P-02-01

The monitoring of cognitive processes in patients with schizophrenia treated with amisulpride during a 12 month period

A. Klasik, I. Krupka-Matuszczyk, K. Krysta, I. Ziajka. Medical University of Katowice Psychiatry and Psychotherapy, Katowice, Poland

Objective: The effect of 11-nd generation neuroleptics on cognition in patients with schizophrenia has been described in detail with regard to most of the substances in this group. Following a review of current literature it was noted that there is insufficient data regarding the long term impact of amisulpride use on cognition in patient with a diagnosis of schizophrenia.

Methods: Therefore a 12 month research was performed describing the influence of amisulpride on cognitive functioning in patients with schizophrenia. The research was carried out as part of the European Long and Short-Term Studies On The Efficiency Of Amisulpride(Solian) E.L.S.A in the Departament of Psychiatry and Psychotherapy of the Medical University of Silesia in Katowice, (Poland).

Results: The study group consisted of 11 patients with schizophrenia selected according to the criteria outlined in the above mentioned research. The patients were examined neuropsychologically with the Vienna Test System - computer version. The following series of tests were performed: CORSI - attention span test (S4 module: UBS and SBB version for clinical patients) RT - reaction test (module S6:diagnostic version, effect of medication on the attention processes in clinical patients),SIGNAL - test for signal detection (module Sl:diagnosing the attention selectivity in clinical patients).The examination of cognitive functions was performed seven times, on the day before the administration of the first dose, on the 7-th day after, on the 14-th day, on the 28-th day, on the day of discharge from hospital, 6- months after the initial dose, 12-months after the initial dose.

Conclusion: Based on the results it was significantly proven that amisulpride had a positive effect on cognitive functioning in patients with schizophrenia.

P-02-02

Efficacy of quetiapine in schizophrenic patients: A retrospective real-life study

M. Tafalla. AstraZeneca Medical, Madrid, Spain

Objective: Most data used to aid clinical decisions originate from clinical trials. Normal clinical practice, however, differs from controlled conditions. This study has been designed to evaluate outcome among real-life schizophrenic patients treated with quetiapine

Methods: A retrospective analysis of patients diagnosed with schizophrenia (DSM-IV) and treated with quetiapine was conducted by 239 psychiatrists in Spain.

Results: A total of 1238 patients were included (57.7% males, mean age 37.4 years). Mean time since diagnosis was 10.27 years; 89.1% had received previous antipsychotic treatment, most commonly with risperidone, olanzapine and haloperidol, and were switched to quetiapine because of tolerability issues (72%), lack of efficacy (23%) or low compliance (5%). The most common adverse events associated with the previous treatment that caused the switch to quetiapine were sexual dysfunction (44%) and extrapyramidal symptoms (43.4%). Mean dose of quetiapine at the

review period was 586.8 mg (SD:270.8). Compliance was quite good: 65.8% of the patients reached a compliance rate of 80% or more. Clinical Global Impression of change (CGI-C) scale assessment show that two thirds (65.2%) of patients were “very much or much improved”, and 93% were improved to some extent. The doctors rated the overall therapeutic effect of the medication on patient’s condition to be marked or moderate in 71% of patients. With regards to tolerability, 42.5% of patients reported no adverse event, and 52.6% had no clinically significant ones.

Conclusion: Although uncontrolled and retrospective design, this analysis demonstrated strong compliance, therapeutic benefit, and an excellent tolerability profile with quetiapine in Spanish schizophrenic patients.

P-02-03

A Naturalistic Study of Aripiprazole Treatment in a General Psychiatric Setting in Europe

J. -N. Beuzen, M. Pans, S. Modell, P. Hagens, R. McQuade, T. Iwamoto, W. Carson. Bristol-Myers Squibb Pharmaceutical Research Inst, Paris, France

Objective: To examine the overall effectiveness of aripiprazole treatment in a naturalistic setting in 14 European countries.

