Use of psychotropic medication before and after psychotherapeutic inpatient treatment

P.6 Othertopics I was administered an i.v, infusionto achieve steady-state concentration of VPA. Subsequently, a dose of 40 mg-kg" PHT was infused for 5 min at a rate of 0.1 ml-min", Likewise, group II received a continuous saline infusion and the same dose of PHT. Group ll/ received only the continuous infusionof VPA.The time courseof the concentration and the anticonvulsant effectwere determined up to 6 hoursafter drugadministration. Theelevations of the TLS and TGS abovetheir baselinerepresented the anticonvulsant effect.The pharmacokinetics of PHT was described by a model with Michaelis-Menten elimination, yielding Km valuesof 8.02 ± 0.6 and 13.9 ± 2.2 JLglml in groups I and Il, respectively. The time delay between PHT plasma concentrations and effect was estimated by an equilibration kinetics model using a hysteresis minimization routine. The anticonvulsant effect of PHT was characterized by an increasein the TGS without alteration of the TI.S. Although the pharmacokinetics of PHT did not vary significantly, a shift in the concentration-effect profile of PHT was observed in the presence of VPA, which was reflected in a reductionof the EC250 values.Taking into accountthat singleadministration of VPA caused negligible changes in the thresholds and no marked differences in protein-binding were detected, one may conclude that there is a synergistic pharmacodynamic interaction betweenVPAand PHT.

IP.6.018I

Assessment of the pharmacodynamic Interaction between phenytoin and sodium valproate by ictal behaviour analysis

o.s, Della Paschoa, R. Hamstra,R.A. Voskuyl, M.R. Kruk,M

Danhof. Division of Pharmacology and Medical Pharmacology; Leiden/Amsterdam Centerfor Drug Research, P.O. Box9503 2300RA Leiden; TheNetherlands; Department of Physiology, Leiden University. P.O. Box 95032300 RA Leiden; TheNetherlands The currentapproaches for the assessmentof anticonvulsant effectare not focusedon the exact discrimination of drug actionon the clinical patterns of seizure activity. We have applied quantitative behavioural analysis to identifydrug-induced changesin the pattern of the motorseizureinduced by cortical stimulation. Aim of the present study was to characterize the pharmacodynamic interaction betweenphenytoin (PHT) and sodium valproate (VPA) by means of ictal behaviour analysis, in parallel to the determination of the concentrarion-anticonvulsant effect profile. Mild seizure activity was elicited by direct cortical stimulation with a rampshapedpulse train in 3 groups of male Wistarrats according to a parallel groupdesign.UsingCAMERA.a videotime-frame encoder/decoder with high resolution, the ictal and post-ictal components of the motor seizure (eyes, gasp, jerk, forelimb clonus, and hindlimb tonus) were evaluated before and after administration of a 40 mg.kg" dose of PHT,givenas a single drug (Group I) and concomitant to an infusion of VPA (Group II) at concentrations inducingminoror no protection. As induction of seizure activity with ramp-shaped pulse trains in the presenceof an antiepileptic drug requires longer stimulation, a third group receiving supramaximal stimulation served as control for the effect of current intensity. The total durationof each componentwas scoredin a frame-by-frame analysisand the .seizure fraction was used as measure for the pharmacological effect. The motor seizure lasted longer after administration of PHT alone and was significantly increasedin the presenceofVPA. This seemingly paradoxical effect actually reflects the anticonvulsant action. because longer stimulation is required to reach the threshold for self-sustained seizure activity. Furthermore. the interaction with VPA caused the suppression of myoclonic jerks (p < 0.01) and reduction of forelimbclonus activity, relative to the effects of administration of PHT alone. These results suggest a synergistic pharmacodynamic interaction between VPA and PHT. since the concentrations of PHT were not alteredby VPA.

