Tryptophan depletion in recovered depressives and recovered bulimics

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

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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.

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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

P Poster Presentations

130 in those who are vulnerable to these disorders but not currently suffering from them. Tryptophan depletion involves the administration of a drink containing amino acids but lacking tryptophan, and lowers plasma tryptophan and brain 5-HT. In a group of recently recovered depressives on medication, tryptophan depletion provoked a transient but full clinical relapse in depressive symptoms [I] . In this study we investigated the effect of tryptophan depletion in two groups of subjects who had suffered from either depressive disorder or bulimia nervosa in the past but who were fully recovered and medication free. All subjects attended for two test days. On one occasion they were given the tryptophan depleted drink and on the other an identical drink containing tryptophan which acted as the control condition. Following the drink subjects spent the next 7 hours in a testing room completing questionnaires and psychological tests to assess their mood. On returning horne they completed a diary of their mood and food intake over the next 48 hours. Preliminary results from the first six recovered depressives and four recovered bulimics show a clinically discernible lowering of mood in 9 out of 10 subjects on the tryptophan depletedday comparedto 0 out of lOon the balanced day. In two subjects there was a transient reappearance of the full depressive syndrome with depressive cognitions specific to that subject. Our studies suggest that decreased 5-HT function may be involved in the pathophysiology of affective illness and eating disorders. KS is supported by the Wellcome Trust [I ] Delgado PL,Charney DS, Price LH, Aghajanian GK, Landis H.Heninger GR. Arch Gen Psychiatr47 (1990) 411-418

IP-12-42! Therapeutic Advantage of Combined Amitriptyline/Lithium and Fluvoxamine/Llthium Treatments B. Miljkovic, M. Pokrajac, I. Timotijevic. Faculty of Pharmacy and lnst. for Mental Health, Belgrade, YU The aim of the study was to investigate both the therapeutic efficac y and a possibility of reducing the necessary time to obtain a clinical improvement by adding lithium (Li) to amitriptyline (AT) and fluvoxamine (FI) monotherapy. The study was conducted in 27 patients with diagnosis of major depressive disorder, according to DSM-Ill-R criteria. who were divided in four groups. Nine patients were on AT monotherapy, six patients on FI monotherapy, six patients on combined AT + Li therapy, and six patients were on combined Fl + Li therapy. The applied doses of the antidepresants agents were: 75 mg of AT per day, and 900 mg of Li per day, both divided in 3 equal daily doses, and I()() mg of Fl as one dose in the evening. The efficacy of the applied therapeutic treatment(AT, Fl, AT + Li and Fl + Li) was assessed by Hamilton Rating Scale for Depression (HRSD). The assessment was done at baseline, two weekslater and after the treatment was finished (four/six weeks later). The results showed that depressive symptoms were reduced after all four therapeutic treatments. The statistical differences in therapeutic efficacy, between ATmonotherapy and combined AT+ Li therapy; were achieved at the sixth week of the treatment (HRSD 7.5 ± 3.4 vs. 4.0 ± 1.6), and between Fl monotherapy and combined Fl + Li therapy at the second week of the treat (HRSD 21.8 ± 5.5 vs 15.5 ± 3.4). These results indicate that Li added to AT and Fl monotherapy increases therapeutic efficacy, and in combined FI + Li therapy reduces the time to obtain therapeutic efficacy.

I P-13-1 I Saccadic Eye Movements in

Gilles-de-Ia-Tourette-Syndrome

N. Miiller, M. Riedel, J.B. Mennicken " Th. Eggen I , A. Straube ' . Psychiatric Hospital, Ludwig-Maximilian-University. Munich; I Department ofNeurology; Ludwig-Maximilian-University, Munich Gilles-de-la-Tourette's syndrome (GTS) is presumed to be an inherited disorder whose pathophysiology is still unclear. An involvement of the basal ganglia is suspected. Beside vocal tics, one of the main symptoms is the presence of motor tics. As eye movements are a specialized part of the motor system, we investigated whether they deviated in some way in GTS patients. It is known that in other diseases of the basal ganglia, such as Parkinson's disease (PD) and Huntington's disease, there are typical oculomotor symptoms, especially in the control of voluntary saccades.