Methods: This multicentre, open-label study of aripiprazole was conducted in outpatients with schizophrenia for whom a switch or initiation of antipsychotic medication was required. A total of 833 patients were randomized in a 4:1 ratio to aripiprazole treatment (n=680) or a safety-control group (n=153) who were prescribed an antipsychotic other than aripiprazole (primarily ziprasidone, amisulpride, quetiapine, olanzapine or risperidone). Aripiprazole treatment was initiated at a 15 mg/day dose, with an option to adjust within a range of 10-30 mg/day. The treatment period was 8 weeks. Effectiveness was evaluated using the CGI- Improvement scale (CGI-1). Patients’ and caregivers’ medication preference was assessed using the preference of medication scale (POM).

Results: At study endpoint, the mean aripiprazole dose was 19.1 mg/day, with 49.8% of patients receiving the 15 mg dose. The effectiveness of aripiprazole treatment was demonstrated as early as week 1. Among patients completing the study, 52% of those in the aripiprazole group responded to treatment (CGI-I score of 1 or 2) with a mean CGI-I score of 2.71. Sixty-eight per cent (68%) of aripiprazole-treated patients and 66% of caregivers rated aripiprazole as slightly better or much better than prior antipsychotic therapy (score of 1 or 2). The only two adverse events reported with aripiprazole treatment with an incidence of 10% or above were nausea (10.2%) and insomnia (16%).

Conclusion: Aripiprazole demonstrated overall effectiveness in patients with schizophrenia in a general psychiatric setting.

P-02-04

Ziprasidone induced priapism requiring surgical treatment

K. Kaufman, L. Stem, A. Mohebati. UMDNJ-RWJMS Psychiatry, New Brunswick, NJ, USA

Objective: Priapism is defined as persistent erection of the penis, usually painful, not associated with sexual desire or stimulation. Priapism is a urologic emergency; if not evaluated and treated appropriately, long-term sequelae include erectile dysfunction and impotence. Both typical and atypical antipsychotic psychotropics have been reported to cause this adverse effect (AE) secondary to alpha- adrenergic blockage. Only two cases of ziprasidone induced priapism have been reported; neither required surgical intervention. This paper addresses the first case of priapism secondary to ziprasidone that required surgical intervention.

Methods: Case analysis with PUBMED literature review.

Results: 31-year-old black male transferred from a community hospital with intense penile pain (10/10) associated with a 4-day priapism non-responsive to initial treatments with phenylephrine injections, Winter procedure, and corporal irrigation. Further aggressive medical intervention (leuprolide, bicalutamide, and pseudoephedrine) failed necessitating definitive surgery with Al- Ghorab corpora cavemosum to spongiosum shunt. By 9th day from initiation of priapism (4th post-operative day), pain and priapism had resolved. Both Sickle Cell Screen and hemoglobin electrophoresis were negative. The patient was previously diagnosed by DSM-IV criteria with schizoaffective disorder, bipolar type. Prior psychiatric treatments included electroconvulsive therapy, divalproex sodium and olanzapine. Ziprasidone monotherapy was initiated and titrated to 160 mg total daily dose one month prior to his priapism. Ziprasidone was discontinued in the community hospital; post-shunt procedure, aripiprazole was initiated.

Conclusion: Ziprasidone can induce irreversible priapism requiring surgical intervention. Though a rare atypical antipsychotic AE, priapism requires emergency intervention. Clinicians and patients should be educated regarding this potential AE.

P-02-05

Course of weight & metabolic benefits 1 year after switching to Ziprasidone

A. Bemtsson, P. Weiden, A. Loebel, S. Murray, R. Yang, H. Lebovitz. Dartderyds Syukhus Psykiatriska Kliniken, Danderyd, Sweden

Objective: To determine time course of weight and lipid reductions in outpatients switched to ziprasidone from other antipsychotics.

Methods: Three open-label, flexible-dose, 1-year extensions enrolled stable completers of 6-week trials switched from conventionals (n=71), olanzapine (n=71), or risperidone (n=43) to ziprasidone. Follow-up to 1 year of ziprasidone monotherapy permitted longitudinal assessment of improvement in weight and metabolic side effects. Mixed-model regression analysis was used to estimate LS mean change over time (58 weeks total).

