- Email: [email protected]
Changes in regional cerebral blood flow in depressed patients treated with electroconvulsive therapy
$226
P.I. Affective disorders and antidepressants
(AUC netto cortisoh r = -.40, p < 0.05). However, the DEX/CRH test results of week 6 did not correlate with treatment response after 6 weeks. At follow up none of the DEX/CRH test parameters did correlate with treatment response. Whereas duration of illness did not correlate with any of the DEX/CRH test results, the number of episodes until study entry was highly correlated with the DEX/CRH test outcome at baseline and at week 6 (Spearman's rho: p < 0.01). However, at follow up none of the DEX/CRH test values correlated with the long-term variables of depression. Although no correlation was found between DEX/CRH test results and recurrences after the index episode, the cortisol response of psychopathologically remitted patients at week 6 was descriptively higher in those with than those without recurrences (relative risk 2.33; p = n.s.). In conclusion, HPA system regulation in depression is associated with early treatment response as well as with therapeutical outcome after a standard treatment period of 6 weeks. Furthermore, long-term course of depression as reflected by number of episodes is significantly correlated with HPA system dysfunction. (Supported by the Swiss NSF Nr 3200-052778.97)
II-J.1.1 O;51 Lumbar bone mineral density in male patients with depression: A preliminary study M.T. Turan, E. Esel*, M. Kula, H. Demir, S. Kartalci, S. Sofuoglu. Erciyes University, Departments of Psychiatry, Nuclear
Medicine and Physical Medicine and Rehabilitation, Kayseri, Turkey Objective: It has been previously reported that past or current depressive episodes are associated with decreased bone mineral density (BMD) (1, 2). This loss of bone density has been put forward to be an endpoint of the cumulative intensity of hypothalamic-pituitary-adrenal axis hyperactivity and hypercortisolemia or changing physical activity in depression. This study was undertaken to determine whether men with major depression exhibit any decrease in BMD. Methods: Sixteen male depressed inpatients (mean age -4- SD: 43.50 ± 9.39 years, range: 37-55, mean duration of illness + SD: 84.62 5:52.68 months) and t6 age-matched healthy male control subjects (mean age 4- SD: 45.75 4- 8.27 years, range: 39-58) were included in the study. All patients were diagnosed with major depressive disorder (recurrent) according to the DSM-IV criteria. None of the subjects were taking any drug affecting BMD, but all patients were treated with antidepressants for various amounts of time. Montgomery-Asberg Depression Rating Scale (MADRS) was used to rate the severity of the patients' depressions, and all patients had 25 or more scores in MADRS. Mean BMD values of the first to fourth lumbar vertebrae were measured by using dualenergy X-ray absorptiometry (Hologic QDR-4500 DXA). Ages and the values of BMD of the patients and controls were compared with Mann-Whitney U test. The correlations between BMD values and some clinical variables (age, the number of depressive episodes, MADRS score) in the patients were investigated by Pearson's correlation test. Results: There was no statistically significant difference between the mean ages of the patient and control groups (U = 112, p > 0.5). Nor was a significant difference found between the mean BMD values of the patients and the controls (U = 98, p > 0.05). We did not find any correlations between BMD values and clinical variables such as age, MADRS score, duration of illness and the number of depressive episodes in the patients, either.
Conclusion: The data show that major depressive disorder does not affect the bone mineral density in men. Although this result seems to be inconsistent with the previous studies reporting BMD loss in depressive patients (1, 2), this discrepancy may be explained by the facts that the sample number was small, our patients were considerably younger and had a shorter duration of illness than those of the previous studies.
References [1] Schweiger,U., Deuschle, M., Kfrner, A., Lammers, C-H., Schmider,J., Gotthardt, U., Holsboer, F., Heuser, I., 1994. Low lumbar bone mineral density in patients with major depression.Am. J. Psychiatry 151, 16911693. [2] Michelson, D., Stratakis, C., Hill, L., Reynolds, J., Galliven, E., Chrousos, G., Gold, P., 1996. Bone mineral density in women with depression. N. Engl. J. Med. 335, 1176--1181.
