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Regional brain responses to serotonin in major depressive disorder
Journal of Affective Disorders 82 (2004) 411 – 417 www.elsevier.com/locate/jad
Research report
Regional brain responses to serotonin in major depressive disorder Amy D. Anderson a, Maria A. Oquendo a,b, Ramin V. Parsey a,b, Matthew S. Milak a,b, Carl Campbell a, J. John Mann a,b,c,* a Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY 10032, USA c Department of Radiology, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY 10032, USA
b
Received 3 November 2003; accepted 5 April 2004
Abstract Background: Positron Emission Tomography (PET) studies have reported altered resting regional brain glucose metabolism in mood disorders. This study examines the relationship of such changes to serotonin system abnormalities associated with depression. Methods: Thirteen male medication free subjects who were inpatients with a DSM-IIIR major depressive disorder and seven healthy male subjects underwent an [18F]-fluorodeoxyglucose (18FDG) PET scan on consecutive days. Three hours prior to 18FDG subjects received single blind placebo or fenfluramine. Comparisons of voxel level regional glucose metabolic rate responses (rCMRglu) between groups in the two states were performed with SPM99. Results: Unlike healthy male subjects who have significant increases in rCMRglu in prefrontal and parietal cortical regions after receiving fenfluramine, depressed male subjects have no significant increases in rCMRglu. Conclusions: Blunted increases in rCMRglu in response to fenfluramine in prefrontal and parietal cortex are consistent with our previous pilot study and the indoleamine hypothesis of depression. Differences in specific brain regions affected between this study and previous studies may be attributable to gender differences. D 2004 Elsevier B.V. All rights reserved. Keywords: Major depressive disorder; D-fenfluramine; Serotonin; Positron emission tomography; Regional glucose metabolic rate response; 18 FDG
1. Introduction Positron emission tomography (PET) studies have reported lower regional glucose metabolism in mood disorders in dorsolateral, ventral subgenual and dorsomedial prefrontal cortical regions, and greater glu* Corresponding author. Unit 42, Departments of Psychiatry and Radiology, Columbia University, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. Tel.: +1-212-543-5571. E-mail address: [email protected] (J.J. Mann). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.04.003
cose uptake in ventrolateral prefrontal cortical and paralimbic regions compared to healthy subjects (Drevets, 2000; Dunn et al., 2002; Kimbrell et al., 2002; Mann et al., 1996b). Studies have used fenfluramine challenge to elucidate regional serotonergic function in addition to measures of resting regional glucose metabolic rate responses (rCMRglu) (Mann et al., 1996b; Newman et al., 1998). DL-Fenfluramine causes a major release of serotonin and regional, brain metabolic responses to release of serotonin can be measured by (18FDG) and PET.
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In healthy volunteers, fenfluramine induces increases in rCMRglu in the left prefrontal cortex and the parietal cortex and decreases in the right occipital lobe and cerebellum (Mann et al., 1996a) and in occipital-temporal regions (Kapur et al., 1994). In contrast, our small pilot study found that depressed subjects do not show significant increases or decreases in glucose metabolism after fenfluramine compared to baseline levels of rCMRglu (Mann et al., 1996b). Gender differences have been described in serotonergic function and glucose metabolism in the brain suggesting that studies of serotonergic function in major depression must take into account gender effects. For example, women are reported to have higher global glucose metabolic rates compared to men (Baxter et al., 1986; Willis et al., 2002), and others have found that in addition to having lower global metabolism, men reportedly show lower regional cortical and subcortical metabolic rates (Willis et al., 2002) or greater relative metabolism in lateral and ventromedial portions of temporal lobe and lower metabolism in middle and posterior cingulate gyrus (Gur et al., 1995). Our original pilot study included twice as many women as men and the depression deficit effects appeared strongest in the women (Mann et al., 1996b). In order to determine whether the regional brain serotonin deficiency was also present in males with depression, we studied medication-free males with a major depressive disorder and healthy male volunteers with PET 18FDG after placebo administration and after fenfluramine administration.
2. Methods Thirteen male subjects with major depressive disorder who met DSM-III-R criteria for a current major depressive episode based on the Structured Clinical Interview for DSM-III-R-Patient Edition (American Psychiatric Association, 1987) and seven healthy control male subjects who had no evidence of axis I or axis II psychopathology or first degree relatives with mood disorders were studied. Subjects were assessed for depression severity with the 17item Hamilton Depression Rating Scale (Ham-D) (Hamilton, 1960) and the Beck Scale for Suicidal Ideation (SSI) (Beck et al., 1979). Suicidal ideation was rated with the Beck Scale for Suicidal Ideation.