Results: Mixed-model analysis showed that subjects switched from olanzapine or risperidone demonstrated progressive, sustained weight loss and BMI reduction. In pre-switch olanzapine group, estimated LS mean weight loss was -3.4 (±0.6 SE) lb at 6 weeks (PO.OOOl) and -21.6 (±3.6) lb at 58 weeks (PO.OOOl). In pre-switch risperidone group, loss was -2.1 (±0.8) lb at 6 weeks (P<0.05) and -15.2 (±4.5) lb at 58 weeks (P0.005). Statistically significant improvements in triglycerides and total cholesterol occurred rapidly during initial 6 weeks of ziprasidone monotherapy, and were sustained through extension endpoints. In pre-switch olanzapine group, estimated LS mean triglyceride reductions were -78.0 (±11.7) mg/dL (PO.OOOl) at 6 weeks and - 54.5 (±15.5) mg/dL (P0.0005) at 58 weeks. In pre-switch risperidone group, respective improvements were -39.2 (±14.6) mg/dL (PO.05) and -36.7 (±18.9) mg/dL.

Conclusion: Subjects switched from olanzapine or risperidone to ziprasidone demonstrated progressive, sustained weight loss and BMI reduction for up to 58 weeks. Lipid improvements were substantial, occurred rapidly, and were sustained during long-term ziprasidone monotherapy.

P-02-06

Neuropsychological outcome before administration atypical and classical antipsychotic treatment. A pilot study.

O. Pino, J. E. Rojo, D. Carmona, G. Guilera, J. Gómez. Bellvitge Hospital Psychiatry, Barcelona, Spain

Objective: To asses changes in cognitive function in patients with stable schizophrenia treated with conventional antipsychotics when 80 mg ziprasidone are added to the treatment

Methods: We asses 10 patients in 4 cognitive domains (including working memory and attention, learning and verbal memory, executive functions and speed of information processing), premorbid QI and psychopathological symptomatology (PANSS scale), during the basal visit. After 3 or 4 weeks of the treatment it was performed the same exploration in order to compare ziprasidone effects into cognitive domains and results obtained by PANSS scale

Results: Working memory in long-delay recall in the category of Fluency Test and the speed of information processing seems to show a positive tendency after ziprasidona treatment. Moreover, similar improvement tendency can be observed in post-treatment PANSS scale results

Conclusion: Our preliminary data show a positive tendency onto cognitive and psychopathological domains we explored, when administration and antipsychotic association treatment

P-02-07

Ziprasidone vs Olanzapine: Contrasts in CHD risk

A. Cheli, D. Harrison, A. Loebel, S. Murray. Pfizer Inc., New York, USA

Objective: This analysis was conducted to examine differences in coronary heart disease (CHD) risk arising from short-term treatment with ziprasidone and olanzapine.

Methods: Hospitalized schizophrenic adults underwent 6 weeks’ randomized, double-blind treatment with ziprasidone or olanzapine, with data collected at baseline and endpoint for fasting lipids and weekly for blood pressure. A Framingham algorithm was used to calculate percentage CHD risk over 10 years in subjects >30 years (per algorithm). Baseline-to-endpoint mean changes in age-adjusted risk by sex were compared using ANCOVA (baseline adjusted).

Results: In men >30 years, there was a significant difference in mean changes in total cholesterol for olanzapine versus ziprasidone (±18.5 mg/dL [n=53] and -8.5 mg/dL [n=44], respectively; P=0.0006). A significant difference was also seen in mean changes in low-density lipoprotein cholesterol for olanzapine versus ziprasidone (±13.0 mg/dL [n—45J and -7.2 mg/dL [n=40], respectively; P=0.004). Mean CHD risk in men increased by 0.6% (baseline 8.1%) with olanzapine (n-53) and decreased by 1.1% (baseline 9.6%) with ziprasidone (n=42). In women ≥30 years, between-group differences were trending toward significance for lipid changes and CHD risk. Neither treatment had significant effects on blood pressure.

Conclusion: The findings indicate that in short-term treatment of men, olanzapine was associated with significant changes in lipid profile versus ziprasidone, with a consequent increase in CHD risk versus ziprasidone. These findings, coupled with those of significant weight gain with olanzapine versus ziprasidone, warrant investigation in longer-term trials.