•
Changes in regional cerebral blood flow in depressed patients treated with electroconvuIsive therapy
E. Esel, M. Kula, A.S. G6niil, M.T. Turan, M. Reyhancan, A. Tutus, M. Basturk, S. Sofuoglu. Erciyes University, Departments
of Psychiatry and Nuclear Medicine, Kayseri, Turkey Objective: There are a lot of data showing impaired regional cerebral blood flow (rCBF) in major depression and bipolar depression (1). Our purpose was to investigate whether there was a difference in rCBF pattern between before and after an electroconvulsive therapy (ECT) cure in depressed patients. This would render some insight as to whether rCBF alteration in depression was a state or trait marker. Methods: Nineteen depressed inpatients (8 males, 11 females; mean age ± SD: 44.77 -4- 10.59 years) and 17 healthy control subjects (8 males, 9 females; mean age 4- SD: 43.76 4- 11.70 years) were included in the study. All the patients and controls were right-handed. Eight of the patients had bipolar I disorderdepressive episode, and 11 of them had major depressive disorder (recurrent) according to the DSM-IV criteria. None of the patients had taken any drug for two weeks before the study. The 17-item Hamilton Rating Scale for Depression (HAM-D) was used to rate the severity of depression before treatment and those who had 16 or more scores in HAM-D were included in the study. Each patient was exposed to 7-10 ECT sessions with anaesthesia totally. Brain SPECT images were obtained by using Tc 99M-HMPAO 2-4 days before the first ECT and 10 days after the last ECT in the patients, and only once in the controls. All patients showed at least 60% reduction in the pretreatment HAM-D score and they were accepted to have response to ECT treatment. For semiquantitative analysis, three transaxial brain slices delineating anatomically defined regions of interest at 33, 49.5 and 66 nun above the orbitomeatal line were used, with the average number of counts for each region of interest normalised to the area of maximal cerebellar uptake. One-way ANOVA was used to compare rCBF values of the controls and those of the patients before and after the course of ECT. When a significant difference was detected, it was investigated by post-hoc paired or independent samples t tests. Results: Before treatment, significant decreases in rCBF were found in left and right high frontal, left and right low frontal, left and right temporal, and left and right parietal cortices compared to controls (F = 10.28, F = 6.16, F = 7.53, F = 4.99, F = 4.02, F = 2.39, F = 5.71, F = 1.72, respectively; for all p < 0.05). When pre-
Ill. Aflective disorders and antidepressants and post-treatment rCBF values of all patients were compared, brain perfusion values in the left high and low frontal cortices were found increased compared to those before ECT. After treatment, no differences were found between rCBF values of the patients and controls. This means that decreased rCBF values before ECT series approached those of the controls after treatment. Conclusion: According to the present study, depressed patients exhibit decreased brain perfusion in the frontal, temporal and parietal regions bilaterally and this reduction of rCBF improves after ECT treatment. Although these data may suggest that hypoperfusion of the brain is a state-marker of depression, we cannot say whether the increase in rCBF after ECT treatment is a specific effect of ECT or a result of clinical improvement of the disorder. References [I] Drevets, W.C., 2000. Neuroimaging studies of mood disorders. Biol. Psychiatry
48, 813-829.
