Lack of proarrhythmic activity for the antipsychotic drug sertindole despite a strong lkr blockade: Comparison to other antipsychotics

P.2. Psychotic disorders and antipsychotics haloperidol 9). The duration of stage 3 SWS increased significantly in the risperidone group (+14 min) versus haloperidol (-3 min, p=0.011). Compared to baseline values, sleep maintenance (defined as sleep duration as a fraction of total sleep time) increased more in the risperidone group compared to haloperidol (p=0.052) and tended to be higher at endpoint (92% vs. 82%). The number of short awakenings (3-30 s) decreased from 44 to 32 in the risperidone group, but was unchanged in patients receiving haloperidol (p=0.059). Subjective sleep quality did not differ between the groups. Both treatments were well tolerated; known side effects of risperidone and haloperidol were observed, but no serious adverse events occurred. Conclusion: This study demonstrated that sleep maintenance and continuity were improved. Furthermore there was a significant prolongation of slow-wave sleep with risperidone compared to haloperidol. Deficits in slow-wave sleep are associated with poor psychosocial performance. Therefore, the positive effects of risperidone on SWS may contribute to a better clinical outcome in schizophrenic patients. Further studies including larger patient samples are warranted.

References [1] KeshavenMS, Reynolds CF, Miewald J, Montrose D. Slow-wavesleep deficits and outcome in schizophreniaand schizoaffectivedisorder. Acta Psychiatr Scand. 1995; 91:289-92 [2] Biological predictors of 1-year outcome in schizophreniain males and females. Goldman M, Tandon R, DeQuardo JR, Taylor SF, Goodson J, McGrath M. Schizophr Res 1996 23;21:65-73 [3] Dursun SM, Patel JK, Burke JG, Reveley MA. Effects of typical antipsychotic drugs and risperidone on the quality of sleep in patients with schizophrenia: a pilot study. J Psychiatry Neurosci. 1999; 24:3337

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reduced stage 1 sleep and lengthened REM latency compared with classical antipsychotics. A trial comparing polysomnographic effects of clozapine, risperidone and olanzapine versus typical antipsychotics demonstrated differences in REM sleep, but not other sleep stages. By contrast, a recent polysomnographic study with risperidone demonstrated a significant prolongation of SWS compared with haloperidol. Improved sleep maintenance and continuity were reported, as was an association between positive clinical results and prolonged stage 2 sleep. In comparative trials, risperidone significantly improved subjective and objective sleep quality compared with typical antipsychotic agents in young and elderlyl schizophrenic patients. Risperidone also improved sleep efficiency in young schizophrenic patients, and restored sleep quality with chronic use. In addition, schizophrenic patients treated with risperidone appear to have significantly better nighttime sleep quality and daytime functioning compared with patients receiving typical antipsychotics. Risperidone also improved sleep quality in psychotic patients with accompanying affective illness. Conclusion: atypical antipsychotics have shown superior efficacy on sleep profile compared to conventional neuroleptics. Most data are available for risperidone, which demonstrate beneficial effects on multiple aspects of sleep patterns. The clinical utility of antipsychotic agents with favourable effects on sleep profile may extend to sleep-related problems in other patient groups, such as night-wandering in elderly patients with dementia. Further controlled trials with larger patient samples are required to confirm and expand current findings.

References [1] Crosthwaite CG, et al. Improved sleep with risperidone compared with conventionalantipsychotic drugs in older patients with psychosis (Abstract). SchizophreniaRes 2000;41(1):202

Sleep quality in schizophrenic patients and the effects of antipsychotic medication

