3H-spiperone binds with high affinity to a non-dopaminergic site on human B-lymphocytes, EBV transformed lymphoblasts and macrophages

S250

P2 Psychotic disorders and antipsychotics

S/F ratio of our control group was 1.64 +/- 0.08. The S/F ratio of our zotepine treated patients showed to be 1.24 +/- 0.04 for the 150 mg group and 1.16 +/- 0.08 for the 300 mg group indicating a mean D2 receptor binding of 67.5% in the 150 mg group and of 77.8% in the 300 mg group. Earlier investigations performed by our study group revealed a high degree of striatal D2 receptor occupancy in 10 haloperidol treated patients (S/F ratio = 1.11 +/- 0.05) and a relatively low occupancy in 6 patients treated with clozapine (S/F ratio = 1.49 +/- 0.10). In our study we could demonstrate that the D2 receptor occupancy of zotepine is 1) dose dependent, and 2) at therapeutic doses considerably lower than that of haloperidol but substantially higher than the D2 receptor occupancy of clozapine.

[PI?.1 141 Long-term treatment cognitive functions

of schizophrenia

-

Focus on

L. VavruSovB,M. Konikovi, U. ForghcovL, Z. ZacharovB, E. B&lentovi. Department ofPsychiatry, Postgmduate 826 06 Bratislaua. Slovakia

Medical Institute, NsP Ruiinoo,

Introduction: Impaired cognitive function in schizophrenia formerly thought to be a secondary effect of psychosis is now seen as an enduring and core characteristic. The degree of dysfunction has a high predictive value for long term disability. In recent years, with development of novel antipsychotics, more attention has been directed towards cognitive dysfunction in schizophrenia. The objective of the study was to follow up the influence of haloperidol, risperidone and clozapine on cognitive deficits /attention, memory and frontal/executive functioning/ and how they fluctuate according to clinical status during period of one year. Method: Patients /n = 181presenting with a first episode of schizophrenia were involved in the study. They were given haloperidol /5 mg per day/, risperidone 13 mg per day/ and clozapine 1200 mg per day/. The clinical status had been evaluated bv PANSS and memorv by WMS at the admission and after 3, 6 and 12 months of treatment. _ _ Results: The first assesment /at the admission/ was highly predictive for the future results /after 3, 6 and 12 months/. Memory tasks were influenced in a positive manner with all antipsychotics. Patient on risperidone had better results /non significantly/ in improvement of cognitive dysfunctions than patients on clozapine and on haloperidol /significantly/. Risperidone was better /after 6 and 12, not after 3 months of treatment/ in improvement of G 15 item - autism than clozapine and this could influenced the final results of memory performance. Both risperidone and clozapine were better than halop&ridol according to PANSS global score and negative and general symptoms subscore after 3, 6 and 12 months of treatment. Conclusions: Risperidone and clozapine influenced cognitive dysfunctions in schizophrenia better than haloperidol during the whole study. There was a slight difference between risperidone and clozapine after 6 and 12 months of treatment, This could be explained by the difference in better score concerning autism item according to PANSS /also other explanations are possible but they exceed limitations of this study/. Cognitive dysfunctions fluctuated according to clinical status of patients.

[ml

Functional the rat

role of brain dopamine

D3 receptors

in

R. de Beaurepaire’, S. Barik2. ILabomtoire de Psychopharmacologic, Hepita Paul Guimud, 94806 fillejul$ ‘ZNSERM U320, 14032 Caen. France The selective functions of dopamine D3 receptors in the brain are still poorly understood, mainly because all the ligands active at dopamine D3 receptors have also a high affinity for the D2 receptors. To overcome this difficulty we have undertaken studies of the effects of dopamine D2/D3 agonists and antagonists microinjected in brain areas containing D3 receptors and devoid of D2 receptors. Studies of the expression of

