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Platelet serotonin2 receptor binding in affective disorders
P Poster Presentations diagnostic validity and prognostic utility, the DST was used in our study in a group of 53 inpatients (male and female) with the diagnosis of major depression according to the DSM illR criteria. HAMD rating scale was used at the baseline and weekly for 6 weeks. DST was applied on the fourth day of trial, as introduced by Carroll (1981). Our results show that more severely depressed patients more frequently show nonsuppression, which is significantly more present in our female population. Nonsuppressors are more and significantly frequent in a group with positive psychiatric history of affective disorders in family and relatives. Nonsuppressors are significantly present in a group of patients with bipolar disorder. No difference whatsoever was found regarding the separate items on HAMD (anxiety, depressed mood, feelings of guilt, suicide) correlated with DST results. The presence of melancholic features, psychotic symptoms, did not significantly relate to the results of DST. There was no significant difference in correlation of the nonsuppressors and the age of patients. Our results confirm the diagnostic validity of DST, but also implicate that further search of correlation between single elements of mental disfunction and neuroendocrine regulation, especially in female population might give a clue to the pathogenesis of depression.
IP-12-37I
5·HT2A Receptor Geneis Intact in Mood Disorder
K Ohara, H.Y. Zhang, T. Ishigaki, D.W. Xie, K Tani, K Miyasato, K Ohara. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan Genes that regulate the serotonin (5-HT) system including 5-HT receptors may be implicated in mood disorders. We studied 5_HT2A receptorexons and the adjacent intron regions in 102 patients with mood disorders (71 depressive disorders, 31 bipolar disorders). In 34 mood disorder cases, the gene encoding 5-HT 1A receptor had been sequenced, but no disease specific polymorphism was found (Xie D-W et al. Neuropsychopharmacol. 12:263-268, 1995). The substitution of C for T at position 102 in exon 1, that had been reported by Warren et al. (1993), was confirmed. The corresponding amino acid, serine, did not change. We found an association between the polymorphism and diagnosis (depressive disorders vs, bipolar disorders). Furthermore, the mean age of onset in the patients with TIC polymorphism was lower than that in those with CIC polymorphism. No other polymorphism in the gene was found.
IP-12-3SI
Anticipation and Repetitive Elements of the Serotonin Transporter Gene in Affective Disorder
M. Hayashida I, T. Tsujita 2, A. Imamura I, Y. Okazaki I, N. Niikawa 2, Y. Nakane I, S. Matsumoto 3. I Department ofNeuropsychiatry, Nagasaki University School of Medicine, Nagasaki, Japan; 2 Department ofHuman Genetics, Nagasaki University School ofMedicine, Nagasaki, Japan; 3 Michinoo Hospital, Nagasaki, Japan Genetic anticipation in families with bipolar affective disorder (BPAD) has been suggested by several studies. The expansion of trinucleotide repeats has been demonstrated to be correlated with anticipation in 'triplet repeat diseases', which include fragile X syndrome. However. another unstable oligonucleotide repeat DNA may possibly be the biological basis of the anticipation. First, to investigate the anticipation in mood disorder, we compared ages of onset between two generation in 19 parent-offspring pairs with DSM-III-R mood disorder. The parent-offspring pairs included a proband of which was admitted to the Nagasaki University Hospital or Michinoo Hospital between 1986-1994. We observed statistically significant decreases in age of onset in the offspring generation (Wilcoxon t 7.0, df 18, P < 0.0001; one tailed). Although ascertainment bias could not be thoroughly ruled out in this sample, these findings suggested that the expansion of unstable DNA sequences may be a possible mode of transmission in patients with mood disorder. Secondly, to investigate the possibility of the change of unstable DNA sequence, we examined the 17 bp repetitive elements of the serotonin transporter (5-HTT) gene, because the 5-HTT is a site of the action of antidepressants. Genomic DNA isolated from leukocytes of 5 parent-offspring pairs with BPAD was analyzed by the method of Lesch et al. [I]. Our sample size were too small to mention the possibility of the change of repetitive elements
=
=
129 ofthe 5-HTT gene. Therefore it is necessary to apply this examination to more parent-offspring pairs with BPAD. [1] Lesch K.-P. et al. J Neural Transm. 95 (1995) 157-162.