s227
BH4 into the crystal structure of the catalytic domain of ligandfree TH or TPH results in complexes in which the pteridine ring n-stacks with Phe300 and the N3 and the amino group at C2 hydrogen bonds with G1332. The pteridine ring also establishes interactions with Leu 294 and Gm310. In addition, in the enzyme active sites, several nonconserved amino acid residues, which define their substrate specificities were identified. Due to unresolved questions of safety and efficacy, synthetic BH4 analogues have been subjected to limited clinical trials. However, the work described here provides a step towards defining a receptor/pharmacophore for tetrahydropteridines, which can be used in order to develop new compounds of this class. Our studies have provided a structural basis for the substrate binding specificity of aromatic ammo acid hydroxylases. Thus, it should also be possible to synthesize new compounds which have an increased selectivity for enhancing serotonergic, noradrenergic and/or dopaminergic function. References
(p.1.1101
Stimulation of catecholaminergic and serotonergic neurotransmission by synthetic cofactors of aromatic amino acid hydroxylases
J. Haavik’, K. Teigen’, K. Toska’, J. McKinney’, W. Pfleidere?, A. Martinez’. ‘Department of Biochemistry and Molecular Biology, University of Bergen, Norway; ‘Fakultiit ftir Chemie, Universitiit Konstanz, Germany antidepressants and antipsychotics are believed to act by modulating monoaminergic neurotransmission. The synthesis of catecholamines and serotonin is regulated by the key biosynthetic enzymes tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), respectively. Tetrahydrobiopterin (BH4) is an obligatory cofactor for TH and TPH and has previously been tested as an antidepressant with inconsistent results, possibly due its poor permeability of the blood-brain barrier (BBB) and limited stability. Synthetic derivatives of BI$ with increased stability, BBB permeability, and cofactor efficiency are considered as candidate antidepressants. A series of synthetic analogues of BI$ with different substituents in positions C2, N3, C4, N5, C6, C7 and NS on the ring were used as active site probes for recombinant human TH and TPH. The 3D structure of TH has been solved using X-ray crystallography, while a model of the structure of human TPH was created using as template the crystal structure of the homologous enzyme phenylalanine hydroxylase (1). Using molecular docking of the tetrahydropterins into the catalytic domains of the enzymes, the mode of binding was investigated. The conformation and distances to the catalytic iron of both L-tryptophan and the cofactor analogue 7,8-dihydrobiopterin (BHz), simultaneously bound to an N-terminal truncated form of human TH and TPH, have been estimated by ‘H NMR spectroscopy (1, 2). Using enzyme kinetic studies, the tetrahydropteridines were classified either as active cofactors or inactive compounds. Some of the inactive compounds were enzyme inhibitors, but several tetrahydropterins had significantly higher catalytic efficiency (V,,/K,) than BH4. TH tolerates rather bulky substituents at C6, as seen by the catalytic efficiency and the coupling efficiency (mol L-DOPA produced/mol tetrahydropterin oxidized) of the cofactors. Substitutions at C2, C4, N5 and N8 abolish the cofactor activity of the pterin analogues. Molecular docking of Most
[I] Martinez, A., Knappskog PM, Haavik, J. (2001) Current medicinal Chemistry (in press). [Z] Almils B., Toska K., Teigen K., Groehn V., Pfleiderer W., Martinez A., Flatmark T., Haavik J. Biochemistry. 2000 39, 13676-86.
Ip.1.1111
Effects of ECT on hypothalamic-pituitary activity: TSH, GH, ACTH and PRL
E. Esel, A.S. G&ill, M. Kula, M.T. Turan, M. Reyhancan, I. Yabanoglu, M. Basturk, S. Sofuoglu. Erciyes University, Departments of Psychiatry and Nuclear Medicine, Kayseri, Turkey Objective: The exact action mechanism of electroconvulsive therapy (ECT) has yet to be established. Since the hypotbalamicpituitary system is controlled by various neurotransmitter systems, the investigation of pituitary hormones in plasma may render some insight into the action mechanism of ECT in depression. We aimed to test the hypothesis that ECT can cause some alterations in pituitary hormones and these responses may change throughout respective ECT sessions. Methods: 19 depressed inpatients (8 males, 11 females; mean age f SD: 44.77 f 10.59 years) were included in the study. Eight of them had bipolar I disorder-depressive episode, and 11 had major depressive disorder (recurrent) according to the DSM-IV criteria. The patients were drug-free for two weeks, and the patients had no neurological, metabolic, cardiologic, renal or endocrinologic disorders. Each patient was exposed to 7 ECT sessions with anaesthesia totally, three times a week. Blood samples were withdrawn before (baseline) and after propofol, immediately after ECT, and 30 and 60 minutes after ECT. In all patients, blood samples were taken during the tirst and last (7”) ECT. Thyroid-stimulating hormone (TSH), growth hormone (GH), adrenocorticotropin (ACTH) and prolactin (PRL.) were measured by commercially available IRMA kits. The data were analysed by analysis of variance (ANOVA) with repeated measures followed by Greenhouse-Geisser correction. When a significant difference was found, post-hoc paired t tests were used to compare the concentrations of hormones in various times. Results: It was found that after anaesthetic agent (propofol) was given TSH increased in both the first and last ECTs, but this increase was most pronounced 30 min after ECT (F = 8.59; df