P-02-08

Olanzapine-treated patients with psychotic disorders improved after changing to risperidone long-acting injectable

W. Chrzanowski, M. Latif, M. Masiak, R. Medori, M. Gastpar. Klinika Psychiatrii AM, Choroszcz, Poland

Objective: Maintained efficacy and safety of a direct transition from olanzapine to risperidone long-acting injectable without an oral risperidone run-in in adults with schizophrenia or other psychotic disorders requiring a change of treatment.

Methods: Patients clinically stable on olanzapine for ≥ 1 month were changed to risperidone long-acting (25 mg, increased to 37.5 mg or 50 mg, if necessary) injected every 14 days for 6 months.

Results: The analysis included 192 patients (63% male) of mean age of 38 years; 134 patients (70%) completed the study. The mean daily olanzapine dose was 15.22 ± 7.63 mg. Insufficient response (43%) and non-compliance (44%) were the main reasons for a treatment change. Mean total PANSS score at baseline was 74; this was significantly reduced after 1 month (mean -5 points) with further improvement until endpoint (mean -8 points) (p<0.001). At endpoint, 32% of patients had a > 20% improvement from baseline in PANSS total score. By CGI-S (Disease Severity), 10% of patients were classified as ‘not ill/borderline ill’ at baseline vs 21% at endpoint. Patient satisfaction with treatment improved significantly; 31% of patients rated their treatment ‘very good’ at endpoint vs 6% at baseline. The ESRS total score was reduced significantly (p<0.001) from baseline to 1 month, and these improvements continued until endpoint. The most frequently reported AEs were anxiety (14.1%) and insomnia (10.9%). Patients’ weight did not change during the trial.

Conclusion: Schizophrenic patients previously considered clinically stable on olanzapine showed significant improvements in symptom control and functioning after changing directly to risperidone long-acting injectable.

P-02-09

Intramuscular olanzapine in acutely agitated manic or schizophrenic patients. A naturalistic study

L. San, B. Arranz, R. Dueñas, J. de la Gandara, V. Perez. Barcelona, Spain

Objective: Agitation is commonly seen in acute manic and schizophrenic patients and it requires rapid and effective treatment approaches in order to protect patient and caregiver from potential injury. We performed a multicenter, open label, naturalistic study including 32 agitated patients attending to psychiatric emergency services (PES) and receiving treatment with intramuscular olanzapine.

Methods: . The study subjects were male and female patients (mean age 36,4±13,8 years, age range 19-75 years), attending to PES, who had a DSM-IV-TR diagnosis of schizophrenia (n=18), manic bipolar disorder (n=8), and Psychotic disorder non otherwise specified (n=6). The primary outcome of efficacy was the excited component of the PANSS (PANSS-EC) (tension, uncooperativeness, hostility, poor impulse control, and excitement), which was completed before starting treatment and at 2 and 24 hours following treatment with 10 mg intramuscular olanzapine. The CGI-S was used to record the severity of illness at baseline.

Results: Basal PANSS excited component was 25,7±6,1 (range 13-35). Basal CGI-S frequencies were: moderately ill in 9,4% of the patients, markedly ill in 28,1% severely ill in 46,9, and among the most severely ill 15,6%. Two hours after the olanzapine injection a statistically significant reduction in the PANSS-EC was noted (25,7±6,1 vs 15±8,5; p=0,002; Student’s ttest, paired). This reduction in the score was observed in all five items from the PANSS-EC. At 24 hours, 87,5% of the patients only needed one injection, with two injections needed in 12,5% of the patients.

Conclusion: This naturalistic study confirms the results obtained in the pivotal clinical trials in real-world agitated patients.

P-02-10

Olanzapine velotab 20 mg.: an experience of SPDC - USL 7 of Siena

A. Giovannoni. Italy

P-02-11

QT changes associated to treatment with clozapine.