A. Schreiner. Janssen-Cilag GmbH, Department of Medical and

Scientific Affairs, Neuss, Germany More than 90% of schizophrenic patients have sleep problems which cause distress and may exacerbate existing psychopathology. Electroencephalographic (EEG) studies demonstrate impaired sleep continuity, decreased slow wave sleep (SWS), and shortened rapid eye movement (REM) sleep latency. Such abnormalities may reflect the underlying psychiatric disorder and/or current or prior antipsychotic treatment. Abnormal REM sleep and deficiencies in delta or slow wave sleep (SWS) have been associated with poor clinical outcomes. Antipsychotic drugs affect sleep regulation during treatment and following withdrawal. These agents vary in their effects on sleep architecture and may influence therapeutic outcomes and patient satisfaction. Several studies have investigated sleep effects of antipsychotic agents in schizophrenic patients; general conclusions are limited by differences in trial design and baseline variables. Available data are reviewed. Typical antipsychotics (e.g. haloperidol, thiothixene, chlorpromazine, pimozide) improve sleep efficiency and increase REM latency without changing the duration of sleep stages. Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone) exert varying effects on sleep due to differences in central receptor interactions. Serotonergic 5-HT2A receptor antagonism may be of particular importance in regulating sleep quality, and duration of SWS. Open treatment with olanzapine reduced stage 1 sleep, and increased stage 2 sleep, delta sleep and REM density in drug-free patients. In a comparative trial, clozapine increased stage 2 sleep,

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of proarrhythmic activity for the antipsychotic drug sertindole despite a strong Ikr blockade: Comparison to other antipsychotics

K. Frederiksen ~ , M. Adamantidis 2, J. Matz 3. 1H. Lundbeck A/S, Biological Research, Copenhagen, Denmark," 2Lille University, Department of Pharmacologic, Lille, France; 3H. Lundbeck A/S, Safety Pharmacology, Copenhagen, Denmark Background: QT prolongation by non-cardiovascular drugs has been associated with cases of life-threatening ventricular arrhythmia, including Torsade de Pointes (TdP). This adverse event has been suggested to be due to inhibition of the rapid delayed rectifier K+ current (IKr) encoded by the human ether-a-go-go related gene (HERG). Method: The potential risk of QT prolongation by new drugs may be identified in rabbit cardiac purkinje fibers as an increase in action potential duration (APD). This in vitro model is also susceptible for the induction of early after depolarisation's (EAD's), which is considered as the initiating cellular event for ventricular arrhythmia. Results: We have tested 5 antipsychotic drugs on Ikr and compared the results with effects in the rabbit cardiac purkinje fiber model. All 5 drugs showed inhibition of the HERG current with the following rank order of potencies (IC50 values in nM in parenthesis): sertindole (62); haloperidol 070); risperidone (1600); clozapine (6000); olanzapine (27000).

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t?.2. Psychotic disorders and antipsychotics

In the rabbit cardiac purkinje fiber model we found the following rank order for prolongation of the APD (lowest statistical effective concentrations in nM): risperidone (100), haloperidol (100), sertindole (300), olanzapine (1000) and clozapine (3000). EAD's were induced with risperidone (7/7), haloperidol (3/6), olanzapine (1/6) and clozapine (1/6), but not with sertindole (0/7). Conclusions: Our data indicate that the prolongation of APD and the development of proarrhythmia in rabbit cardiac purkinje fibers can not be positively correlated with the blocking effect on Ikr. This suggests that other cardiac ion channels or receptor blocking properties are opposing the effect on Ikr. For sertindole, we found a complete lack of proarrhythmic activity in rabbit cardiac purkinje fibers, supporting the presence of an important counter-regulatory mechanism(s) against arrhythmogenic events.

~ T h e antipsychotic potential of the anandamide transporter inhibitor AM-404 in rodents B. Pouzet, M. Didriksen, P. Hegel. H. Lundbeck A/S, Dept. of Psychopharmacology, Valby, Denmark The endogenous cannabinoid anandamide has been suggested to regulate dopaminergic activity by strengthen signalling via dopaminergic D2 auto-receptors and to inhibit post-synaptic D2 receptor-mediated transmission. In line with this hypothesis, anandamide transporter inhibitors have been reported to normalise hyperactivity in spontaneously hyperactive SHR rats, as well as antagonising yawning induced by apomorphine in rats (Beltramo et al., J. Neurosci., 2000, 20(9): 3401-3407). Consequently, the anandamide transporter has been suggested as a drug target for treatment of various CNS disorders associated with hyperdopaminergia such as schizophrenia (Piomelli et al., TIPS, 2000, 21:218-224). Thus, we aimed to investigate the effect of blocking the anandamide transporter in three animal models predictive of antipsychotic action. We studied the effect of acute treatment with the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide, AM-404 (Beltramo et al., Science, 1997, 277: 1094-1097) on d-amphetamine-induced hyperactivity and disruption of prepulse inhibition (PPI) in rats, two models with high predictive validity for positive symptoms. We also tested its effect in a model related to glutamatergic hypoactivity, i.e. PCP-induced hyperactivity in mice. Finally, its motor depressant effect in rats and mice, as well as its cataleptic potential in rats were investigated. AM-404 (2.540 mg/kg) partially reversed d-amphetamine-induced hyperactivity in rats. However, AM-404 did neither reverse d-amphetaminedisrupted PPI, nor PCP-induced hyperactivity within the dose range tested. AM-404 did not induce motor depressant effect nor catalepsy at the doses tested. Consequently, these results indicate that AM-404 affects certain behaviour mediated by dopaminergic activity, but does not seem effective against NMDA mediated behaviours. Taken together, our results suggest that AM-404 on its own has a limited therapeutic potential in the treatment of schizophrenia.