[ P-12-39I Platelet Serotonin2 Receptor Binding in Affective Disorders T. Tsujimura, T. Asou, M. Hayashida, A. Himeno, H. Minami, Y. Okazaki, Y. Nakane. Department ofNeuropsychiatry, Nagasaki University School of Medicine, Nagasaki, Japan It has been suggested that affective disorders are associated with abnormalities in central serotonergic function. In particular hyper-functioning of central serotonin- (5-HT 2) receptors may exist in some groups of affective disorders. Blood platelet has attracted attention as a possible model for the central 5-HT neuron because of its pharmacological and genetic similarities with brain preparations. In the present study, we applied in vitro receptor autoradiography to quantitate platelet 5-HT 2 receptors in affective disorders. Patients diagnosed with depressive disorder according to ICD-IO criteria were studied. All patients and normal controls were drug-free at the time of blood sampling. Five ml of blood was collected into vacuum syringe with containing EDTA-2Na. We incubated 20 !tm thick sections from platelet pellets with 12 51-Lysergic acid diethylamide 25I-LSD), and analyzed the radioactivities of these sections using the imaging plate system. The mean (± SEM) Kd for the control group was 0.87 ± 0.05 nM (n =5) which was not significantly different from the patient group 1.10 ± 0.10 nM (n = 5). The Bmax of 12 51-LSD binding was significantly increased in the patient group (5.56 ± 0.63 fmol/mg) compared to the control group (3.14 ± 0.20 fmol/mg, p < 0.01). We followed platelet 5-HT2 measurements and Hamilton's rating scale for depression (HAMD) repeatedly after treatment in two cases. The comparison of the Bmax of I 2 51-LSDbinding and HAMD demonstrated significant linear correlation. There is a possible relationship between increased platelet 5-HT2 receptor concentrations and the symptoms of depression.
e
I P-12-40 I Strong and Long-Lasting Inhibition of 5·HT Uptake of Platelets in Subjects Treated by Duloxetine, an Antidepressant Candidate T. Kasahara, E. Nagata, A. Takahashi, J. Ishigooka, M. Murasaki, S. Miura. Department of Psychiatry, Kitasato University School of Medicine, Sagamihara, Japan Duloxetine is an inhibitor of serotonin and norepinephrine uptake, being expected for a new antidepressant. In the present study using healthy volunteers who took 20 mg of duloxetine for seven days, plasma concentrations of duloxetine and serotonin uptake rate in the platelet were simultaneously monitored during and after the administration. Furthermore a comparison was made by measuring parameters for serotonin uptake and 3H-paroxetine binding before and after the administration. Actual values of uptake inhibition rate were stronger than those expected in spite of dilution of plasma in the experiment, and the inhibitory effect was seen even after the drug was not detected in plasma. No significant changes were observed in Vmax, KIn, Bmax and Kd. Thereafter the effects of washing procedure in platelets treated with duloxetine was examined in comparison with those of different antidepressants. Minimum effect was seen in platelets treated by duloxetine or paroxetine, while desipramine treated platelets showed susceptibility to the procedure. These results suggested that duloxetine was hardly dissociated from serotonin uptake site, which was responsible for the strong and long-lasting effect in plasma.
IP-12-41 I Tryptophan Depletion in Recovered Depressives and Recovered Bulimics KA. Smith, C.G. Fairburn, PJ. Cowen. University Department of Psychiatry, Oxford There is evidence of impaired serotonin (5-HT) function in depressive disorder and bulimia nervosa. We used the technique of tryptophan depletion to investigate whether there is an abnormality of 5-HT neurotransmission
IP-12-37I
5·HT2A Receptor Geneis Intact in Mood Disorder
K Ohara, H.Y. Zhang, T. Ishigaki, D.W. Xie, K Tani, K Miyasato, K Ohara. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan Genes that regulate the serotonin (5-HT) system including 5-HT receptors may be implicated in mood disorders. We studied 5_HT2A receptorexons and the adjacent intron regions in 102 patients with mood disorders (71 depressive disorders, 31 bipolar disorders). In 34 mood disorder cases, the gene encoding 5-HT 1A receptor had been sequenced, but no disease specific polymorphism was found (Xie D-W et al. Neuropsychopharmacol. 12:263-268, 1995). The substitution of C for T at position 102 in exon 1, that had been reported by Warren et al. (1993), was confirmed. The corresponding amino acid, serine, did not change. We found an association between the polymorphism and diagnosis (depressive disorders vs, bipolar disorders). Furthermore, the mean age of onset in the patients with TIC polymorphism was lower than that in those with CIC polymorphism. No other polymorphism in the gene was found.
