside Hospital on a weekly basis, at which time clinical ratings for depressive and anxiety symptoms were performed (Hamilton Rating Scale for Depression–24 item [Ham-D30], Hamil-
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Citalopram and Cerebral Glucose Metabolism ton Anxiety Rating Scale [Ham-A31], Beck Depression Inventory [BDI32], CGI, and Geriatric Depression Scale [GDS33]). PET Imaging Procedures The PET scans were performed with a GE Advance Tomograph at North Shore University Hospital as described previously.24 Briefly, all PET studies began at the same time of day (10 A.M.). Upon arrival at the laboratory, one catheter was placed in a vein in the left arm for radiotracer and placebo/citalopram infusion, and a second catheter was placed in a vein in the right arm for sampling of citalopram and neuroendocrine levels. The study was single-blinded, in that the subjects were told that they would receive either citalopram or placebo before each study, but the investigator knew the identity of the infusion. The infusions of placebo (250 ml of saline) or citalopram (40 mg of the drug diluted in 250 ml saline) were performed over 60 minutes. Fifteen to 30 minutes after the end of the infusion of placebo/citalopram, 5 mCi of [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) was injected as an intravenous bolus. Subjects were positioned in the GE Advance Tomograph. A 10-minute transmission scan and a 5-minute two-dimensional emission scan were acquired first to perform photon-attenuation correction.34 A threedimensional emission scan began at 35 minutes after radiotracer injection and lasted for 10 minutes. At the end of the PET scan, subjects were removed from the PET scanner, and the intravenous lines were removed after completion of the blood sampling. Subjects were debriefed as to their perception of the study and observed for a minimum of 1 hour after the PET scan was completed. Data and Image Analysis Glucose metabolic rates were calculated on a pixelby-pixel basis as described previously.24,35 Data-processing was performed with the statistical parametric mapping program (SPM99).36 The PET scans for each subject were aligned and nonlinearly warped into Talairach space. The images were smoothed with an isotropic Gaussian kernel (FWHM 8-mm for all planes). The glucose metabolic rates were normalized by scaling to a common mean value across all scans. Differences between treatment conditions (placebo/citalopram) were compared by the paired t-test option in SPM99.
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The between-condition comparisons were considered significant at a t threshold greater than 3.30 (z⳱2.81; p⬍0.005; two-tailed, uncorrected for multiple independent comparisons). Given the small sample sizes for the study, a more stringent probability value was used to correct for the number of comparisons performed.
RESULTS The VAS scores for the drug and placebo conditions for the patients and comparison subjects are shown in Table 1. The patients demonstrated an improvement in the ratings of “Happy” (an increase in scores reflects greater ratings of Happy), “Sad,” and “Anxious” for the citalopram condition, as compared with the placebo condition, whereas the scores for the comparison subjects were not different across conditions. However, the differences between the VAS ratings performed at comparable times between the placebo and citalopram treatment did not reach statistical significance for either group (comparison subjects: pre-infusion: Anxious: t[5]⳱1.4; p⬎0.05; Depressed: t[5]⳱1.0; p⬎0.05; Happy: t[5]⳱ –0.78; p⬎0.05; post-infusion: Anxious: t[5]⳱ –0.39; p⬎0.05; Depressed: t[5]⳱1.0; p⬎0.05; Happy: t[5]⳱ –0.76; p⬎0.05; post-scan: Anxious: t[5]⳱0.38; p⬎0.05; Depressed: t[5]⳱ –1.0; p⬎0.05; Happy: t[5]⳱1.0; p⬎0.05; patients pre-infusion: Anxious: t[5]⳱0.79; p⬎0.05; Depressed: t[5]⳱0.0; p⬎0.05; Happy t[5]⳱2.7; p⬎0.05; post-infusion: Anxious: t[5]⳱ TABLE 1.