A. Pons, V. Vails, A. Romero, G. Massana, M. García-Amador. Hospital Clinic Institut Clinic Neurociemcies, Barcelona, Spain

Objective: Neuroleptic drugs can prolong cardiac depolarization and repolarization phases, often causing reversible and mild abnormalities. The prolongation of the QT is far less frequent but clinically more relevant. To assess changes in the length of the QT interval, the ECG records of psychotic patients before and after a 6- month treatment with clozapine were compared.

Methods: An experienced cardiologist assessed the ECG records of 40 patients. The Bazett formula was used in order to calculate the correction of the QT interval.

Results: Unespecific abnormalities in the T wave were the most frequent finding. The analysis of the QTcB interval revealed a mean prolongation of 14.37 msec in the assessments carried out after six months of treatment with clozapine. Such difference was statistically significant, though the mean value of the QTcB (409.70 msec) is still in the normal interval.

Conclusion: ECG changes caused by clozapine do often appear at the beginning of the treatment. While ECG abnormalities show a dose-dependent association that is statistically significant, prolongation of the QTcB does not. Thus, clozapine appears to be a safe drug in terms of cardiovascular risks. However, prospective data on this issue are scarce and ECG monitoring continues to be advisable.

P-02-12

Haematic follow-up of patients treated with clozapine

A. Pons, A. Romero, X. Camé, G. Massana. Hospital Clinic Institut Clinic Neurociemcies, Barcelona, Spain

Objective: The incidence of agranulocytosis in patients treated with clozapine has markedly decreased thanks to follow-up programs. In this study the main aim was to assess the risk of neutropenia and agranulocytosis in patients followed up and monitored in our Clozapine Clinic.

Methods: The course of the differential leucocytic count was analyzed in our sample of 215 psychotic patients treated with clozapine during a minimum of 18 weeks and a maximum of 24 months.

Results: No cases of agranulocytosis were identified, though three cases of neutropenia appeared during the study period. On the contrary, 23 cases of neutrophilia were observed.

Conclusion: The well-proved efficacy of clozapine is inconsistent with its rather limited use. One of the main reasons for this is probably the claimed risk of agranulocitosis. While such risk is higher during the first 6 months of treatment, from there on, the ratio risk/benefit becomes reversed. Haematic dyscrasias induced by clozapine in our ethnical and geographic setting are scarce, suggesting the involvement of genetic factors in its etiology. A less restrictive follow-up program seems advisable bearing in mind that other drugs with similar risks are not bound by such a strict control.

P-02-13

Bifeprunox: A unique, atypical antipsychotic

A. McCreary. Solvay Pharmaceuticals Researc Biological Lead Optimization U, Weesp, Netherlands

Objective: The effect of bifeprunox was evaluated in a number of preclinical models which have been useful in predicting antipsychotic action in man: conditioned avoidance response, antagonism of amphetamine and phencyclidine-induced hyperactivity. Haloperidol, clozapine, risperidone, olanzapine and aripiprazole were used as reference agents.

Methods: Bifeprunox was shown to have potent antipsychotic like effects in a therapeutic model sensitive to all antipsychotic agents (suppression of conditioned avoidance behavior in rats, MED of 0.25 mg/kg sc). Administration of phencyclidine [PCP, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors] results in a psychotomimetic state that has been suggested to be a valid pharmacological model of schizophrenia. In rats and mice, PCP administration leads to hyperactivity and stereotypy, as well as cognitive deficits. Bifeprunox inhibited the PCP-induced hyperactivity in mice (ED50=0.00096 mg/kg sc), while inhibition of baseline activity was seen only at much higher doses (ED50=0.083 mg/kg sc). The high potency and degree of selectivity compared to base-line activity, of bifeprunox against PCP-induced hyperactivity, is unique compared to known antipsychotic drugs.

Results: Bifeprunox more potently antagonized overt behavior stimulated by d-amphetamine (ED50=0.005 mg/kg and 0.02 mg/kg sc versus low dose (0.5 mg/kg) and high dose (2.0 mg/kg) amphetamine, respectively) as compared to the doses needed for affecting baseline activity (ED50=0.036 mg/kg sc) in rats. The selectivity, between inhibition of amphetamine (0.5 mg/kg)- induced hyperactivity and baseline activity, was highest for aripiprazole, followed by bifeprunox and risperidone.