Patients were medication free at least 14 days prior to PET studies (6 weeks for fluoxetine and 1 month in the case of oral antipsychotics). Subjects with major depressive disorder were all inpatients and bipolar patients were excluded from the study. All subjects were free of medical illness based on history, physical examination and laboratory tests, including liver function tests, hematologic profile, thyroid function tests, urinalysis and toxicology. Subjects had PET studies on two consecutive days after fasting from midnight and throughout the challenge test. They received placebo on the first day and fenfluramine on the second in a single blind design. On each study day, an intravenous catheter was inserted at 8:00 AM and a solution of 5% dextrose and .45% saline was infused. An oral dose of approximately 0.8 mg/kg of DL-fenfluramine (or identical pills containing placebo) was administered at 9:00 AM on each day. Fenfluramine was always given on the second day to avoid enduring pharmacological effects. In order to capture the maximal response to fenfluramine, a bolus injection of approximately 5 mCi 18 FDG was administered three hours after the administration of placebo/fenfluramine. Subjects gazed at a uniform visual stimulus (cross hairs) in a dimmed room during the first 15 min of the 18FDG distribution phase. Subjects were then transferred to the scanner where they lay supine. A custom made thermoplastic mask was used to minimize head movement. The head was positioned so that the lowest scanning plane was parallel to the canthomeatal line and approximately 1.0 cm above it and then the laser crosshair positions on the mask were marked. For the second study, the head was positioned as closely as possible to the first study by using the original mask and the laser light marks from the previous study. A Siemens ECAT EXACT 47 scanner (in plane spatial resolution 5.8 mm, axial resolution 4.3 mm FWHM at center) was used to acquire a 60-min emission scan in 2D mode as a series of twelve 5-min frames. The attenuation correction was based on a 15-min 68Ge/68Ga transmission scan. Images were reconstructed with a Shepp radial filter, cutoff frequency of 35 cycles per projection rays and a ramp axial filter, cutoff frequency of 0.5 S. Regions of significant differences in rCMRglu between unipolar and healthy males on placebo day and fenfluramine day were evaluated using Statistical Parametric Mapping (SPM), Version 99 (SPM99;
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
Wellcome Department of Cognitive Neurology, London, UK; Friston et al., 1995). Automated image coregistration (Woods et al., 1992) was used to align the 12 frames within each study (Mann et al., 1996a). The resulting summed image was transformed into MNI standard stereotaxic atlas space. Each image was smoothed by applying an isotropic Gaussian kernel to increase the signal to noise ratio. Proportional scaling was applied within each condition controlling for global CMRglu. For each group, the adjusted mean rCMRglu and variance were computed at each voxel for both placebo day and fenfluramine day. These were
413
used to perform a t-test and p values (uncorrected and corrected for multiple comparisons) were computed for the differences of the means between groups for each study day at each voxel. A whole brain parametric map was constructed based on t values displaying all voxels with p < 0.01. (Friston et al., 1995).
3. Results Depressed subjects were not significantly statistically older than normal controls (mean age = 41.2 F
Fig. 1. Areas of greater relative regional cerebral metabolism rate for glucose (rCMRglu) in healthy male subjects compared to unipolar male subjects after fenfluramine administration (day 2). Compared p values for extent of cluster and voxel height and respective (x, y, z) coordinates in significantly different clusters: Extent of Cluster P (voxels, Z)
Voxel height corrected p (Z)
0.000 (4241, 4.05)
0.298 (4.05) 0.348 (3.99) 0.792 (3.54)
(x, y, z) coordinates 22, 32, 54 24, 15, 49 32, 39, 2
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12.4, 30.3 F 13.8 years, respectively; df = 18, t = 1.8, p = 0.09) and were moderately depressed at the time of the study (HAM 17 = 21.3 F 3.3). There were six suicide attempters in the depressed group. The average age of onset of first major depressive episode was 24.2 F 12.5 years and the average number of previous depressive episodes was 3.7 F 2.3. The average length of the current depressive episode was 118.5 F 206.4 days or about 4 months and the suicidal ideation at the time of admission was in the moderate range (SSI = 10.8 F 8.0).