~ T h e effect of quetiapine on aggresive/hostility symptoms in patients with schizophrenia J. Giner1, J. Gibert2, J. Jimenez3, H. Bovio 3, S. Herranz 3, A. Pereza, C. Ovejero4, E Rico-Villademoros4. 1Hospital

Virgen de la Macarena, Sevilla, Spain," 2University of Cadiz, Faculty of Medicine, Cadiz, Spain," 3AstraZeneca, Madrid, Spain," 4Biometrica, Madrid, Spain Objective: Aggressive behavior of psychotic patients impacts all aspects of their clinical care. Better treatments are needed, and atypical antipsychotics, such as clozapine, risperidone, and perhaps quetiapine, have shown promise (Volavka, 1999). Preliminary data indicate that quetiapine has an antihostility effect which is independent of the antipsychotic effect (Hellewell,1999). The purpose of this report is to evaluate the effect ofquetiapine on hostility symptoms in a large sample of patients with schizophrenia and in the subgroup &patients with schizophrenia with prominent hostility symptoms. Methods: After obtaining written informed consent, patients aged 18 or over meeting DSM-IV criteria for schizophrenia and for the whom the participant psychiatrists had decided to prescribe quetiapine as part of their normal clinical practice were included in this naturalistic, non-comparative, prospective study. The study was reported to the Ministry of Health. Efficacy measures consisted of Brief Psychiatric Rating Scale and Clinical Global Impression. Tolerability was monitored with a modifiedUKU scale. The effectiveness analysis includes the intention-totreat population. Response was defined as a reduction of at least 20% in the hostility cluster or hostility factor. The subgroup Prominent Hostility Symptoms (PHS) included patients with a score of at least 4 in the hostility item of the BPRS. All patients were included in the analysis of tolerability. Results: In the global sample, 686 patients, the response rates at month 6 on the Hostility Cluster and the Hostility Factor were 70,3% and 68,4% respectively, and 78,4% and 78,8% in the subgroup patients with PHS, (249 patients). In the global sample the percentage of patients with high level of hostility ( score of 6 or 7 in the Item 10 of the BPRS), fell from 9,9% at baseline to 2,0% at month 6 and from 26,3% at baseline to 4,6% in the subgroup PHS. In addiction a multivariate analysis using a stepwise forward selection logistic regression model was performed, The model does not suggest that prominent hostility increase antipsychotic response in the overall sample (n=666 evaluable patients), however it does in the female sample (n=265) (OR:2.2, 95%CI: 1.2-3.9). Conclusions: Our results suggest that long-term quetiapine treatment was effective in the improvement of aggression and hostility regardless the criteria used, comparable to that of clozapine (Volavka,1993) and suggest that quetiapine is a suitable antipsychotic for the hostile schizophrenic patient in the clinical practice setting. The clinical relevance of the gender differences we found is uncertain; further research is needed to clarify this issue.

References [1] Hellewell J, et al. 'Seroquel': efficacy in aggression, hostility and low mood of schizophrenia. Int J Neuropsychopharmacol 1999;2 (suppl 1): Sl12. [2] Volavka J, Zito JM, Vitral J, Czobor P. Clozapine effects on hostility and agresi6n in schizophrenia. J Clin Psychopharmacol 1993;287~89. [3] Volavka J, Citrome L. Atypical antipsychotics in the treatment of the persistently aggressive psychotic patient: methodologicalconcerns. Schizophrenia Res 1999;35:$23-$33