IP.6.019I New therapeutic strategy for migraine treatment: Desensitization with a dopamine agonist

M. Lai, A. Cherchi,V.Loi, M. Del Zompo. Headache Center, Department ofNeurosciences "B.B. Brodie", University of Cagliari, Cagliari, Italy In spite of recent advances, the pathogenesis of migraine remains unknown. Clinicaland pharmacological evidences supportthe hypothesis of

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a dopamine (DA)receptors hypersensitivity in migrainepatients. This hypothesisis supported by observation that a classicalDA receptoragonist, apomorphine, often evokes in migraineurs the pain and extra-pain phenomena which are characteristic of migraine, such as yawning, nausea, vomiting, hypotension and syncope, at the dosage ineffective in control subjects (Cangi et al., 1985). The aim of our study is to evaluate the presenceof this hypersensitivity in migraine patients and to desensitize the DA systemwith apomorphine. We studied three patients, one male and two females aged 41-57, suffering from migraine without aura resistant to the prophylactic treatments and with a high frequency of attacks. We first tested in these patients individual sensitivity by a single i.m, low dose of apomorphine to assess the lowest effective dose to be administered s.c. in continuous infusion without side effects. Moreover, since growth hormone (GH) is released by stimulation of hypothalamic DA2receptors (La! et aI., 1991), we measured GH plasma levels after the apomorphine to evaluate the effective stimulation of DA receptors. In the apomorphinetest the patients firstreceive placeboi.m, and, one hour later,apomorphine i.m. at the dose of I JLg/kg in the first,3 JLg/kg in the secondand 5 j.Lg/kg in the third day. Clinical evaluation, blood pressure and heart rate were recorded before palcebo or apomorphine administration and monitoredevery 15 minutes for I hour after each injection. The treatment consists in the continuous subcutaneous infusionof apomorphine at the dosage previously assessed by the test for threeto four weeks. No subject reported any adverse effect during chronic apomorphine treatment. Nodifference in bloodpressureand heart rate wasfoundduring test and treatment. The treatment waseffective in reducing frequency and severity of attacks. These results supportthe hypothesis of an involvement of the DA system in the migraine syndrome. Therefore we suggest to utilize the DA agonist apomorphine as a clinical marker of the grade of supersensitivity of DA receptors in migrainepatients. In conclusion, the benefits of long-term treatment with low doses of apomorphine could be partially correlated with a desensitization of DA receptors. References Cangi, F, Fanciullacci, M., Pietrini, U.. Boccuni, M. and Sicuteri, F. (1985)Emergenceof pain and extra-pain phenomena from lkJpa1ninomimctics in migraine, In: Pfaffenrath V., Lundberg, P.O. and Sjaastad, O. eds. Updating in Headache. Berlin, Heidelberg, NewYork, Tokyo: Springer; 276-280. Lal, S., Vasavan Nair. N.P., Tbavundayil, I.X.. Tawar, Y., Quirion, R. andGuyda, H. (I991) Stereospecificty of thedopamine receptor mediating the growth hormone 10 apomorphine in man. J. Neural Transm. [Gen. Sect.185, 157-164.

IP.6.020 I Use of psychotropic medication before and after psychotherapeutic Inpatient treatment

G. Laux, U. Mey. DistrictHospital Gabersee, Dep.ofPsychiatry and Psychotherapy, D-83512 Wasserburgnnn, Germany

Introduction: Up until today there has only been limited data available regarding the effect of in-patient psychotherapeutic treatment on the consumption of psychotropic drugs by psychosomatic patients. Due to the even more important consideration of economic aspects within the evaluation of psychotherapeutical treatments, the follow-up study presented here concentrates especially on the cost-related aspect of these results. Method: Between April and June 1993,we examined92 patients from two psychosomatic hospitalsin the Bonn area who wheretreated using a psychodynamically orientated therapy. The data were obtained by using a semistandardized questionnaire. Six weeks and six months after the end of inpatienttreatment, the patientsreceived additional questionnaires. Almost70% of the patients answered the two questionnaires, and 54.5% of all patientstook partin bothcatamneses. There were no significant differences between patients who answeredthe questionnaires and patients who didn't. Therefore,the results can be consideredto be representative of the total sampling. The patients were diagnosted as anxiety disorders (259'0), "neurotic" depressions (23%). adjustment disorders (20%), personality disorders (ll%) and somatoform disorders (8%) mainly. The average age of the samplingwas 37.8 years, 63% of the patients were female. The average duration of treatmentwas 87.3 days.