A repeated measures general linear model showed that, as expected fenfluramine plus norfenfluramine increased significantly over the course of the study (Pillai’s trace F = 79.67, df = 15, p < 0.0001). However there were no significant differences in fenfluramine plus norfenfluramine levels in controls compared to depressed subjects ( F = 4.12, df = 1, 19, p = 0.06). Figs. 1 and 2 depict the results of the voxel-based analyses comparing rCMRglu in patients and volunteers, after controlling for global glucose metabolic rates. In Fig. 1, after the administration of fenflur-
Fig. 2. Areas of greater relative regional cerebral metabolism rate for glucose (rCMRglu) for healthy male subjects on the fenfluramine day compared to the placebo day. Extent of Cluster P (voxels, Z)
Voxel height corrected p (Z)
(x, y, z) coordinates
0.014 (859, 4.22)
0.917 0.967 1.000 0.954 0.995
20, 24, 8 12, 22, 12 14, 10, 12 40, 42, 5 42, 56, 8
0.031 (734, 4.12)
(4.22) (4.07) (3.32) (4.12) (3.86)
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
amine, healthy volunteers show a significantly greater rCMRglu in prefrontal and frontal cortex, particularly the superior frontal gyrus (BA 8, 4), the middle frontal gyrus (BA 9, 10), the inferior frontal gyrus (BA 44, 45, 46) and the inferior parietal lobe (BA 40) and the superior parietal lobe (BA 5) compared to depressed subjects. The areas in which healthy volunteers have higher rCMRglu than depressed males are mostly left sided (Fig. 1). Fig. 2 shows rCMRglu after placebo compared to rCMRglu after fenfluramine in healthy volunteers. There are two distinct clusters that show an increase in rCMRglu after fenfluramine administration when compared to rCMRglu after placebo. One cluster ( p = 0.014) is in the left prefrontal and frontal cortex in the middle frontal gyrus (BA 45, 10) and in the caudate nucleus. The second cluster ( p = 0.031) is in the right middle frontal gyrus (BA 10). A similar analysis in the unipolar depressed subjects showed no areas of increased rCMRglu after fenfluramine compared to after placebo.
4. Discussion After fenfluramine administration, healthy male subjects exhibit significantly greater rCMRglu responses compared to male depressed subjects. The areas of greater rCMRglu responses in healthy subjects are in the superior, middle and inferior frontal gyrus of the prefrontal cortices and in the inferior and superior parietal cortex. Increases are mostly on the left side. This is consistent with what we reported previously in a different sample of male and female depressed subjects (Mann et al., 1996a). In this previous study, healthy volunteers had areas of greater rCMRglu compared to depressed subjects in the prefrontal and parietal cortices as well as in the temporal cortex. That study included four females and two males in each group and sex differences may explain the variation on regional differences. Our current study also found that healthy volunteers differed significantly in rCMRglu on placebo compared to fenfluramine with significant increases seen in the right and left middle frontal gyrus and the left caudate. The depressed subjects did not have a significant change after fenfluramine. This result is also consistent with our prior report in which the compar-
415
ison of scans after placebo and after fenfluramine demonstrated that healthy subjects had increases in rCMRglu in their left prefrontal and temporoparietal cortex and right orbital frontal cortex, whereas depressed subjects had no areas of increased relative glucose metabolism after administration of fenfluramine compared to placebo (Mann et al., 1996a). Healthy subjects demonstrated an increase in rCMRglu in the caudate after receiving fenfluramine. Past studies have found lower metabolism in the caudate nucleus in unipolar depression (Videbech, 2000). Our finding that depressed patients did not show a significant increase in caudate rCMRglu after receiving fenfluramine further indicates an abnormality in caudate function that may involve serotonergic transmission. Major depressive disorder is thought to be related to serotonergic dysfunction in the brain. Mayberg (1997) proposed a model of depression involving a disruption of limbic-cortical pathways based on evidence showing rCMRglu alterations in depressed patients and changes in metabolism after treatment with antidepressants. She found that in both induced sadness and major depression, decreases in rCMRglu were seen in anterior and posterior cingulate and prefrontal regions and increases were found in the ventral paralimbic areas. These brain regions showed a more normal level of activation as illness symptoms subsided. It has also been reported that induced transient sadness causes significant decreases in the inferior parietal lobe and the right dorsal prefrontal cortex and dorsal cingulate (Mayberg et al., 1999). Our current study supports this model in that depressed subjects exhibited significantly lower rCMRglu in prefrontal and frontal cortex and the inferior parietal lobe and the insula compared to healthy subjects. Additionally, after receiving fenfluramine, healthy subjects showed significant increases compared to baseline levels of rCMRglu and, in contrast, depressed patients exhibited no change. Although we found nonsignificant increases in rCMRglu in the ventral and paralimbic regions in depressed patient, we did find significantly lower rCMRglu in depressed patients in the inferior parietal lobe and the inferior frontal gyrus. Although our results show non-significant increases in the limbic and paralimbic regions, our results do support the findings that the inferior parietal lobe and dorsal prefrontal cortex are involved in depres-