To study the control of saccades in GTS, different paradigms were used to elicit saccades, which were either externally triggered and visually guided or internally triggered and without visual target GTS patients (n = 10) showed an increase of the saccade latency, especially in the internally guided saccades; an highly impaired performanceof sequences of memory-guided saccades and a reduction of the peak velocity in the antisaccades. Overall the results were similar to those described with similar paradigms in PD patients. This suggests that the cortex, especially the frontal cortex, is not activated in the normal way by ascending loops from the basal ganglia to the thalamus and the frontal cortex. The general function of the frontal cortex - frontal eye field, prefrontal cortex - does not seem to be impaired, because the performance of memory-guided saccades and the effect of a fixation target on saccadic latency (gap effect) were normal.

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P-13-2 1 In Vivo Examination of the Pre-and Postsynaptic Dopamine Neurons in Huntington's Disease

N. Ginovart, A. Lundin, L. Farde, C. Halldin, e.G. Swahn, S. Pauli, G. Sedvall. KarolinskaInstitutet, Stockholm, Sweden Huntington's disease (HD) is a degenerative disorder primarily affecting the basal ganglia. In the present study, positron emission tomography and radioligands for the pre- and postsynaptic neurons were used to investigate the dopamine system in vivoin HD. Five healthy controls and five sex- and age-matched patients with early HD werestudied with [' IC]SCH 23390, [' IC]raclopride, and [ 'I c] ,8-CIT for DI-, D2-receptor and dopamine transporter examination, respectively. All subjects had an MRl scan for detailed anatomical investigations. DI and D2 dopamine receptor binding was evaluated by the ratio of regional specific binding to cerebellum activity. [ I I c] ,8-CIT uptake was analyzed using a multiple-time graphical analysis. MRl showed early and severe atrophies of the caudate, putamen and external globus pallidus, together with moderate but significant abnormalities in the thalamus, the frontal and temporal cortex. Decline in Dl and D2 binding sites were observed in the striatum. The declines for the two receptor subtypes were parallel and correlated significantly with duration of illness. A selective loss of D2, but not DI, receptors was observed in the external globus pallidus. A new finding was the reduced density of DI receptors in the temporal cortex. A significant reduction in the binding of [I I c] ,8-CIT to the presynaptic dopamine transporter was observed in the caudate (50%) and putamen (44%). These reductions mightreflect either a decreaseddensityof presynaptic striatal terminals. or a perikaryal dysfunction in the substantia nigra associated with deficient production, processing or transport of the dopamine transporter to these terminals. It is concluded that besides widespread anatomical changes, the preand postsynaptic neurons of the dopaminergic nigrostriatal system are severely altered in HD. In addition, the decline in DI receptor density in the tempral cortex draws attention to the potential significance of cortical degeneration for the cognitive deficits observed in HD.

I P-13-31

The Effects of Cues on Executive Functions of Parkinsonian Patients C.T. Tai, C.H. Juan, c.x. Liu, R.T. Lin, c.i, Lai. Department of Neurology, Kaohsiung Medical College. Taiwan The present study is aimed to investigate the effects of instructional cues on executive function of Parkinsonian patients in an Odd-Man Out paradigm. Forty non-demented Parkinsonian patients (PD group), as well as forty-eight non-demented subjects (Control group), are recruited for the present study. The subjects in both the PD and Control groups are randomly divided into four subgroups, according to the types of 'instructional cue' they will receive in a 2 x 4 factorial study design: i.e., Disease (PD or Control) X Cue (Nil, Nonverbal, Mix, or Full cues). It is found that there is a significant Disease X Cue interaction. Post-hoc examination demonstrates that this is because the subjects in the PD-Nonverbal group are significantly impaired in their ability of concept formation and in reaction time whencomparedwith those in the Control-Nonverbal group. Whereas, with other types of Cue, there are no significant difference between the PD and Control group. It is concluded that there is a great