Zotepine: Preclinical support for antidepressant activity

BIOL. PSYCHIATRY

poster session ill

8tld the acute 5 HT blocage may result In Increase In 5 HT tumover, so we

cloSed whole blood 5 HT. The study concemed 12 chronic refractory para• noid IChlzOPhrenlc in patients (OSM IV), (duration of Illness 6 to 25 years).

Treatment started In our hospitalization unit with Cloza up to a maximum of

eoo mgfday. Clinical evaluations (BPRS, Quality of Ufe Scale), regular blood

rnonltOriflg were conducted at the same time, (6 to 24 months). All of them ~ ~ery quickly. Some of them develop a depression, treated with

tIlloxetin8 (20 mglday). For therapeutic response without risk of side effects and withOUt agranulocytosis we preconlzed for P Cloza 200 to 700 nglml and lot RBC Cloza 100 to 400 nglml. We noticed an Important Increase (> 100%) tor whole bloOd 5 HT, about 4 weeks after Cloza. May such an Increase be representative of therapeutic effect? And Is there a threshold before toxical manifestation?

~ Effects of clozaplne and rlsperldone on noradrenaline transporter In cultured adrenal medullary cells R. YQ&himura. N. Yanaglhara 1, T. Terao, K. Abe, F. Izumi 1. Dept. of Psychiatry. University of OCCupational & Environmental Health, SChool of I.fBc:IiCin« KItakYushu 807, Japan, 1Dept. of Pharmacology. University of & Environmental Health. School of Medicine. Kitakyushu 807.

OCcupational

Japan ApproxJmately 30% of schizophrenic patients do not respond to conventional ~cs. Clozapine and risperidone are new drugs with antagonistic properties to 02 and 5-HT2 receptors and demonstrate superiority over other entional antipsychotics In the treatment of refractory schizophrenic pa• We examined the effects of these two new drugs on noradrenaline er In adrenal medullary cells. (1) Clozapine at therapeutic con· (30-1000 nglml) suppressed desipramine-sensitive [3Hj nora· chnaIine uptake In a doslHlependent manner, while risperidone at upper limil of therapeutic concentrations (100 nglml) did not. (2) Clozapine (1000 deCr88Sed both Bmu and Kct value in [SHjdesipramlne binding to the ~~. These results suggest that clozapine but not risperidone i'1lIuenC8S noradrenaline transporter in adrenal medullary cells.

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165-64] Effects of centrally acting drugs on PI response and C-klnase activation of human platelets t TIIJkah8t8. H. Wakatabe, K. Hieda. Y. Ohnuki, J. Ishlgooka, M. Murasaki, Miura. Department of psychiatry. Kitasato University School of Medicine. S4gamihafB. Japa!I Thrombin stimulation of platelets Is known to result In phosphatldyllnositol er (PI response), the activation of protein kinase C (C-klnase). and ea2+ mobilization. We studied the effects of centrally acting ........ on these responses. .. ~ • platelets were obtained from a healthy volunteer and Incubated ·PI The labeled platelets suspension was Incubated with the WIlh stimulated with thrombin until 180 sec. The radioactivities drugS. eln PI PI-4 monophosphate (PIP), PI-4. 5 bisphosphate (PIP2), : = t e (PA) were measured. Then, the concentrations of intracell~lar eaz. e also measured. The drugs were as follows: chlorpromazine w~ ridol (HPO), SCH23390 (SCH), ritanserin (RTS), prazosin (CPZ). ~loI (PPL). scopolamine (SCP), chlorphenilamine (CPH). ~Following thrombin stimulation, a timlHlependent intensification oIlhe ~p/lOrylation In 40 K protein and PA. and a reduction of PIP were Cpz. SCH, PAZ. CPH Inhibited 40 Kprotein phosphorylation, and CPH Inhibited PA phosphorylation. CPZ, RTS. PPL Inhibited the

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IIduclion of PIP.