Visual analog scale (VAS) ratings, mean (standard deviation)
Elderly comparison subjects Placebo Pre-infusion End of infusion Post-scan Citalopram Pre-infusion End of infusion Post-scan Geriatric depression Placebo Pre-infusion End of infusion Post-scan Citalopram Pre-infusion End of infusion Post-scan
Anxious
Depressed
Happy
2.3 (2.4) 1.6 (2.0) 1.7 (1.5)
0.9 (2.1) 0.4 (0.7) 0.07 (0.3)
6.9 (1.5) 5.9 (2.0) 6.9 (1.9)
1.9 (2.3) 1.3 (2.2) 0.9 (2.1)
0.6 (1.2) 0.4 (0.8) 0.5 (0.9)
6.7 (2.3) 6.7 (2.0) 6.7 (1.9)
5.7 (2.3) 4.2 (3.4) 5.5 (3.1)
4.1 (3.1) 3.5 (3.3) 3.7 (2.7)
3.3 (1.0) 1.8 (1.2) 2.0 (1.9)
4.2 (2.9) 3.7 (2.5) 2.8 (1.9)
4.1 (3.5) 3.5 (2.3) 2.7 (2.9)
1.2 (1.5) 2.2 (2.0) 3.2 (1.9)
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Smith et al. –0.24; p⬎0.05; Depressed: t[5]⳱ –0.13; p⬎0.05; Happy: t[5]⳱0.21; p⬎0.05; post-scan: Anxious: t[5]⳱1.8; p⬎0.05; Depressed: t[5]⳱0.87; p⬎0.05; Happy: t[5]⳱ –0.76; p⬎0.05). The clinical ratings for the patients during 8 weeks of citalopram treatment are shown in Table 2. The baseline Ham-D scores for the six patients were 28, 23, 31, 28, 27, and 25. The patients’ Week 12 scores were 1, 3, 8, 3, 2, and 5, respectively. For the Ham-D, the ratings were significantly reduced from 1 to 12 weeks after initiation of treatment (Week 1: t[5]⳱2.7; p⬍0.05; Week 2: t[5]⳱2.6; p⬍0.05; Week 3: t[5]⳱ 4.1; p⬍0.01; Week 4: t[5]⳱4.0; p⬍0.05; Week 5: t[5]⳱3.2; p⬍0.05; Week 6: t[5]⳱3.7; p⬍0.05; Week 7: t[5]⳱8.7; p⬍0.001; Week 8: t[5]⳱8.1; p⬍0.001; Week 9: t[5]⳱7.6; p⬍0.001; Week 10: t[5]⳱7.9; p⬍0.001; Week 11: t[5]⳱10.6; p⬍0.001; Week 12: t[5]⳱9.7; p⬍0.001). For the Ham-A, the ratings were significantly reduced from baseline on Weeks 1, 3, 4, 6, and thereafter, significant at the p⬍0.05 and p⬍0.01 levels (Week 1: t[5]⳱3.9; p⬍0.05; Week 2: t[5]⳱1.5; p⬎0.05; Week 3: t[5]⳱2.9; p⬍0.05; Week 4: t[5]⳱ 3.1; p⬍0.05; Week 5: t[5]⳱2.1; p⬎0.05; Week 6: t[5]⳱3.3; p⬍0.05; Week 7: t[5]⳱5.7; p⬍0.01; Week 8: t[5]⳱5.0; p⬍0.01; Week 9: t[5]⳱5.2; p⬍0.01; Week 10: t[5]⳱6.3; p⬍0.01; Week 11: t[5]⳱3.9; p⬍0.01; Week 12: t[5]⳱4.6; p⬍0.01). For the BDI, the ratings were significantly reduced from baseline on Weeks 4, 6, 7, 9, and thereafter, but these differences were significant at the p⬍0.05 and
p⬍0.01 levels only (Week 1: t[5]⳱0.5; p⬎0.05; Week 2: t[5]⳱1.1; p⬎0.05; Week 3: t[5]⳱1.8; p⬎0.05; Week 4: t[5]⳱3.2; p⬍0.05; Week 5: t[5]⳱1.5; p⬎0.05; Week 6: t[5]⳱4.2; p⬍0.01; Week 7: t[5]⳱3.4; p⬍0.05; Week 8: t[5]⳱2.4; p⬎0.05; Week 9: t[5]⳱5.2; p⬍0.01; Week 10: t[5]⳱3.8; p⬍0.05; Week 11: t[5]⳱4.9; p⬍0.01; Week 12: t[5]⳱6.0; p⬍0.01). For the Geriatric Depression Scale (GDS), the ratings were significantly reduced from 6 to 12 weeks after initiation of treatment (Week 6: t[5]⳱3.4; p⬍0.05; Week 7: t[5]⳱8.8; p⬍0.001; Week 8: t[5]⳱19.3; p⬍0.001; Week 9: t[5]⳱16.0; p⬍0.001; Week 10: t[5]⳱8.8; p⬍0.001; Week 11: t[5]⳱13.1; p⬍0.001; Week 12: t[5]⳱21.2; p⬍0.001. All of the six patients would have