P.6 Other topics

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Results: Before the therapy started, 58.3% of the patients took psychotropic drugs regularly (antidepressants 47.9%); benzodiazepines 27.1%; neuroleptics 19%). By the time they were discharged from hospital, this proportion was reduced to 12.5%. After their discharge, the consumption of psychotropic drugs amongst all patients first rose to 14.6%after six weeks and then significantly to 31.3%after six months. In order to study a connection between the extent of psychotherapeutic pre-treatment and the frequency of drug consumption, we observed three categories of patients separately; i.e, those with purely psychiatric pre-treatment, those with psychotherapeutic pre-treatment and those who where exclusively treated by their family doctor. Surprisingly there was no difference regardingthe frequency in taking drugs: in all three groups the averagepercentageof consumerswas about60%. Furthermore, a continuous out-patient treatment seemed to have no influence on the development of the utilisation of psychotropic drugs during the period after discharge: both in the group of patients who started or resumed out-patient psychotherapy after being discharged and in the group of patients who were not treated further, the drug consumption equallyrose again. Discussion: As far as the reductionof drug-related costs is concerned, the efficacy of psychtherapeutic treatment is challenged by the quickly renewed risein psychotropic drug consumption after in-patient treatment. The missing differences regarding the extent of drug consumption in groups of patients with different pre-treatments lead to the speculation that the majority of psychotropic drugs are prescribed by family doctors and internists with limited psychiatric or psychotherapeutic knowledge. This might be equally valid for numerous drug prescriptions after discharge from hospital, provided that patients don't fall back in their own drug supplies withoutconsultinga doctor. The results of the catamnestic study therefore suggest to especially monitor in detail the practice of prescriptions, while analysing the consumptionof psychotropic drugs. On the one hand, psychotropic drugsare often prescribedcarelesslyand inadequately, especially by non-specialist doctors. On the other hand, the strict refusalof psychotropic drugsin the treatment of psychoneurotic disorders contradicts the finding that there is no difference in the response to antidepressants, whether the genesis of the disorder is "neurotic" or "endogenous". Having the indication of the prescriptions during the periodafter discharge checkedby a specialist wouldalso reduce the dangerof wronglyinterpreting the prescriptions not indicated by specialists as a failure of the psychotherapeutic treatment.

IP.6.021 I Effects of sexandaging on3H-paroxetine binding to human platelets

O. Marazziti, A. Rossi, L. Palego, G. Giannaccini ' . A. Lucacchini I, G.B. Cassano. InstituteofPsychiatry and "Istituto Policattedra di Discipline Biologiche ", University ofPisa; via Roma67,56100 Pisa. Italy The striking similarities betweenthe sodium-and temperature dependent serotonin (5HT) transporter in human platelets and brain has led to the widespread use of these cells as a peripheral tool in the study of the central serotonergic neurons. Tricyclic antidepressants (TCAs) and selective 5HT reuptake inhibitors (SSRIs) are the most potent drugs interacting at the level of the 5HT transporterand, tritiated imipramine e H-IMI), a TCA, has been widelyused to label it. However, subsequently, it emerged that 3H-1MI binding was heterogenous, so that, in recent years, it has been demonstrated that the more selective ligand.3H-paroxetine e H-Par) binds to a singlesite probablycorresponding to the neuronal transporter. In order to clarify the possible effects of physiological factors such as age and sex on the specific binding of 3H-paroxetine, we compared it in plateletsof healthy youngand elederlysubjects. Twenty-one healthy young subjects (8 women and 13 men; age between 24 and 33 years, mean ± SD: 28 ± 4) and 20 elderly subjects (10 women and 10 men; age between 65 and 83 years, mean ± SO: 78 ± 3) who volunteered for the study.were included. Plateletmembranes and 3H-paroxetine binding assay were performed according to the method of Marazziti et al. (1995). The binding parameters (Bmax in frnollmg protein. and Kd in oM) were calculated by means of microcomputer programs (EBOA and UGAND). The difference bewteen the binding parameters of young and elderly subjects was measured according to