P.I. Affective disorders and antidepressants
(AUC netto cortisoh r = -.40, p < 0.05). However, the DEX/CRH test results of week 6 did not correlate with treatment response after 6 weeks. At follow up none of the DEX/CRH test parameters did correlate with treatment response. Whereas duration of illness did not correlate with any of the DEX/CRH test results, the number of episodes until study entry was highly correlated with the DEX/CRH test outcome at baseline and at week 6 (Spearman's rho: p < 0.01). However, at follow up none of the DEX/CRH test values correlated with the long-term variables of depression. Although no correlation was found between DEX/CRH test results and recurrences after the index episode, the cortisol response of psychopathologically remitted patients at week 6 was descriptively higher in those with than those without recurrences (relative risk 2.33; p = n.s.). In conclusion, HPA system regulation in depression is associated with early treatment response as well as with therapeutical outcome after a standard treatment period of 6 weeks. Furthermore, long-term course of depression as reflected by number of episodes is significantly correlated with HPA system dysfunction. (Supported by the Swiss NSF Nr 3200-052778.97)
II-J.1.1 O;51 Lumbar bone mineral density in male patients with depression: A preliminary study M.T. Turan, E. Esel*, M. Kula, H. Demir, S. Kartalci, S. Sofuoglu. Erciyes University, Departments of Psychiatry, Nuclear
Medicine and Physical Medicine and Rehabilitation, Kayseri, Turkey Objective: It has been previously reported that past or current depressive episodes are associated with decreased bone mineral density (BMD) (1, 2). This loss of bone density has been put forward to be an endpoint of the cumulative intensity of hypothalamic-pituitary-adrenal axis hyperactivity and hypercortisolemia or changing physical activity in depression. This study was undertaken to determine whether men with major depression exhibit any decrease in BMD. Methods: Sixteen male depressed inpatients (mean age -4- SD: 43.50 ± 9.39 years, range: 37-55, mean duration of illness + SD: 84.62 5:52.68 months) and t6 age-matched healthy male control subjects (mean age 4- SD: 45.75 4- 8.27 years, range: 39-58) were included in the study. All patients were diagnosed with major depressive disorder (recurrent) according to the DSM-IV criteria. None of the subjects were taking any drug affecting BMD, but all patients were treated with antidepressants for various amounts of time. Montgomery-Asberg Depression Rating Scale (MADRS) was used to rate the severity of the patients' depressions, and all patients had 25 or more scores in MADRS. Mean BMD values of the first to fourth lumbar vertebrae were measured by using dualenergy X-ray absorptiometry (Hologic QDR-4500 DXA). Ages and the values of BMD of the patients and controls were compared with Mann-Whitney U test. The correlations between BMD values and some clinical variables (age, the number of depressive episodes, MADRS score) in the patients were investigated by Pearson's correlation test. Results: There was no statistically significant difference between the mean ages of the patient and control groups (U = 112, p > 0.5). Nor was a significant difference found between the mean BMD values of the patients and the controls (U = 98, p > 0.05). We did not find any correlations between BMD values and clinical variables such as age, MADRS score, duration of illness and the number of depressive episodes in the patients, either.
Conclusion: The data show that major depressive disorder does not affect the bone mineral density in men. Although this result seems to be inconsistent with the previous studies reporting BMD loss in depressive patients (1, 2), this discrepancy may be explained by the facts that the sample number was small, our patients were considerably younger and had a shorter duration of illness than those of the previous studies.
References [1] Schweiger,U., Deuschle, M., Kfrner, A., Lammers, C-H., Schmider,J., Gotthardt, U., Holsboer, F., Heuser, I., 1994. Low lumbar bone mineral density in patients with major depression.Am. J. Psychiatry 151, 16911693. [2] Michelson, D., Stratakis, C., Hill, L., Reynolds, J., Galliven, E., Chrousos, G., Gold, P., 1996. Bone mineral density in women with depression. N. Engl. J. Med. 335, 1176--1181.