165-6~ Effect of SM-13496, a novel antipsychotic agent, on

the central dopamlnerglc system IIhlb85hI Yo Ohno, K. Tokuda, R. Tojlma, T. Horizawa, M. Nakamura. ~ Cs~ter, Sumitomo Pharmaceuticals Co.. Ltd.• Osaka. Japan 96 Is a novel antipsychotic candidate that preferentially acts on SM-134 D2 and 5-HT2 receptors. SM·13496 (0.3-10 mglkg, p.o.) in• clcJpamineariOU& behaviors Induced by dopamine agonlsts. but It had only hbted v ctlons In Inducing catalepsy and bradykinesia (E050 > 1000 nr.f9~':'13496 showed high affinities for 02 (K, = 1.68 nM), 5-HT2 (K, ~). and 5-HT1A (K, • 6.75 nM) receptors in rat brain membrane. ~;~h-30 mglkg, p.o.) Increased the levels of dopamine metabolites,

1997:42:15-2975

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OOPAC and HVA, in the frontal cortex, striatum, thalamus, hypothalamus and hippocampus. SM·13496-lnduced Increase of dopamine tumover, as Indexed by OOPACIdopamine and HVAldopamlne ratios, was compatible in the striatum and frontal cortex or slightly higher in the latter structure whereas haloperidol predominantly increased the striatal dopamine tumover: Furthermore, SM·13496 showed a very weak activity for Induction of the stri· atal Oofos mRNA expression, which was markedly enhanced by haloparidol. These findings suggest that SM-1349Bls a novel atypical antipsychotic with preferential action on the mesocortical (versus nigrostriatal) dopamlnergic system.

I65-66 ! Inhibition by arlpiprazole, a novel antipsychotic, on dopamlnergic excitatory transmission In striatal neurons M. Sass, H. Matsubayashl. T. Amano. Department of Pharmacology. Hiroshima University School of Medicine. Hiroshima 734. Japan Aripiprazole Is a unique antipsychotic drug that Inhibits dopamine (OA) neurons In the ventral segmental area as a OA agonist and suppresses dopamlnerglc transmission of postsynaptic nucleus accumbens neurons as a OA antagonist. The present study was performed to determine If arlplprazole acted on striatal neurons as an agonist or an antagonist. Methods: Single neuronal activities were recorded In the striatum of chloral hydrate-anesthetized rats using a glass mlcroelectrode attached along a seven-barreled micropipette. Each barrele of the micropipette was filled with aripiprazole. domperidone (02 antagonist), quinpirole (02 agonist), glutamate and 3 M NaCI accordingly. These drugs were microlontophoretically applied to the Immediate vicinity of the target neuron being recorded. A bipolar stimulating electrode was Inserted In the substantia nigra pars compacta (SN) for evoking spikes. Results: Microlontophoretic application of ariplprazole Inhibited spike generation Induced by SN stimulation In the striatal neurons. where the stimulus·induced spike was blocked by domperidone. Qulnpirole-lnduCed firing was also Inhibited by ariplprazole and domperidone, whereas gluta• mate-induced firing was not affected by either drug. These results suggest that aripiprazole acts on striatal neurons as a OA antagonist

165-671 Amlsulprlde Is a preferential D3 dopamine receptor antagonist Gh. Perrault. H. Schoemaker, R. Oepoortere. Y. Claustre, O.J. Sanger, B. SCatton. CNS Research Department. Synthelabo Recherche. Bagneux. France Amisulpride, a benzamlde derivative. which displays a unique pharmacolog• Ical profile, binds selectively to recombinant human 03 and 02 dopamine (OA) receptors with high and similar affinity (KI-3 nM) Ex vivo. amisulpride preferentially displaced [1 25 1]iodosulprlde in rat brain areas enriched In 03 receptors (lobule 10 of the cerebellum, Islands of calleja) as compared to the striatum (area enriched In O2receptors). In vivo In mice, amisulpride reversed dopamine agonlst·induced hypothermia (a 03 receptor mediated effect) at doses 10 times lower than those required to Inhibit apomorphine-Induced climbing (an effect Involving 01 and O2 receptors). In rats, Its ability to coun• teract the Inhibition by 7-QH-OPAT of OA synthesis after blockade of nerve impulse flow, may be related to its preferential affinity for presynaptic 0 3 receptors. Similarly, the selectivity of amisulpride for limbic structures as indio cated by a preferential displacement of In vivo [3Hjraclopride In rats In these brain regions as compared to the striatum (limbic selectivity ratio. 3) In rats and by its preferential blockade of hypermotility produced by d-amphetamlne or apomorphine In comparison to the lack of (d-amphetamine) or weak (apo• morphine) antagonism of drug-Induced stereotypies, may also be associated with its selectivity for 03 receptors. Thus. amisulpride is a preferential 03 dopamine antagonist, Which may account for Its clinical efficacy as an antipsychotic without the motor side effects associated with 02 receptor blockade.