the Student's t-test, The possible influence of age and sex on binding parameters was analysed according to the methodof Pearson. The results showed that the Bmax values were not significantly different in the 2 groups (1539 ± 607 vs 1354 ± 517 frnollmflprotein in the young vs the aged subjects), as were not the Kd values (0.12 ± 0.5 vs 0.54 ± 0.57). When we compared the SUbjects according to the sex, it turned out that the young females had a statistically significant lower Kd than the males (0.081 ± 0.039 vs 0.14 ± 0.051. P < 0.02), while the contrary was true for the elderlywomen(0.13 ± 0.069 vs 0.078 ± 0.025, p < 0.02). In summary, the findings of the present study shows that sex appears to provoke significant age-related changes in the KD, that is the inverse of the affinity constant, of 3H-paroxetine binding to platelet membranes: young women had a significant lower KD which increased in the elderly age. This might reflect modifications in the 5-HT transporter that would constitute the basis for a different sex-related vulnerability to disorders, such as depression, where a dysfunction at this level is hypothesised. Reference Marazziti D., Rossi A., GiannacciniG., Martini C.. Castrogiovanni S., MicaliM.G.• Lucacchini A.. Cassano G.B. (1995)Correlation betweenthe sites labelledby3H_ 8 hydroxy-2·(di-N-propylamioo)tetralin and 3H-imipramine in humanplatelets. Human PsycbophannacoI. 100:417-421, 1995

IP.6.022I Histamine mediates long-term potentiation of excitability In rat hippocampus

O. Selbach, H.L. Haas. Institute of Physiology II, Heinrich-Heine-University; D4000] Dusseldorf, Germany The action of histamine (HA) on CAl pyramidal-cells in vitro was investigated in rat hippocampal slices perfused with solution containing 0.2 roM ea2+/4.0 roM Mg2+. Extracellular recordings of spontaneous discharges revealed that HA caused a long-lasting increase in cellexcitability, reminiscent the long-term potentiation (LTP) of population spikes [1]. The HA-mediated response was characterized by a quickly rising initial short-term (STPe) and a subsequent long-term potentiation of excitability (LTPe) consisting of an early (I) and later phases (IIIIII) withadditional increases in cell-firing. Low concentrations of HA (0.1 - I /LM) caused an HI-receptor mediated depression of excitability (STDe) which was mimicked by the Hj-receptor-agonist FPHA. Higher concentrations of HA (5 min; 1-10 /LM) exertedin an almost all-or-none manner strongnon-declining LTPe. All HA-induced excitations wereprevented by theH2-receptor-antagonist cimetidine (50--100 /LM). and mimicked by the H2-receptor-agonist impromidine (IMP; 3 /LM). Notably, in contrast to binding data., IMP was less effective than HA. 8-BrcAMP (50 to 100 /LM) and the protein-kinase A (pKA)-aetivator Sp-cAMPS (5- 50 /LM) mimicked IMP-mediated LTPe, whereas the adenylyl-cyclase (AC)inhibitorTHFA(50--500 /LM) or the PKA-inhibitor Rp-cAMPS (1-10 j1.M) blockedthem. Presynaptic Hj-recepror activation by R-a-methyl-histamine was ineffective in 0.2 roM Ca2+/4.0 roM Mg2+ , indicating predominantly postsynaptic actionsunder these conditions. However, the NMDA-receptor-antagonist APV and the Hj-receptorantagonist mepyramine (1-10 /LM) significantly attenuated HA-induced LTPe to a level of the isolated H2-receptor-response. The IMP-response wasnotsignificantly affected by APVor MEP, indicatingan H1·INMDAreceptor-conditioned potentiation of H2-receptor-mediated cAMPIPKAdependent LTPein low ea2+fhjgh Mg2+, presumably mediated by tonic ambientglutamate in the slice preparation. CAI-neurons were refractory for induction of additional LTPe during an early stage of ongoing LTPe. Second applications during this stages (phase I, 30 min) did not induce LTPe but STPe, whereas second applications during later phases (II1IIl, > 60 min) caused full additional non-declining LTPe. Remarkably, the refractoriness during early phases (I) for the LTPe-induction by Gs-Protein-coupled pathways could he removed by prior activation of Gi/q-Protein-coupJed Hj/a2-receptors. Lithium (2 roM) almost entirely blocked all HA- and IMP-mediated excitations, probablyby blocking G-proteins. Noradrenaline and the ,B-receptor-agonist isoprotenerol caused re-