•
Changes in regional cerebral blood flow in depressed patients treated with electroconvuIsive therapy
E. Esel, M. Kula, A.S. G6niil, M.T. Turan, M. Reyhancan, A. Tutus, M. Basturk, S. Sofuoglu. Erciyes University, Departments
of Psychiatry and Nuclear Medicine, Kayseri, Turkey Objective: There are a lot of data showing impaired regional cerebral blood flow (rCBF) in major depression and bipolar depression (1). Our purpose was to investigate whether there was a difference in rCBF pattern between before and after an electroconvulsive therapy (ECT) cure in depressed patients. This would render some insight as to whether rCBF alteration in depression was a state or trait marker. Methods: Nineteen depressed inpatients (8 males, 11 females; mean age ± SD: 44.77 -4- 10.59 years) and 17 healthy control subjects (8 males, 9 females; mean age 4- SD: 43.76 4- 11.70 years) were included in the study. All the patients and controls were right-handed. Eight of the patients had bipolar I disorderdepressive episode, and 11 of them had major depressive disorder (recurrent) according to the DSM-IV criteria. None of the patients had taken any drug for two weeks before the study. The 17-item Hamilton Rating Scale for Depression (HAM-D) was used to rate the severity of depression before treatment and those who had 16 or more scores in HAM-D were included in the study. Each patient was exposed to 7-10 ECT sessions with anaesthesia totally. Brain SPECT images were obtained by using Tc 99M-HMPAO 2-4 days before the first ECT and 10 days after the last ECT in the patients, and only once in the controls. All patients showed at least 60% reduction in the pretreatment HAM-D score and they were accepted to have response to ECT treatment. For semiquantitative analysis, three transaxial brain slices delineating anatomically defined regions of interest at 33, 49.5 and 66 nun above the orbitomeatal line were used, with the average number of counts for each region of interest normalised to the area of maximal cerebellar uptake. One-way ANOVA was used to compare rCBF values of the controls and those of the patients before and after the course of ECT. When a significant difference was detected, it was investigated by post-hoc paired or independent samples t tests. Results: Before treatment, significant decreases in rCBF were found in left and right high frontal, left and right low frontal, left and right temporal, and left and right parietal cortices compared to controls (F = 10.28, F = 6.16, F = 7.53, F = 4.99, F = 4.02, F = 2.39, F = 5.71, F = 1.72, respectively; for all p < 0.05). When pre-
Ill. Aflective disorders and antidepressants and post-treatment rCBF values of all patients were compared, brain perfusion values in the left high and low frontal cortices were found increased compared to those before ECT. After treatment, no differences were found between rCBF values of the patients and controls. This means that decreased rCBF values before ECT series approached those of the controls after treatment. Conclusion: According to the present study, depressed patients exhibit decreased brain perfusion in the frontal, temporal and parietal regions bilaterally and this reduction of rCBF improves after ECT treatment. Although these data may suggest that hypoperfusion of the brain is a state-marker of depression, we cannot say whether the increase in rCBF after ECT treatment is a specific effect of ECT or a result of clinical improvement of the disorder. References [I] Drevets, W.C., 2000. Neuroimaging studies of mood disorders. Biol. Psychiatry
48, 813-829.