the genes encoding for D2 and D3 receptors have shown that the two receptors are expressed in anatomically distinct areas. There are two main areas in the brain that contain D3 receptors and are devoid of D2 receptors: the islands of Calleja, and the lobules 9 and 10 of the cerebellum. We studied on locomotor activity the effects of dopamine D3 agonists and antagonists microinjected in the nucleus accumbens and in the lobules 9 and 10 of the cerebellum. Agonists and antagonists decreased locomotor activity in the cerebellum, except the two mixed D2/D3 antagonists, amisulpride and nafadotide, which had a dose dependent effect, decreasing locomotion at high doses (10 pg in .2 pl), and increasing it at low doses (10 to 100 ng). In the nucleus accumbens, amisulpride and nafadotride produced the same effcts, however with a greater intensity. In the nucleus accumbens, D3 agonists (quinelorane, 7-OH-DPAT and quinpirole, 1 pg in .2 ~1) increased locomotion, an effect which was strongly potentiated by the Dl agonist SKF 38393 (1). In the island of Calleja Magna, we found that D3 agonists (quinpirole, 7-OHDPAT and quinelorane, 1 pg in .2 ~1) decrease body temperature, and that this effect is potentiated by the concomitant injection of the Dl agonist SKF 38393. In the nucleus accumbens, D3 agonists had almost no thermic effects, but quinelorane stimulated locomotor activity, and the stimulant effects were potentiated by SKF 38393. We also found that the potency of the D3 agonists to decrease body temperature in the island of Calleja Magna was closely related to their pharmacological affinity for the D3 receptor (2). Therefore, the ability of dopamine D3 agonists to decrease body temperature in the island of Calleja Magna provides a valuable behavioral test for measuring the agonist potencies of D3 ligands. References

[I]

Batik S, de Beaurepaire R. Evidence for afunctional role of the dopamine 03 receptors in the cerebellum. Brain Res 1996; 737: 347-350 [2] Batik S, de Beaurepaire R. Hypothermic e@xts of dopamine 03 receptor agonists in the island of Calleja Magna. Potentiation by Dl activation. In press, Pharmacol Biochem Behav 1998

[ml

U.

3H-spiperone binds with high affinity to a non=dopaminergic site on human B-lymphocytes, EBV-transformed iymphoblasts and macrophages

Henning, K. Krieger, A. Klimke

??

of Duesseldorf; Bergische Landstmsse

Psychiatric Department, University 2, 40629 DuesseldorJ Germany

Purpose of the Study: The findings of LeFur et al. (1983) and Bondy et al. (1985) that the binding to native lymphocytes is elevated in schizophrenia and possibly in affective psychosis (Fartacek et al., 1997) stimulated the search for the pharmacological basis of this binding site. However, blood-derived lymphocytes consist of several subpopulations, which might influence the results of these studies in neuropsychiatric disorders. Therefore we investigated the binding of 3H-spiperone using different white blood cells including cultivated human cell lines. Methods: B-lymphocytes and macrophages were characterised by a saturable (Ko 0.1 nM, B,, 0.5-2.5 x lo-l5 mo1/106 cells) and a nonsaturable binding above 1 nM 3H-spiperone. EBV-transformed lymphoblasts of B-cell origin had nearly the same affinity for spiperone but the number of binding sites was about three times higher. Membrane preparations of these lymphoblasts exhibited a similar binding profile as native cells. Summary of Results: T-cells (which represent up to 70% of native lymphocyte suspensions), granulocytes and T-cell derived MOLT-3 cells did only present a nonsaturable binding which increased threefold after immunological stimulation. The pharmacological profile of the high-affinity 3H-spiperone binding site was clearly different from dopaminergic D2 and D4, serotonergic 5-HT2, histaminergic HI, noradrenergic al and a2 and cholinergic Ml receptors. Conclusion: We conclude that circadian and immunological factors might contribute to a different composition of cellular subtypes of white blood cells, which in turn leads to a different apparent density of spiperone binding sites in psychiatric patients and controls, due to

P2 Psychotic disorders and antipsychotics variable amounts of binding to saturable (e.g., B-cells) and unsaturable (e.g., T-cells) binding sites. Homogenous EBV-transformed cell lines are recommended for further pharmacological investigations of the spiperone binding site.