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sion. The fact that our results only show non-significant increases, unlike our previous studies that did have significant increases in rCMRglu, may be attributable to our small, unisex sample. Consistent with our current study, we had previously reported asymmetric increases in the left lateral prefrontal cortex occurring in healthy subjects after fenfluramine compared to baseline scans (Mann et al., 1996b). Asymmetrical changes in rCMRglu have been reported consistently in other studies. In a study by Kennedy et al. (2001), rCMRglu was measured in a sample of male patients suffering from major depression before and after treatment with paroxetine. This study supports the findings of the current study in that successful treatment with paroxetine was associated with mainly left sided significant increases in rCMRglu in prefrontal and inferior parietal regions. Our sample of healthy male subjects exhibited mainly left sided increases after receiving fenfluramine. With successful treatment, the sample of depressed patients in the Kennedy study showed similar rCMRglu patterns as a group of healthy subjects. Martinot et al. (1990) also reported that lower left prefrontal rCMRglu in a sample of depressed subjects improved after treatment. Unlike Mann et al. (1996b), our current study did not find healthy subjects to have significant changes in the temporoparietal cortex after receiving fenfluramine. These differences may be attributable to gender differences. Those studies included men and women. It has been suggested that women have greater global glucose metabolic rates at baseline, and other studies have found that men have lower metabolism at baseline (Baxter and Willis). Volkow et al. (1997) found that healthy women had greater glucose metabolism in the temporal poles at baseline FDG scans compared to healthy male subjects, whereas Gur et al. (1995) determined males to have greater metabolism in the temporal poles. Although these two studies contradict each other in terms of specific differences, they both suggest that men and women have regional differences in glucose metabolism. Therefore, it is possible that differences between our current results and past results are attributable to the inclusion of males only. To our knowledge there are no existing studies looking at gender effects after fenfluramine challenge, an area that requires future studies that include women
and men in the same study. A limitation of our study is that the sample of healthy volunteers is not large. Another area of future inquiry is the effect of recovery on the observed abnormalities to determine if they are state or trait dependent.
Acknowledgements This study was supported by MH40695, MH62185 and the American Foundation for Suicide Prevention. References American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R). APA Press, Washington, DC. Baxter, L.R., Mazziotta, J.C., Phelps, M.E., Selin, C.E., Guze, B.H., Fairbanks, L., 1986. Cerebral glucose metabolic rates in normal human females versus normal males. Psychiatry Res. 21, 237 – 245. Beck, A.T., Kovacs, M., Weissman, A., 1979. Assessment of suicidal intention: the scale for suicidal ideation. J. Consult. Clin. Psychol. 47, 343 – 352. Drevets, W.C., 2000. Neuroimaging studies of mood disorders. Biol. Psychiatry 48, 813 – 829. Dunn, R.T., Kimbrell, T.A., Ketter, T.A., et al., 2002. Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression. Biol. Psychiatry 51, 387 – 399. Friston, K.J., Holmes, A.P., Worsley, K.J., Poline, J.B., Frith, C.D., Francowiak, R.S.J., 1995. Statistical parametric maps in functional imaging: a general linear approach. Hum. Brain Mapp. 2, 189 – 210. Gur, R.C., Mozley, L.H., Mozley, P.D., et al., 1995. Sex differences in regional cerebral glucose metabolism during a resting state. Science 267, 528 – 531. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56 – 62. Kapur, S., Meyer, J., Wilson, A.A., Houle, S., Brown, G.M., 1994. Modulation of cortical neuronal activity by serotonergic agent: a PET study in humans. Brain Res. 646 (2), 292 – 294. Kennedy, S.H., Evans, K.R., Kruger, S., Mayberg, H.S., Meyer, J.H., McCann, S., Arifuzzman, A.I., Houle, S., Vaccarino, F.J., 2001. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am. J. Psychiatry 158, 899 – 905. Kimbrell, T.A., Ketter, T.A., George, M.S., et al., 2002. Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol. Psychiatry 51, 237 – 252. Mann, J.J., Malone, K.M., Diehl, D.J., Perel, J., Cooper, T.B., Mintun, M.A., 1996a. Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients. Am. J. Psychiatry 153, 174 – 182.