s227
BH4 into the crystal structure of the catalytic domain of ligandfree TH or TPH results in complexes in which the pteridine ring n-stacks with Phe300 and the N3 and the amino group at C2 hydrogen bonds with G1332. The pteridine ring also establishes interactions with Leu 294 and Gm310. In addition, in the enzyme active sites, several nonconserved amino acid residues, which define their substrate specificities were identified. Due to unresolved questions of safety and efficacy, synthetic BH4 analogues have been subjected to limited clinical trials. However, the work described here provides a step towards defining a receptor/pharmacophore for tetrahydropteridines, which can be used in order to develop new compounds of this class. Our studies have provided a structural basis for the substrate binding specificity of aromatic ammo acid hydroxylases. Thus, it should also be possible to synthesize new compounds which have an increased selectivity for enhancing serotonergic, noradrenergic and/or dopaminergic function. References
(p.1.1101
Stimulation of catecholaminergic and serotonergic neurotransmission by synthetic cofactors of aromatic amino acid hydroxylases
J. Haavik’, K. Teigen’, K. Toska’, J. McKinney’, W. Pfleidere?, A. Martinez’. ‘Department of Biochemistry and Molecular Biology, University of Bergen, Norway; ‘Fakultiit ftir Chemie, Universitiit Konstanz, Germany antidepressants and antipsychotics are believed to act by modulating monoaminergic neurotransmission. The synthesis of catecholamines and serotonin is regulated by the key biosynthetic enzymes tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), respectively. Tetrahydrobiopterin (BH4) is an obligatory cofactor for TH and TPH and has previously been tested as an antidepressant with inconsistent results, possibly due its poor permeability of the blood-brain barrier (BBB) and limited stability. Synthetic derivatives of BI$ with increased stability, BBB permeability, and cofactor efficiency are considered as candidate antidepressants. A series of synthetic analogues of BI$ with different substituents in positions C2, N3, C4, N5, C6, C7 and NS on the ring were used as active site probes for recombinant human TH and TPH. The 3D structure of TH has been solved using X-ray crystallography, while a model of the structure of human TPH was created using as template the crystal structure of the homologous enzyme phenylalanine hydroxylase (1). Using molecular docking of the tetrahydropterins into the catalytic domains of the enzymes, the mode of binding was investigated. The conformation and distances to the catalytic iron of both L-tryptophan and the cofactor analogue 7,8-dihydrobiopterin (BHz), simultaneously bound to an N-terminal truncated form of human TH and TPH, have been estimated by ‘H NMR spectroscopy (1, 2). Using enzyme kinetic studies, the tetrahydropteridines were classified either as active cofactors or inactive compounds. Some of the inactive compounds were enzyme inhibitors, but several tetrahydropterins had significantly higher catalytic efficiency (V,,/K,) than BH4. TH tolerates rather bulky substituents at C6, as seen by the catalytic efficiency and the coupling efficiency (mol L-DOPA produced/mol tetrahydropterin oxidized) of the cofactors. Substitutions at C2, C4, N5 and N8 abolish the cofactor activity of the pterin analogues. Molecular docking of Most
[I] Martinez, A., Knappskog PM, Haavik, J. (2001) Current medicinal Chemistry (in press). [Z] Almils B., Toska K., Teigen K., Groehn V., Pfleiderer W., Martinez A., Flatmark T., Haavik J. Biochemistry. 2000 39, 13676-86.
Ip.1.1111
Effects of ECT on hypothalamic-pituitary activity: TSH, GH, ACTH and PRL
E. Esel, A.S. G&ill, M. Kula, M.T. Turan, M. Reyhancan, I. Yabanoglu, M. Basturk, S. Sofuoglu. Erciyes University, Departments of Psychiatry and Nuclear Medicine, Kayseri, Turkey Objective: The exact action mechanism of electroconvulsive therapy (ECT) has yet to be established. Since the hypotbalamicpituitary system is controlled by various neurotransmitter systems, the investigation of pituitary hormones in plasma may render some insight into the action mechanism of ECT in depression. We aimed to test the hypothesis that ECT can cause some alterations in pituitary hormones and these responses may change throughout respective ECT sessions. Methods: 19 depressed inpatients (8 males, 11 females; mean age f SD: 44.77 f 10.59 years) were included in the study. Eight of them had bipolar I disorder-depressive episode, and 11 had major depressive disorder (recurrent) according to the DSM-IV criteria. The patients were drug-free for two weeks, and the patients had no neurological, metabolic, cardiologic, renal or endocrinologic disorders. Each patient was exposed to 7 ECT sessions with anaesthesia totally, three times a week. Blood samples were withdrawn before (baseline) and after propofol, immediately after ECT, and 30 and 60 minutes after ECT. In all patients, blood samples were taken during the tirst and last (7”) ECT. Thyroid-stimulating hormone (TSH), growth hormone (GH), adrenocorticotropin (ACTH) and prolactin (PRL.) were measured by commercially available IRMA kits. The data were analysed by analysis of variance (ANOVA) with repeated measures followed by Greenhouse-Geisser correction. When a significant difference was found, post-hoc paired t tests were used to compare the concentrations of hormones in various times. Results: It was found that after anaesthetic agent (propofol) was given TSH increased in both the first and last ECTs, but this increase was most pronounced 30 min after ECT (F = 8.59; df