met the criteria for treatment response used in previous studies: a 50% reduction in Ham-D scores, a HamD score ⱕ10, and a CGI rating of “Much Improved” or “Very Much Improved.”1,25 The between-group comparisons for the acute citalopram effect are shown in Table 3. Topographic maps of the greater and lesser areas of decrease in the patients’ metabolism relative to comparison subjects are shown in Figure 1. The comparison subjects demonstrated greater metabolic decreases than the patients in right (middle frontal, fusiform, inferior parietal, precuneus, and supramarginal) cortices, whereas the patients showed greater decreases than the comparison subjects in left (middle frontal and inferior parietal) cortices. The patients demonstrated greater increases than the comTABLE 3.
TABLE 2. Week of Treatment Baseline 1 2 3 4 5 6 7 8 9 10 11 12
Effects of continued citalopram treatment on depressive symptoms, mean (standard deviation) Ham-D
Ham-A
BDI
GDS
27.0 (2.8) 19.0 (5.3) 19.8 (5.2) 13.7 (6.2) 11.5 (8.8) 11.8 (9.2) 8.8 (8.6) 4.8 (4.5)* 4.6 (4.4)* 4.0 (4.3) 4.2 (4.6)* 3.8 (3.1)* 3.4 (2.7)*
15.0 (5.9) 8.8 (4.5) 10.2 (6.2) 8.7 (6.0) 5.5 (4.6) 7.5 (6.4) 4.6 (4.2) 3.8 (6.8) 4.6 (5.2) 3.0 (2.8) 3.2 (4.5) 5.0 (3.1) 3.4 (2.9)
10.3 (2.4) 9.7 (3.9) 7.8 (4.1) 6.8 (4.8) 6.2 (4.6) 6.0 (7.0) 4.3 (3.6) 1.6 (3.0) 2.0 (4.0) 1.8 (2.2) 2.2 (3.0) 2.4 (2.3) 1.2 (1.8)
22.2 (3.5) 16.7 (4.0) 16.2 (5.9) 16.2 (6.4) 14.2 (8.2) 12.6 (7.1) 11.5 (6.8) 5.6 (4.8)* 4.0 (5.0)* 4.8 (5.1)* 5.2 (6.7)* 4.2 (5.3)* 3.6 (5.1)*
Note: Ham-D: Hamilton Rating Scale for Depression; Ham-A: Hamilton Anxiety Rating Scale; BDI: Beck Depression Inventory; GDS: Geriatric Depression Scale. *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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Cerebral-metabolic effects of acute citalopram administration relative to placebo: comparisons between patients and comparison subjects
Greater decreases in comparison subjects than patients 38, 54, 18 Right-middle-frontal cortex (BA 10) 26, ⳮ40, ⳮ14 Right fusiform cortex 48, ⳮ40, 44 Right inferior parietal lobule (BA 40) 24, ⳮ54, 44 Right parietal cortex (precuneus; BA 07) 56, ⳮ38, 32 Right parietal cortex (supramarginal cortex)
4.16 3.52 3.60 3.18 3.05
Greater decreases in patients than in comparison subjects ⳮ44, 50, ⳮ10 Left-middle-frontal cortex ⳮ48, 34, 18 Left-middle-frontal cortex ⳮ36, ⳮ44, 42 Left inferior-parietal lobule
2.97 3.03 4.37
Greater increases in patients than in comparison subjects 24, 16, 2 Right putamen 24, 2, 10 Right putamen 30, ⳮ66, ⳮ10 Right occipital cortex 26, ⳮ54, ⳮ10 Right occipital cortex (BA 19) ⳮ16, ⳮ64, 4 Left occipital cortex ⳮ14, ⳮ82, ⳮ28 Left cerebellum
3.88 3.59 3.37 3.17 3.47 2.94
Note: Values in first column are Talairach coordinates (mm). *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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Citalopram and Cerebral Glucose Metabolism FIGURE 1.