165-681 Zoteplne: Preclinical support for antidepressant activity P.L Needham. M.J. Skill, S.C. Cheetham. O.J. Heal. Knoll Pharmaceuticals Research and Development. Nottingham, NGt tGF, UK Zotepine, an atypical antipsychotic, efficacious against positive and negative symptoms of schizophrenia, with low extrapyramidal side-effect potential

176S

Poster session m

BIOL. PSYCHIATRY 1991;42:IS--mS

(Petit et ai, 1996, Psychopharmacol BuU, 32, 61), is particularly effective In treating anxiety/depression in schlzophrenlc patients (ibid; Fleischhacker et ai, 1969, Psychopharmacol Bull, 25. 97). Here, we examine zotepine in models predictive of antidepressant activity. Methods: Male, CD rats (-200 g) or CD1 mice (-25 g) were used in all tests. For behaviour. zotepine was administered po, 1 h before test evaluation. Reserpine hypothermia (RH), Porsolt swim test (PS) and reserpine ptosis (RP) were determined as previously (Luscombe et ai, 1993 Neuropharmacology, 26, 129). Noradrenaline (NA) uptake In rat cortical synaptosomes in vitro was adapted (ibId). Catalepsy was measured as descnbed (Needham et ai, 1996, pSychopharmacol Bull. 32, 126). Results: Zotepine inhibited NA uptake (Ki '" 21 nM), reversed RH (EDso 26 mglkg) and increased PS motility (100 mglkg). RP was unaffected by 30 mglkg, (am~riptyline RP EDso • 48 mglkg); at higher doses, zotepine alone caused ptosis. Catalepsy EDso values for zotepine, in rat and mouse, were 31 and 26 mglkg, po. respectively. Discussion: RH data are consistent with zotepine's potent inhibition of NA uptake, but Increases in motility were surprising in view of the catalepsy EDso, and are in marked contrast to the neuroleptic chlorpromazine, which also Inhibits NA uptake, but decreases motility in the Porsolt test at eqUiv• alent doses. These findings demonstrate an antidepressant mechanism for zotepine which may contribute to its beneficial clinical profile.

165-69 1 Antipsychotics haloperidol and rlsperldone and psychotomimetic amphetamine affect neuropeptldes and monoamlnes Susanne H.M. Gruber, A.A. Mathe. Karollnska InstItute, Inst Clin Neuroscience, St G6ran's HospItal, Stockholm. Sweden Background and RaUonale: Neuropeptides are stored and co-released with classical neurotransmitters In CNS. CBlwonln gene-related peptide, neuropeptlde Y and neurotensin are of particular interest In the study of psychotic disorders as they interact with dopamine (DA) and noradrenaline (NA) in selected brain regions. Previously we found that psychotomimetics, such as amphetamine as well as MK-801 and phencyclidine affect both tissue and microdialysate peptide concentrations. Consequently we decided to explore whether antipsychotic drugs also have an effect on peptldes and if those actions are of pathophYSiologic and/or therapeutic relevance. experimental Design: Rats were fed chow supplemented with haloperi• dol (1.15 or 2.3 mgl100 glood), risperidone (1.15 mg/100 g food), or vehicle. After 30 days the rats were assigned to one of the two subgroups: (1) animals were sacrificed, the brains dissected into hypothalamus, frontal cortex, stria• tum. occipital cortex and hippocampus and the peptides and monoamines extracted from the same samples. CGRP, NPY and NT were measured with AlA and CA, COPAC, HVA, serotonin, 5-HIAA, NA and MHPG measured with rp-HPLC, (2) ventral segmental area was microdialysed and the samples col· lected before and after injection of amphetamine (1.5 mglkg) or saline. Results: Complicated pattem of neuropeptide and monoamine changes. both in tissues and dialysates emerged and will be presented. Conclusion: We have shown that both antipsychotics and psychotomimet• ics affect neuropeptide tissue concentrations in and release from brain regions. The findings indicate a novel property of these compounds. Supported by the Swedish Medical Aesearch Council. 1110414, Karolin• lka Institute and the Swedish Medical AssociationlSc5derstrOm·KOnigska Foundation.