(p.2.1171

Saccadic eye movements in schizophrenic patients: The influence of neuroleptic treatment

M.O. Krebs, A. Gut, I. Amado, D. Levy, M.C. Bourdel, D. Willard, A. Berthoz, J.P Olie, M.F. Poirier. Service Hospitalo-Universitaire de Santg Mentale et Thtkapeutique, Pr H LOO et Pr JP OLIE, Hopital Sainte-Anne, 75014 Paris, France Previous reports have shown that voluntary saccadic eye movements can be disturbed in schizophrenic patients, although simple reflex saccades are usually considered as normal or subnormal. The influence of chronic neuroleptic treatment is usually considered as minimal. However, most studies were done in treated schizophrenic patients and longitudinal observations patients seen before and after treatment are seldom. Ten untreated schizophrenic patients (DSMIIIR criteria), among which 7 neuroleptic-ndive patients, were examined with a standardized clinical interview (DIGS). Clinical (including eventual substance abuse) and therapeutic history was carefully examined with a standardized record form. Parkinsonism (Simpson Angus scale), akathisia (Barnes), abnormal movements (AIMS) were assessed as well as neurological soft signs (NSSS). Oculomotor paradigms included predictable and unpredictable saccades tasks. Neuropsychological tasks were also performed. Whenever possible, a re-evaluation was performed after neuroleptic introduction, 1 to 3 months after optimal dosage was found. Their performances were also compared to those of nine stabilized treated patients. Preliminary analysis on 19 patients showed non significant differences between untreated and treated patients in reflex predictable and unpredictable saccades tests. However, in treated patients, latencies tend to be longer and anticipation in predictable paradigm was lower than in untreated patients. There was a significant correlation of latencies with neurological soft signs. When available, the reevaluation after treatment showed an increase in saccadic latencies in most patients in reflex saccade tasks suggesting that even chronic neuroleptics induce an oculomotor retardation. Similarly, in agreement of what is seen in parkinsonian patients, anticipation in predictable tasks tend to be decreased. However, in one patient with severe disorganized symptomatology at the first evaluation, opposite evolution was seen, indicating the need to take into account as covariate the evolution of the symptomatology. Further analysis in an extended population will be presented.

Ip.2.1181

The effect of treatment with risperidone vs phenothiazine neuroleptics on eye tracking of schizophrenic patients during two fixation tasks

J.K. Rybakowski’, A. Borkowska*, W. Droidi*, A. Araszkiewicz*, A. KuCma3. ‘Department of Adult Psychiatry, University of Medical Sciences, Poznari; ‘Department of Psychiatry, Medical Academy, Bydgoszcz; ‘Janssen-Cilag, Poland Introduction: Various eye tracking dysfunctions have been reported in schizophrenia, e.g. visual fixation deficits (Rosse et al., 1992). These abnormalities are thought to be trait markers which do not vary with neuroleptic treatment (Holzman, 1987). The purpose of this study was to compare the possible effect of treatment with atypical neuroleptic, risperidone, with that of phenothiazine neuroleptics on eye tracking of schizophrenic patients during two fixation tasks. Patients and Methods: The study was performed on 30 patients with paranoid schizophrenia aged 19-48 (mean 30) years. Fifteen patients (8 male, 7 female) were receiving risperidone and fifteen (7 male, 8 female) were treated with phenothiazine neuroleptics (chlorpromazine,