Changes in cerebral glucose metabolism in geriatric depressed patients compared with elderly control subjects, superimposed on an MRI template
Note: The image on the left shows greater decreases in patients than in control subjects. The image on the right shows greater decreases in control subjects than in patients.
parison subjects in the right putamen, bilaterally in the occipital cortex, and left cerebellum. Comparing 8 weeks of citalopram treatment with baseline (placebo condition, as shown in Table 4 and Figure 2), reductions were observed in the right anterior cingulate cortex, bilaterally in the superior frontal cortices, right inferior frontal cortex, right superior temporal cortex, left middle temporal cortex, right insula, left post-central cortex, right parahippocampal gyrus, and right midbrain. Increases were observed in the
TABLE 4.
Cerebral-metabolic effects of 8 weeks of citalopram treatment relative to baseline in patients
Decreases 4, 42, 6 14, 40, 6 34, 42, ⳮ16 34, 20, ⳮ12 ⳮ22, 44, 16 ⳮ50, ⳮ18, 48 36, ⳮ12, 16 52, ⳮ48, 18 ⳮ40, ⳮ10, ⳮ12 28, 6, ⳮ18 0, ⳮ28, ⳮ20 4, ⳮ14, ⳮ8
Right anterior cingulate (BA 24) Right anterior cingulate Right superior frontal cortex Right inferior frontal cortex Left superior frontal cortex Left post-central cortex (BA 5) Right insula (BA 13) Right superior temporal cortex Left middle-temporal cortex Right parahippocampal gyrus Right brainstem (pons) Right brainstem (midbrain)
4.37 3.41 3.28 3.79 3.92 3.21 4.13 3.16 3.00 2.89 4.23 3.56
Increases 32, ⳮ50, 52 44, ⳮ44, 38 ⳮ34, ⳮ80, ⳮ2 24, ⳮ2, 10 24, 8, 8 20, ⳮ28, 8
Right superior parietal lobule (BA 7) Right inferior parietal lobule Left occipital cortex Right putamen Right putamen Right thalamus (pulvinar)
3.69 3.31 3.26 3.05 2.82 2.82
Note: Values in first column are Talairach coordinates (mm). *Results of paired t-tests (df 4,5 for the comparison subjects and patients, respectively), p⬍0.005).
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right superior and inferior parietal lobules, left occipital cortex, right putamen, right thalamus, and left cerebellum. Some homologous regions showed effects that were slightly above the significance threshold used (p⬍0.007); specifically, the left anterior cingulate cortex, left putamen, and right occipital cortex.