Conclusion: These data indicate that bifeprunox has antipsychotic like activity in a wide range of animal models.

P-02-14

Binding characteristics of bifeprunox to dopamine and serotonin receptors

A. McCreary. Solvay Pharmaceuticals Researc Biological Lead Optimization U, Weesp, Netherlands

Objective: Bifeprunox was investigated in a number of in vitro test systems for its receptor binding profile, and interaction with the dopamine D2 receptor. Bifeprunox has high affinity for hD2, hD3 and hD4 receptors and a partial agonist effect at serotonin 5-HT1A receptors, but virtually no affinity for 5-HT2A and 5-HT2C, noradrenergic 1 and 2, muscarinic and histaminergic receptors.

Methods: In a functional assay (adenylate cyclase activity in CHO cells expressing hD2L receptors), bifeprunox showed incomplete antagonism of the effects of the dopamine agonist quinpirole, and weak agonist properties. Bifeprunox inhibited D2 receptor-sensitive adenylate cyclase activity in rat striatal slices. In the same preparation, measuring the inhibitory effect on K+- induced release of [3H]-dopamine, bifeprunox acted as a potent antagonist at presynaptic D2 receptors. Of all reference antipsychotic drugs tested (haloperidol, clozapine, risperidone, olanzapine and aripiprazole), only aripiprazole showed a comparable partial agonist profile in vitro.

Results: These functional assays support the dopamine D2 partial agonistic properties of bifeprunox and aripiprazole in vitro. Partial agonist-like effects were induced when endogenous dopamine tonus was low, e.g. adenylate cyclase activity assays in CHO cells and in striatal slices. However, when the endogenous dopamine level was high, the partial agonists acted as functional antagonists.

Conclusion: These findings confer a unique antipsychotic profile: in brain regions (n. accumbens) where dopaminergic neurotransmission is believed to be increased in schizophrenia, the partial agonists act as functional antagonists, thus moderating dopaminergic activity. In contrast, in prefrontal cortex, where the dopaminergic system is believed to be hypoactive, the partial agonists restore dopaminergic neurotransmission.

P-02-15

Behavioral and neurochemical effects of bifeprunox

A. McCreary. Solvay Pharmaceuticals Researc Biological Lead Optimization U, Weesp, Netherlands

Objective: Bifeprunox has been compared to four reference dopaminergic drugs in a number of in vivo models predictive of modulation of dopamine-mediated behavior.

Methods: In rats, with unilateral 6-OHDA lesion of the dopaminergic input into the striatum, quinpirole and preclamol caused contralateral turning behavior resulting from stimulation of lesion-induced, supersensitive, postsynaptic D2 receptors. Bifeprunox caused comparable behavior, however the effect of aripiprazole was minimal and failed to reach the criterion of 50% established for apomorphine.

Results: In microdialysis studies in the nucleus accumbens of the freely moving rat, bifeprunox dose-dependently decreased extracellular dopamine and serotonin levels to 80% of control levels. This is believed to be a consequence of presynaptic D2 receptor and 5-HT1A receptor activation, respectively. The D2 receptor partial agonist preclamol, and the full dopamine agonist quinpirole, decreased extracellular dopamine levels, while aripiprazole was without effect on dopamine and 5-HT levels. The D2 receptor antagonist haloperidol acted differently, increasing dopamine levels without affecting 5-HT levels. In addition to dopamine agonistic behaviors, bifeprunox acted as a dopamine partial agonist in vivo, inhibiting dopamine agonist mediated behavior. The dopamine partial agonist aripiprazole and the antagonist haloperidol showed a comparable effect, while the partial agonist preclamol inhibited amphetamine-induced locomotor activity, but not apomorphine-induced climbing behavior.

Conclusion: In conclusion, bifeprunox shows a profile, consistent in many ways with that of existing antipsychotic agents, an ability to antagonize behaviors caused by dopamine agonists, but unlike dopamine antagonists, also able to stimulate dopaminergic receptors in situations where the dopaminergic tone is low, or dopamine receptors have become supersensitive.