s25

I

levomepromazine, fluphenazine, perphenazine). Eye tracking were measured by means of infrared reflectometry, with frequency system of 400 Hz and measurement time 20 set, during two tasks: 1) visual fixation on the point and 2) visual fixation (response to stabilizing points) during elicited horizontal nystagmus. In each patient, the assessment was tirst performed during acute psychotic episode, before starting pharmacological treatment (mean total PANSS score in whole group 116 f sd 23) and after 4-10 (mean 7) weeks of drug treatment (mean PANSS 77 i sd 16). Results: On point fixation task, following risperidone treatment, a significant decrease of rapid catch-up saccades (RCS) (Q 100 msec) and total duration of RCS + slow catch-up saccades (SCS) (>I00 msec) was found. Also, a tendency (p = 0.06) to normalization of eye tracking recording was observed. No difference was found as to the frequency of SCS. Treatment with phenothiazine neuroleptics brought no difference to any of these parameters. On horizontal nystagmus fixation task, following risperidone treatment, a significant improvement in response to stabilizing points was found as well as a decrease of frequency of horizontal nystagmus in right eye was observed. The only change found in patients treated with phenothiazine neuroleptics was a trend (p = 0.08) toward a decrease in frequency of horizontal nystagmus in right eye. Conclusions: The results obtained suggest that risperidone unlike phenothiazine neuroleptics may exert a beneficial effect on some eye tracking dysfunctions in schizophrenic patients in terms of improving the ability of eye concentration during fixation tasks. References [l] Row R.B., Malhora A.K., Kim S.Y., Deutsch S.I. (1992) Visual fixation deficits and evidence of cognitive impairment in schizophrenia. Biol. Psychiatry 31, 412414. [2] Nobman P.S. (1987) Recent studies of psychophysiology in schizophrenia. Schizophr. Bull. 13, 49-75.

Ip.2.1191

Creatine kinase levels in adolescents psychosis

at early acute

I. Manor’, H. Hermesh’, D. Stein*, T. Shechtman*, Y. Benjamini3, H. Munitz’, A. Weizman’. ‘Geha Psychiatric Hospital, Rabin Medical Center, Beilinson Campus, Petah Tiqva; 2Abarbanel Psychiatric Hospital, Bat-Yam; ‘School of Mathematics. Tel Avio Universi@, Israel Elevated levels of serum CK are very often observed in adult acute psychotic patients and highly elevated levels (>lOOO IU/L) occurs in about 10% of the cases (1, 2). Other psychiatric conditions of CKemia include neuroleptic malignant syndrome (NMS) and febrile catatonia (1, 2). The CK level relates almost exclusively to a rise in CKMM isoenzyme (1). The reason for high serum CK levels in psychosis remains obscure. The CKemia is found to be a recurrent pattern in specific patients, and is more common among males (3). Since there are scarcely any reports on psychosis-related CKemia among adolescent, we studied this population. The population included adolescent inpatients admitted due to acute psychosis (BPRS >_ 40). The psychiatric diagnoses were established according to DSM-IV criteria, following a SCID. None of the participants suffered from any condition known as a cause of CKemia. CK measurements (Sigma procedure) were taken on the first two days of hospitalization, before any treatment was initiated. Patients with recurrent separate psychotic episodes were further evaluated for CK level. The following data were recorded: age, gender, ethnic&y, weight and myoglobinuria. CK levels were converted to their natural logarithm (Ln), to normalize the distribution. 84 patients met the inclusion criteria, with mean age of 17.2 i 1.9 years. Their diagnoses were: 24 psychotic major affective disorders, 25 schizophrenic spectrum disorders, 35 brief psychoses. Mean BPRS score of all the patients was 51.5 i 13.0. Male: female ratio was 55:29. 21 patients (25%) had CK 2 1000 IU/L, while the mean CK level in the CKemic group was 3074 f 2582 IUIL, vs. 254 i 212 IUiL for the normal-CK group. None of the CKemic patients exhibited myoglobimuia. The M:F ratio in the CKemic group was 17:3, as opposed to 38:26 in the normal-CK group (p < 0.04). ANOVAs also showed that