DISCUSSION The acute administration of citalopram improved mood and anxiety ratings (below statistical significance) in the patients, but not in the comparison subjects. Since it was not possible to randomize the order of placebo and citalopram administration, it is possible that order effects may have influenced the behavioral (and presumably the neuroimaging) results, despite the fact that baseline levels of anxiety did not differ between the 2 days of study. With respect to the effects of acute citalopram administration on cerebral metabolism, the comparison subjects demonstrated greater relative righthemisphere decreases in cortical metabolism, whereas the patients demonstrated greater relative left- hemisphere decreases in cortical metabolism. Also, the patients demonstrated greater relative increases in the right putamen and left occipital regions. The observations of greater metabolic decreases in the left hemisphere and greater increases in striatal and occipital cortical regions between the patients and comparison subjects may represent compensatory responses to the blunted right-hemisphere cortical response, as reductions in the anterior cingulate have been observed in comparison subjects.29 The spatial normalization in-
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Smith et al. volved in the Statistical Parametric Mapping (SPM) analysis method might introduce noise into the data, especially in a geriatric cohort. However, visual inspection of the MRI scans for the patients and control subjects in the study did not reveal significant levels of atrophy or white-matter hyperintensities that would introduce significant distortion into the data. In the present study, the observation of a blunted right cortical metabolic response to citalopram treatment in patients is consistent with the hypothesis of serotonergic hypofunction in depression and is consistent with some reports in the literature.8 A decreased cortical- metabolic response to fenfluramine in middleaged depressed patients was reported in one study, but a second study reported no differences in response between patients and comparison subjects.9 The two studies differed in methodology (glucose metabolism versus regional cerebral blood flow [rCBF] measurements), preparation and route of administration of fenfluramine (d,l-fenfluramine/oral versus d-fenfluramine/IV), and clinical characteristics (e.g., unipolar/bipolar diagnoses and suicidality), all of which may have contributed to the discrepant results. Another acute intervention that produced a reduction in cortical metabolism is total sleep deprivation (TSD), as observed in middle-aged21 as well as late-life depressed patients.22,37 These early metabolic alterations after TSD (and recovery sleep) have been shown recently to be correlated with the improvement of depressive symptoms after 12 weeks of antidepressant treatment.37,38 With regard to the effects of 8 weeks of citalopram treatment, the patients demonstrated reduced metabolism relative to baseline in the right anterior cingulate cortex and bilateral changes in other cortical regions. FIGURE 2.
Increased metabolism was observed in subcortical structures (right putamen and thalamus), left occipital cortex, and left cerebellum. The cortical metabolic alterations observed after chronic citalopram treatment are similar to the findings reported in two other studies of the effects of antidepressant treatment on rCBF or metabolism in geriatric depressed patients.39,40 The report of the cerebral metabolic effects of antidepressant treatment also observed increased metabolism in the putamen and cerebellum, in addition to the decreases in cortical metabolism.40 Given that all of the six patients studied responded clinically to citalopram treatment, the continued-treatment results may be due to either the euthymic mood state or to the effects of citalopram. In the present study, decreased metabolism in the anterior cingulate cortex in the patients was observed with continued, but not acute, citalopram treatment, perhaps indicative of a blunted acute serotonin response. The cortical effects involve decreased metabolism in cortico–cortical association pathways and reciprocal changes in anterior (decrease) and posterior (increase) cortical regions, as well as cortico-striatal and cortico-thalamic pathways. The chronic treatment effects reported in mid-life depression23,38 also involve reciprocal changes in cortical–subcortical pathways, however, the nature of these interactions is different (increased cortical/decreased subcortical metabolism in mid-life depression and decreased cortical/increased subcortical metabolism in late-life depression). Also, middle-aged depressed patients demonstrate metabolic changes in limbic and paralimbic structures early in the course of treatment, followed later by changes in cortical metabolism.23 In geriatric depressed patients, the
Changes in cerebral metabolism after 8 weeks of citalopram treatment
Note: The image on the left shows decreases in metabolism after 8 weeks of citalopram treatment. The image on the right shows increases in metabolism after 8 weeks of citalopram treatment.