IP-12-3SI
Anticipation and Repetitive Elements of the Serotonin Transporter Gene in Affective Disorder
M. Hayashida I, T. Tsujita 2, A. Imamura I, Y. Okazaki I, N. Niikawa 2, Y. Nakane I, S. Matsumoto 3. I Department ofNeuropsychiatry, Nagasaki University School of Medicine, Nagasaki, Japan; 2 Department ofHuman Genetics, Nagasaki University School ofMedicine, Nagasaki, Japan; 3 Michinoo Hospital, Nagasaki, Japan Genetic anticipation in families with bipolar affective disorder (BPAD) has been suggested by several studies. The expansion of trinucleotide repeats has been demonstrated to be correlated with anticipation in 'triplet repeat diseases', which include fragile X syndrome. However. another unstable oligonucleotide repeat DNA may possibly be the biological basis of the anticipation. First, to investigate the anticipation in mood disorder, we compared ages of onset between two generation in 19 parent-offspring pairs with DSM-III-R mood disorder. The parent-offspring pairs included a proband of which was admitted to the Nagasaki University Hospital or Michinoo Hospital between 1986-1994. We observed statistically significant decreases in age of onset in the offspring generation (Wilcoxon t 7.0, df 18, P < 0.0001; one tailed). Although ascertainment bias could not be thoroughly ruled out in this sample, these findings suggested that the expansion of unstable DNA sequences may be a possible mode of transmission in patients with mood disorder. Secondly, to investigate the possibility of the change of unstable DNA sequence, we examined the 17 bp repetitive elements of the serotonin transporter (5-HTT) gene, because the 5-HTT is a site of the action of antidepressants. Genomic DNA isolated from leukocytes of 5 parent-offspring pairs with BPAD was analyzed by the method of Lesch et al. [I]. Our sample size were too small to mention the possibility of the change of repetitive elements
=
=
129 ofthe 5-HTT gene. Therefore it is necessary to apply this examination to more parent-offspring pairs with BPAD. [1] Lesch K.-P. et al. J Neural Transm. 95 (1995) 157-162.
[ P-12-39I Platelet Serotonin2 Receptor Binding in Affective Disorders T. Tsujimura, T. Asou, M. Hayashida, A. Himeno, H. Minami, Y. Okazaki, Y. Nakane. Department ofNeuropsychiatry, Nagasaki University School of Medicine, Nagasaki, Japan It has been suggested that affective disorders are associated with abnormalities in central serotonergic function. In particular hyper-functioning of central serotonin- (5-HT 2) receptors may exist in some groups of affective disorders. Blood platelet has attracted attention as a possible model for the central 5-HT neuron because of its pharmacological and genetic similarities with brain preparations. In the present study, we applied in vitro receptor autoradiography to quantitate platelet 5-HT 2 receptors in affective disorders. Patients diagnosed with depressive disorder according to ICD-IO criteria were studied. All patients and normal controls were drug-free at the time of blood sampling. Five ml of blood was collected into vacuum syringe with containing EDTA-2Na. We incubated 20 !tm thick sections from platelet pellets with 12 51-Lysergic acid diethylamide 25I-LSD), and analyzed the radioactivities of these sections using the imaging plate system. The mean (± SEM) Kd for the control group was 0.87 ± 0.05 nM (n =5) which was not significantly different from the patient group 1.10 ± 0.10 nM (n = 5). The Bmax of 12 51-LSD binding was significantly increased in the patient group (5.56 ± 0.63 fmol/mg) compared to the control group (3.14 ± 0.20 fmol/mg, p < 0.01). We followed platelet 5-HT2 measurements and Hamilton's rating scale for depression (HAMD) repeatedly after treatment in two cases. The comparison of the Bmax of I 2 51-LSDbinding and HAMD demonstrated significant linear correlation. There is a possible relationship between increased platelet 5-HT2 receptor concentrations and the symptoms of depression.
e
I P-12-40 I Strong and Long-Lasting Inhibition of 5·HT Uptake of Platelets in Subjects Treated by Duloxetine, an Antidepressant Candidate T. Kasahara, E. Nagata, A. Takahashi, J. Ishigooka, M. Murasaki, S. Miura. Department of Psychiatry, Kitasato University School of Medicine, Sagamihara, Japan Duloxetine is an inhibitor of serotonin and norepinephrine uptake, being expected for a new antidepressant. In the present study using healthy volunteers who took 20 mg of duloxetine for seven days, plasma concentrations of duloxetine and serotonin uptake rate in the platelet were simultaneously monitored during and after the administration. Furthermore a comparison was made by measuring parameters for serotonin uptake and 3H-paroxetine binding before and after the administration. Actual values of uptake inhibition rate were stronger than those expected in spite of dilution of plasma in the experiment, and the inhibitory effect was seen even after the drug was not detected in plasma. No significant changes were observed in Vmax, KIn, Bmax and Kd. Thereafter the effects of washing procedure in platelets treated with duloxetine was examined in comparison with those of different antidepressants. Minimum effect was seen in platelets treated by duloxetine or paroxetine, while desipramine treated platelets showed susceptibility to the procedure. These results suggested that duloxetine was hardly dissociated from serotonin uptake site, which was responsible for the strong and long-lasting effect in plasma.
IP-12-41 I Tryptophan Depletion in Recovered Depressives and Recovered Bulimics KA. Smith, C.G. Fairburn, PJ. Cowen. University Department of Psychiatry, Oxford There is evidence of impaired serotonin (5-HT) function in depressive disorder and bulimia nervosa. We used the technique of tryptophan depletion to investigate whether there is an abnormality of 5-HT neurotransmission