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417 Mann, J.J., Malone, K.M., Diehl, D.J., Perel, J., Nichols, T.E., Mintun, M.A., 1996b. Positron emission tomographic imaging of serotonin activation effects on prefrontal cortex in healthy volunteers. J. Cereb. Blood Flow Metab. 16, 418 – 4126. Martinot, J.L., Hardy, P., Feline, A., Huret, J.D., Mazoyer, B., AttarLevy, D., Pappata, S., Syrota, A., 1990. Left prefrontal glucose hypometabolism in the depressed state: a confirmation. Am. J. Psychiatry 147, 1313 – 1317. Mayberg, H.S., 1997. Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry 9, 471 – 481. Mayberg, H.S., Liotti, M., Brannan, S.K., McGinnis, S., Mahurin, R.K., Jerabek, P.A., Silva, J.A., Tekell, J.K., Martin, C.C., Lancaster, J.K., Fox, P.T., 1999. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675 – 682.
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Newman, M.E., Shapira, B., Lerer, B., 1998. Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review. Int. J. Neuropsychopharmacol. 1, 49 – 69. Videbech, P., 2000. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatry Scand. 101, 11 – 20. Volkow, N.D., Wang, G.J., Fowler, J.S., Hitzermann, R., Pappas, N., Pascani, K., Wong, C., 1997. Gender differences in cerebellar metabolism: test-retest reproducibility. Am. J. Psychiatry 154, 119 – 121. Willis, M.W., Ketter, T.A., Kimbrell, T.A., 2002. Age, sex and laterality effects on cerebral glucose metabolism in healthy adults. Psychiatry Res. 114, 23 – 37. Woods, R.P., Cherry, S.R., Mazziotta, J.C., 1992. Rapid automated algorithm for aligning and reslicing PET images. J. Comput. Assist. Tomogr. 16, 620 – 633.
Research report
Regional brain responses to serotonin in major depressive disorder Amy D. Anderson a, Maria A. Oquendo a,b, Ramin V. Parsey a,b, Matthew S. Milak a,b, Carl Campbell a, J. John Mann a,b,c,* a Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY 10032, USA c Department of Radiology, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY 10032, USA
b
Received 3 November 2003; accepted 5 April 2004
Abstract Background: Positron Emission Tomography (PET) studies have reported altered resting regional brain glucose metabolism in mood disorders. This study examines the relationship of such changes to serotonin system abnormalities associated with depression. Methods: Thirteen male medication free subjects who were inpatients with a DSM-IIIR major depressive disorder and seven healthy male subjects underwent an [18F]-fluorodeoxyglucose (18FDG) PET scan on consecutive days. Three hours prior to 18FDG subjects received single blind placebo or fenfluramine. Comparisons of voxel level regional glucose metabolic rate responses (rCMRglu) between groups in the two states were performed with SPM99. Results: Unlike healthy male subjects who have significant increases in rCMRglu in prefrontal and parietal cortical regions after receiving fenfluramine, depressed male subjects have no significant increases in rCMRglu. Conclusions: Blunted increases in rCMRglu in response to fenfluramine in prefrontal and parietal cortex are consistent with our previous pilot study and the indoleamine hypothesis of depression. Differences in specific brain regions affected between this study and previous studies may be attributable to gender differences. D 2004 Elsevier B.V. All rights reserved. Keywords: Major depressive disorder; D-fenfluramine; Serotonin; Positron emission tomography; Regional glucose metabolic rate response; 18 FDG
1. Introduction Positron emission tomography (PET) studies have reported lower regional glucose metabolism in mood disorders in dorsolateral, ventral subgenual and dorsomedial prefrontal cortical regions, and greater glu* Corresponding author. Unit 42, Departments of Psychiatry and Radiology, Columbia University, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. Tel.: +1-212-543-5571. E-mail address: [email protected] (J.J. Mann). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.04.003
cose uptake in ventrolateral prefrontal cortical and paralimbic regions compared to healthy subjects (Drevets, 2000; Dunn et al., 2002; Kimbrell et al., 2002; Mann et al., 1996b). Studies have used fenfluramine challenge to elucidate regional serotonergic function in addition to measures of resting regional glucose metabolic rate responses (rCMRglu) (Mann et al., 1996b; Newman et al., 1998). DL-Fenfluramine causes a major release of serotonin and regional, brain metabolic responses to release of serotonin can be measured by (18FDG) and PET.