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Citalopram and Cerebral Glucose Metabolism cortical changes in metabolism occur early and persist with continued treatment, as was observed in both the citalopram and TSD studies, and alterations in limbic and paralimbic regions are not as prominent. The possibility cannot be eliminated that alterations in limbic and paralimbic regions may be observed with a larger sample size. It is also possible that the lack of a response in these regions may be due to age-related changes in response. A greater anterior-cortical response to acute citalopram administration has also been observed in the normal aging process (Goldberg S et al., unpublished, 2002), and, in geriatric depression, there is evidence of greater cortical responses, as well. The enhanced cortical responses may reflect a compensation for diminished limbic and paralimbic function. This preliminary study describes the differences in the cerebral-metabolic response to acute citalopram treatment between geriatric depressed patients and comparison subjects as well as the progressive alterations in glucose metabolism that occur with 8 weeks of citalopram treatment in the patients. The results are not only consistent with the hypothesis of serotonin hypofunction in geriatric depression, but indicate potential compensatory responses for the blunted cerebralmetabolic response in the right hemisphere. The data
indicate altered cortico–cortical interactions in the acute response to citalopram and additional alterations in cortico–striatal and cortico–thalamic pathways after 8 weeks of antidepressant treatment in geriatric depression. Subsequent studies will be conducted in a larger sample of patients and comparison subjects to determine whether the acute and chronic effects of serotonin reuptake inhibition on cerebral glucose metabolism represent a biological marker of serotonergic function that relates to treatment outcome. These data were presented in preliminary form at the American Association of Geriatric Psychiatry Annual Meeting 2002. We gratefully acknowledge David Bjelke, CNMT, and Claude Margouleff, B.S., for their contribution to the conduct of the PET studies. We gratefully acknowledge also Ann Hourihane, N.P., C.C.R.C., and Pam O’Byrne R.N., C.C.R.C., for nursing oversight. This work was supported in part by National Institute of Health grants MH49936, MH57078, MH01621, MH 01509, and MH 60575, the General Clinical Research Center of the North Shore–Long Island Jewish Research Institute, and an unrestricted educational grant from Forest Laboratories.
References 1. Dew MA, Reynolds CF III, Houck PR, et al: Temporal profiles of the course of depression during treatment: predictors of pathways toward recovery in the elderly. Arch Gen Psychiatry 1997; 54:1016–1024 2. Little JT, Reynolds CF III, Dew MA, et al: How common is resistance to treatment in recurrent, nonpsychotic geriatric depression? Am J Psychiatry 1998; 155:1035–1038 3. Maes M, Meltzer H: The serotonin hypothesis of major depression, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom F, Kupfer D. New York, Raven, 1995, pp 933–944 4. Owens MJ, Nemeroff CB: The serotonin transporter and depression. Depress Anxiety 1998, 8(suppl1):5–12 5. Mann JJ: Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology 1999; 21(suppl2):99S–105S 6. Meltzer C, Smith G, DeKosky S, et al: Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 1998; 18:407–430 7. Mann JJ, McBride PA, Malone KM, et al: Blunted serotonergic responsivity in depressed inpatients. Neuropsychopharmacology 1995; 13:53–64 8. Mann JJ, Malone KM, Diehl DJ, et al: Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients. Am J Psychiatry 1996; 153:174–182 9. Meyer JH, Kennedy S, Brown GM: No effect of depression on [(15)O]H2O PET response to intravenous d-fenfluramine. Am J Psychiatry 1998; 155:1241–1246