165-70 I Distribution of fos expression Induced by

long-acting haloperidol decanoate treatment In rat brain

chronic haloperidol-treated rats also Induced comparable increases in Fos ImmunoreaClJvlty In most of these areas. The rats treated with acute vehicle after chronic haloperidol showed persistent Fos increases in the confined brain regions including the amygdala, lateral septum, and entorhinal cortex. The persisting effects of haloperidol in the amygdala. lateral septum and entorhlnaJ area may be of significance to the efficacy of long-term hal~ treatment

165-71

I Clozaplne - A survey of protocols and prescribing

A. Thampi, S.J. Cooper. Department of Mental Health, Queen's University of Belfast, N Ireland The Aim of this survey was to assess adherence to locally agreed prescribing

protocols and identify problems encountered. Methods: note review and patient Interviews were used to COllect data on all patients commenced on clozapine since 1990 in a Belfast psychiatric unit. Results: A total of 23 patients were identified. The mean duration of illness prior to clozapine treatment was eight years with an average eight previous admissions. All patients had received trials of two neuroleptics prior to treatment and 65% had received doses greater than 1000 chlorpromazine eqUivalents. The mean duration 01 treatment with clozapine was 19 months with 57% receiving doses greater than 300 mg and a mean dose of 364 mg. In this group. 53% showed good response and 30% partial response to treatment Eighty-seven percent had documented side effects. most commonly Sedation (48%) and sialorrhoea (26%). Seven patients were w~hdrawn from c10zapine treatment. Patients reported high levels of satisfaction with treatment in terms of reduced symptoms. While some knowledge of side effects was knowledge of relative risks were inaccurate. Conclusions: this survey confirmed adherence to prescribing ProtOCOls and identified high levels of patient satisfaction with c10zapine treatment

case

common.

165-721

Continual antipsychotic therapy 8S a condition for the maintenance of remission In schizophrenic patients

Lj. TrajanovlC, O. tiki~. O. Skaki~. ClInic for Mental Health, Clinical Center Ni6. N/~, Yugoslavia

The most frequent question, that schizophrenic patients asked for, is why they have to take drugs after the acute episode of disease is improved. The aim of this research is to show that the continuity of antipsychotic drugs treatment significantly Impacts the maintenance of remission period of schizophrenia, and so gives the answer to the question mentioned above. Method: The 60 SCH patients were followed one year after the improve• ment of the last acute episode of disease. With all 60 subjects maintenance antipsychotic drug therapy was recommended. Resulta: After one year period, 30 subjects had the remission that lasted 12 months, other 30 had the relapse of the disease. In the first group 24 patients were taking their medication continuously. In the Second group ~Iy 10 patients were taking antipsychotic drugs, while 20 of them spontan~ and self-Initiatively stopped taking their drugs. Statistical data processing shows that continuity and regularity in maintenance antipsychotic medication: one year after the last episode of SCH disease, is statistically very significant (p < 0.001) factor for the maintenance of remission In a chronic SCH patients. This research also gives the evidence about the justification of the antipsychotic long-term treatment of SCH.

Y.oJ. Sun, M. SUZUki, M. Murata, M. Kurachi. Department of NeuropsychIatry. Toyama Medical and Pharmaceutical UniversIty, Toyama, Japan

165-731

To identify sites of antipsychotic drug action, effects of haloperidol decanoate on Fos protein expression in rat brain regions were examined immunohis• tochemically. Male Wlstar rats were injected with haloperidol decanoate (40 mglkg, I.m.) or vehicle. Fourteen days after the injection, each rat received acute administration with either haloperidol (0.25 mglkg) or vehicle Intramus• cularly, and was perfused 2 hours after the last injection. A single dose of haloperidol to the chronic vehicle-treated rats produced significant increases in Fos positive neurons in the several cortical areas, caudate-putamen, nucleus accumbens, lateral septum, hippocampal areas, amygdala. and mecencephalic dopaminergic nuclei. Additional haloperidol injection to the

L Femil.ndez-Novoa, L. Corzo, X.A. Alvarez, R. Cacabelos. EuroEspes BiomedIcal Research Center. La Coruna, Spain

Whole blood and serum histamine In healthy subjects and In schizophrenic patients: Correlation analysis with transcranlal Doppler Ultrasonography

Schizophrenia Is a psychiatric disorder thet affects 1% of the POPUlation. In this study, we evaluated the correlations between whole blood (BHA) and serum histamine (SHA), and transcranial Doppler Ultrasonography (TCO parameters in healthy subjects (C) and In schizophrenic patients (SCHj) In previous studies, we observed that SChizophrenic patients shoWed ~ decrease In resistance (RI) and pulsatility (PI) Indices and an Increase • the effective pulsatility range (EPA) in both middle cerebral arteries (MeAi.