412
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
In healthy volunteers, fenfluramine induces increases in rCMRglu in the left prefrontal cortex and the parietal cortex and decreases in the right occipital lobe and cerebellum (Mann et al., 1996a) and in occipital-temporal regions (Kapur et al., 1994). In contrast, our small pilot study found that depressed subjects do not show significant increases or decreases in glucose metabolism after fenfluramine compared to baseline levels of rCMRglu (Mann et al., 1996b). Gender differences have been described in serotonergic function and glucose metabolism in the brain suggesting that studies of serotonergic function in major depression must take into account gender effects. For example, women are reported to have higher global glucose metabolic rates compared to men (Baxter et al., 1986; Willis et al., 2002), and others have found that in addition to having lower global metabolism, men reportedly show lower regional cortical and subcortical metabolic rates (Willis et al., 2002) or greater relative metabolism in lateral and ventromedial portions of temporal lobe and lower metabolism in middle and posterior cingulate gyrus (Gur et al., 1995). Our original pilot study included twice as many women as men and the depression deficit effects appeared strongest in the women (Mann et al., 1996b). In order to determine whether the regional brain serotonin deficiency was also present in males with depression, we studied medication-free males with a major depressive disorder and healthy male volunteers with PET 18FDG after placebo administration and after fenfluramine administration.
2. Methods Thirteen male subjects with major depressive disorder who met DSM-III-R criteria for a current major depressive episode based on the Structured Clinical Interview for DSM-III-R-Patient Edition (American Psychiatric Association, 1987) and seven healthy control male subjects who had no evidence of axis I or axis II psychopathology or first degree relatives with mood disorders were studied. Subjects were assessed for depression severity with the 17item Hamilton Depression Rating Scale (Ham-D) (Hamilton, 1960) and the Beck Scale for Suicidal Ideation (SSI) (Beck et al., 1979). Suicidal ideation was rated with the Beck Scale for Suicidal Ideation.
Patients were medication free at least 14 days prior to PET studies (6 weeks for fluoxetine and 1 month in the case of oral antipsychotics). Subjects with major depressive disorder were all inpatients and bipolar patients were excluded from the study. All subjects were free of medical illness based on history, physical examination and laboratory tests, including liver function tests, hematologic profile, thyroid function tests, urinalysis and toxicology. Subjects had PET studies on two consecutive days after fasting from midnight and throughout the challenge test. They received placebo on the first day and fenfluramine on the second in a single blind design. On each study day, an intravenous catheter was inserted at 8:00 AM and a solution of 5% dextrose and .45% saline was infused. An oral dose of approximately 0.8 mg/kg of DL-fenfluramine (or identical pills containing placebo) was administered at 9:00 AM on each day. Fenfluramine was always given on the second day to avoid enduring pharmacological effects. In order to capture the maximal response to fenfluramine, a bolus injection of approximately 5 mCi 18 FDG was administered three hours after the administration of placebo/fenfluramine. Subjects gazed at a uniform visual stimulus (cross hairs) in a dimmed room during the first 15 min of the 18FDG distribution phase. Subjects were then transferred to the scanner where they lay supine. A custom made thermoplastic mask was used to minimize head movement. The head was positioned so that the lowest scanning plane was parallel to the canthomeatal line and approximately 1.0 cm above it and then the laser crosshair positions on the mask were marked. For the second study, the head was positioned as closely as possible to the first study by using the original mask and the laser light marks from the previous study. A Siemens ECAT EXACT 47 scanner (in plane spatial resolution 5.8 mm, axial resolution 4.3 mm FWHM at center) was used to acquire a 60-min emission scan in 2D mode as a series of twelve 5-min frames. The attenuation correction was based on a 15-min 68Ge/68Ga transmission scan. Images were reconstructed with a Shepp radial filter, cutoff frequency of 35 cycles per projection rays and a ramp axial filter, cutoff frequency of 0.5 S. Regions of significant differences in rCMRglu between unipolar and healthy males on placebo day and fenfluramine day were evaluated using Statistical Parametric Mapping (SPM), Version 99 (SPM99;
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
Wellcome Department of Cognitive Neurology, London, UK; Friston et al., 1995). Automated image coregistration (Woods et al., 1992) was used to align the 12 frames within each study (Mann et al., 1996a). The resulting summed image was transformed into MNI standard stereotaxic atlas space. Each image was smoothed by applying an isotropic Gaussian kernel to increase the signal to noise ratio. Proportional scaling was applied within each condition controlling for global CMRglu. For each group, the adjusted mean rCMRglu and variance were computed at each voxel for both placebo day and fenfluramine day. These were
413
used to perform a t-test and p values (uncorrected and corrected for multiple comparisons) were computed for the differences of the means between groups for each study day at each voxel. A whole brain parametric map was constructed based on t values displaying all voxels with p < 0.01. (Friston et al., 1995).