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10. Malone KM, Thase ME, Mieczkowski T, et al: Fenfluramine challenge test as a predictor of outcome in major depression. Psychopharmacol Bull 1993; 29:155–161 11. Kapitany T, Schindl M, Schindler S, et al: The citalopram challenge test in patients with major depression and in healthy controls. Psychiatry Res 1999; 88:75–88 12. Parsey RV, Oquendo MA, Zea-Ponce Y, et al: Dopamine D2 receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001; 50:313–322 13. Anand A, Verhoeff P, Seneca N, et al: Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. Am J Psychiatry 2000; 157:1108–1114 14. Newhouse PA, Sunderland T, Tariot PN, et al: The effects of acute scopolamine in geriatric depression. Arch Gen Psychiatry 1988; 45:906–912 15. Kapur S, Mann JJ: Role of the dopaminergic system in depression. Biol Psychiatry 1992; 32:1–17 16. Brown AS, Gershon S: Dopamine and depression. J Neural Trans 1993; General Section 91(2–3):75–109 17. Janowsky DS, Overstreet DH: The role of acetylcholine mechanisms in mood disorders, in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 945–956 18. Alexopoulos G, Katz IR, Reynolds CF III, et al: Pharmacotherapy of Depressive Disorders in Older Patients. Postgrad Med Special Report 2001, 1–88 19. Meyer JH, Cho R, Kennedy S, et al: The effects of single-dose nefazodone and paroxetine upon 5-HT2A binding potential in hu-
Am J Geriatr Psychiatry 10:6, November-December 2002
Smith et al. mans using [18F]-setoperone PET. Psychopharmacology 1999; 144:279–281 20. Smith G, Kirschner MA, Soriso D, et al: Evaluation of citalopram as a pharmacologic intervention of the serotonin system (abstract). Biol Psychiatry 200; 47(suppl1):99 21. Wu J, Buchsbaum MS, Gillin JC, et al: Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry 1999; 156:1149–1158 22. Smith G, Reynolds CF III, Houck P, et al: The glucose metabolic response to total sleep deprivation, recovery sleep, and acute antidepressant treatment as functional neuroanatomic correlates of treatment outcome in geriatric depression. Am J Geriatr Psychiatry 2002; 10:561–567 23. Mayberg HS, Brannan SK, Tekell JL, et al: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48:830–843 24. Smith G, Ma Y, Dhawan V, et al: Serotonin modulation of cerebral glucose metabolism measured with positron emission tomography (PET) in human subjects. Synapse 2002; 45:105–112 25. Mulsant B, Houck P, Gildengers A, et al: What is the optimal duration of an acute antidepressant trial when treating geriatric depression? (abstract) Am J Geriatr Psychiatry 2002; 10(suppl1):75 26. Sackeim H: How long should antidepressant trials be in geriatric depression? (abstract) Am J Geriatr Psychiatry 2002; 10(suppl1):42 27. First M, Spitzer R, Gibbon M, et al: Structured Clinical Interview for DSM-IV Axis I Disorders: Patient Edition (SCID-I/P). New York, New York Psychiatric Institute, 1995 28. National Institute of Mental Health: Clinical Global Impressions, in Manual for the ECDEU Assessment Battery, 2nd Edition. Edited by Guy W, Bonato RR. Rockville, MD, National Institute of Mental Health, 1976, p 12 29. Guy W: ECDEU: An Assessment Manual for Psychopharmacology.
Am J Geriatr Psychiatry 10:6, November-December 2002
U.S. Department of Health, Education, and Welfare Publication (ADM) 1976, 76:336 30. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62 31. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50–55 32. Beck AT, Steer RA, Ball R, et al: Comparison of Beck Depression Inventories –IA and –II in psychiatric outpatients. J Pers Assess 1996; 67:588–597 33. Yesavage JA: Geriatric Depression Scale. Psychopharmacol Bull 1988; 24:709–711 34. Dhawan V, Kazumata K, Robeson W, et al: Quantitative brain PET: comparison of 2-D and 3-D acquisition on the GE Advance Scanner. Clinical Positron Imaging 1998; 1:135–144 35. Takikawa S, Dhawan V, Spetsieris P, et al: Noninvasive quantitative fluorodeoxyglucose PET studies with an estimated input function derived from a population-based arterial blood curve. Radiology 1993; 188:131–136 36. Friston KJ, Holmes AP, Worsley, KJ, et al: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2:189–210 37. Smith G, Reynolds C, Pollock, B, et al: Acceleration of the cerebral glucose metabolic response to antidepressant treatment by total sleep deprivation in geriatric depression. Am J Psychiatry 1999; 156:683–689 38. Buchsbaum MS, Wu J, Siegel BV, et al: Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 1997; 41:15–22 39. Nobler MS, Roose SP, Prohovnik I, et al: Regional cerebral blood flow in mood disorders, V: effects of antidepressant medication in late-life depression. Am J Geriatr Psychiatry 2000; 8:289–296 40. Little J, Smith G, Meltzer C, et al: Cerebral metabolic changes with paroxetine treatment in geriatric depression. Am J Geriatr Psychiatry 2002; 10(suppl1):73
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