3. Results Depressed subjects were not significantly statistically older than normal controls (mean age = 41.2 F
Fig. 1. Areas of greater relative regional cerebral metabolism rate for glucose (rCMRglu) in healthy male subjects compared to unipolar male subjects after fenfluramine administration (day 2). Compared p values for extent of cluster and voxel height and respective (x, y, z) coordinates in significantly different clusters: Extent of Cluster P (voxels, Z)
Voxel height corrected p (Z)
0.000 (4241, 4.05)
0.298 (4.05) 0.348 (3.99) 0.792 (3.54)
(x, y, z) coordinates 22, 32, 54 24, 15, 49 32, 39, 2
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A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
12.4, 30.3 F 13.8 years, respectively; df = 18, t = 1.8, p = 0.09) and were moderately depressed at the time of the study (HAM 17 = 21.3 F 3.3). There were six suicide attempters in the depressed group. The average age of onset of first major depressive episode was 24.2 F 12.5 years and the average number of previous depressive episodes was 3.7 F 2.3. The average length of the current depressive episode was 118.5 F 206.4 days or about 4 months and the suicidal ideation at the time of admission was in the moderate range (SSI = 10.8 F 8.0).
A repeated measures general linear model showed that, as expected fenfluramine plus norfenfluramine increased significantly over the course of the study (Pillai’s trace F = 79.67, df = 15, p < 0.0001). However there were no significant differences in fenfluramine plus norfenfluramine levels in controls compared to depressed subjects ( F = 4.12, df = 1, 19, p = 0.06). Figs. 1 and 2 depict the results of the voxel-based analyses comparing rCMRglu in patients and volunteers, after controlling for global glucose metabolic rates. In Fig. 1, after the administration of fenflur-
Fig. 2. Areas of greater relative regional cerebral metabolism rate for glucose (rCMRglu) for healthy male subjects on the fenfluramine day compared to the placebo day. Extent of Cluster P (voxels, Z)
Voxel height corrected p (Z)
(x, y, z) coordinates
0.014 (859, 4.22)
0.917 0.967 1.000 0.954 0.995
20, 24, 8 12, 22, 12 14, 10, 12 40, 42, 5 42, 56, 8
0.031 (734, 4.12)
(4.22) (4.07) (3.32) (4.12) (3.86)
A.D. Anderson et al. / Journal of Affective Disorders 82 (2004) 411–417
amine, healthy volunteers show a significantly greater rCMRglu in prefrontal and frontal cortex, particularly the superior frontal gyrus (BA 8, 4), the middle frontal gyrus (BA 9, 10), the inferior frontal gyrus (BA 44, 45, 46) and the inferior parietal lobe (BA 40) and the superior parietal lobe (BA 5) compared to depressed subjects. The areas in which healthy volunteers have higher rCMRglu than depressed males are mostly left sided (Fig. 1). Fig. 2 shows rCMRglu after placebo compared to rCMRglu after fenfluramine in healthy volunteers. There are two distinct clusters that show an increase in rCMRglu after fenfluramine administration when compared to rCMRglu after placebo. One cluster ( p = 0.014) is in the left prefrontal and frontal cortex in the middle frontal gyrus (BA 45, 10) and in the caudate nucleus. The second cluster ( p = 0.031) is in the right middle frontal gyrus (BA 10). A similar analysis in the unipolar depressed subjects showed no areas of increased rCMRglu after fenfluramine compared to after placebo.
4. Discussion After fenfluramine administration, healthy male subjects exhibit significantly greater rCMRglu responses compared to male depressed subjects. The areas of greater rCMRglu responses in healthy subjects are in the superior, middle and inferior frontal gyrus of the prefrontal cortices and in the inferior and superior parietal cortex. Increases are mostly on the left side. This is consistent with what we reported previously in a different sample of male and female depressed subjects (Mann et al., 1996a). In this previous study, healthy volunteers had areas of greater rCMRglu compared to depressed subjects in the prefrontal and parietal cortices as well as in the temporal cortex. That study included four females and two males in each group and sex differences may explain the variation on regional differences. Our current study also found that healthy volunteers differed significantly in rCMRglu on placebo compared to fenfluramine with significant increases seen in the right and left middle frontal gyrus and the left caudate. The depressed subjects did not have a significant change after fenfluramine. This result is also consistent with our prior report in which the compar-
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ison of scans after placebo and after fenfluramine demonstrated that healthy subjects had increases in rCMRglu in their left prefrontal and temporoparietal cortex and right orbital frontal cortex, whereas depressed subjects had no areas of increased relative glucose metabolism after administration of fenfluramine compared to placebo (Mann et al., 1996a). Healthy subjects demonstrated an increase in rCMRglu in the caudate after receiving fenfluramine. Past studies have found lower metabolism in the caudate nucleus in unipolar depression (Videbech, 2000). Our finding that depressed patients did not show a significant increase in caudate rCMRglu after receiving fenfluramine further indicates an abnormality in caudate function that may involve serotonergic transmission. Major depressive disorder is thought to be related to serotonergic dysfunction in the brain. Mayberg (1997) proposed a model of depression involving a disruption of limbic-cortical pathways based on evidence showing rCMRglu alterations in depressed patients and changes in metabolism after treatment with antidepressants. She found that in both induced sadness and major depression, decreases in rCMRglu were seen in anterior and posterior cingulate and prefrontal regions and increases were found in the ventral paralimbic areas. These brain regions showed a more normal level of activation as illness symptoms subsided. It has also been reported that induced transient sadness causes significant decreases in the inferior parietal lobe and the right dorsal prefrontal cortex and dorsal cingulate (Mayberg et al., 1999). Our current study supports this model in that depressed subjects exhibited significantly lower rCMRglu in prefrontal and frontal cortex and the inferior parietal lobe and the insula compared to healthy subjects. Additionally, after receiving fenfluramine, healthy subjects showed significant increases compared to baseline levels of rCMRglu and, in contrast, depressed patients exhibited no change. Although we found nonsignificant increases in rCMRglu in the ventral and paralimbic regions in depressed patient, we did find significantly lower rCMRglu in depressed patients in the inferior parietal lobe and the inferior frontal gyrus. Although our results show non-significant increases in the limbic and paralimbic regions, our results do support the findings that the inferior parietal lobe and dorsal prefrontal cortex are involved in depres-
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sion. The fact that our results only show non-significant increases, unlike our previous studies that did have significant increases in rCMRglu, may be attributable to our small, unisex sample. Consistent with our current study, we had previously reported asymmetric increases in the left lateral prefrontal cortex occurring in healthy subjects after fenfluramine compared to baseline scans (Mann et al., 1996b). Asymmetrical changes in rCMRglu have been reported consistently in other studies. In a study by Kennedy et al. (2001), rCMRglu was measured in a sample of male patients suffering from major depression before and after treatment with paroxetine. This study supports the findings of the current study in that successful treatment with paroxetine was associated with mainly left sided significant increases in rCMRglu in prefrontal and inferior parietal regions. Our sample of healthy male subjects exhibited mainly left sided increases after receiving fenfluramine. With successful treatment, the sample of depressed patients in the Kennedy study showed similar rCMRglu patterns as a group of healthy subjects. Martinot et al. (1990) also reported that lower left prefrontal rCMRglu in a sample of depressed subjects improved after treatment. Unlike Mann et al. (1996b), our current study did not find healthy subjects to have significant changes in the temporoparietal cortex after receiving fenfluramine. These differences may be attributable to gender differences. Those studies included men and women. It has been suggested that women have greater global glucose metabolic rates at baseline, and other studies have found that men have lower metabolism at baseline (Baxter and Willis). Volkow et al. (1997) found that healthy women had greater glucose metabolism in the temporal poles at baseline FDG scans compared to healthy male subjects, whereas Gur et al. (1995) determined males to have greater metabolism in the temporal poles. Although these two studies contradict each other in terms of specific differences, they both suggest that men and women have regional differences in glucose metabolism. Therefore, it is possible that differences between our current results and past results are attributable to the inclusion of males only. To our knowledge there are no existing studies looking at gender effects after fenfluramine challenge, an area that requires future studies that include women
and men in the same study. A limitation of our study is that the sample of healthy volunteers is not large. Another area of future inquiry is the effect of recovery on the observed abnormalities to determine if they are state or trait dependent.
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