Clinical efficacy and safety of olanzapine in Japanese schizophrenics

P Poster Presentations the haloperidolgroup. Patients treated with olanzapine experienced much fewer extrapyramidal symptoms and prolactin elevation than patients treated with haloperidol. One hundred seventy-five patients completed the acute phase and continued into the double-blind extension phase. Both Olz-L and Olz-H were statistically significantly superior to OlzJ.O in one year completion rates whereas no statistically significant difference between Hal and Olzl.0 was seen. Although no statistically significant differences were found, the survival analysis of relapse prevention found that the Olz-L, Olz-M, Olz-H, and Hal treatment groups had larger estimated percentages not relapsing than the Olzl.O treatmentgroup.The results of this study indicate that, in both acute and long-term treatment, olanzapinewas efficaciousin treating the symptomsof schizophrenia and was well tolerated.

IP-7-41

Acuteand Long-Term Results of the North American Double-Blind Olanzapine Trial P.Tran, C. Beasley, G. Tollefson, M. Dellva, S. Hamilton,R. Van Ostrand, S. Paul. Eli Lilly and Company, Lilly Corporate Center, DC

0538, Indianapolis, IN 46285

Study HGAD (n = 335) was a multicenter, double-blind, parallel trial comparing 3 fixed dose-ranges of olanzapine (Olz-L, 5.0 ± 2.5 mg/day; Olz-M, 10.0 ± 2.5 mg/day; and Olz-H, 15.0 ± 2.5 mg/day) to placebo and haloperidol (Hal, 15.0 ± 5.0 mg/day) with schizophrenic inpatients. The acute phase of the study lasted 6 weeks followed by a double-blind extension phase of at least 12 months where patients received the same initial study drug at the same dose-range. Acute phase efficacy analyses indicated that, with regard to overall psychotic symptomatology, the Olz-M, Olz-H and Hal treatment groups experienced statistically significantly greater mean improvement in BPRS Total score than the placebo treatment group. With regard to negative symptomatology, the Olz-H treatmentgroup experiencedstatistically significantly greatermean improvement in SANS Summary score than both the placebo and Hal treatment groups. Patients treated with olanzapine experienced fewer extrapyramidal symptoms and prolactin elevation than patients treated with haloperidol. Ninety-five patients completedthe acute phase and continued into the double-blind extension phase. Statistically significantly more patientsin the Olz-H treatmentgroup completedone year of therapy than in either the placebo or Hal treatment groups. Survival analysis of relapse prevention indicated that statistically significantly fewer patients in the Olz-L and Olz-H treatment groups experiencedrelapseat any given point in time than patients in the placebo treatment group. Comparable analysis indicated that the relapse rate for haloperidol treated patients did not differ statistically significantly from the rate for placebo treated patients. The results of this study indicate that olanzapine, in both acute and long-term treatment, was efficacious in treating the symptoms of schizophreniaand was well tolerated.

59 negative. Positive symptom improvement was comparable. Olanzapine also had significantly greater improvement on the MADRS total score from baseline to endpoint compared to haloperidol. There was statistically significantly less treatment emergent dystonia, parkinsonism, and akathisia with olanzapine than with haloperidol. Scores on the Simpson Angus, Bames, and AIMS decreased for olanzapine treated patients and mean changes on these scales were all statistically significantly different from the changes observed with haloperidol. These results indicate that olanzapine was superior to haloperidol in the treatment of overall psychotic symptomatology includingnegativeand affectivesymptomatology and was well tolerated.

[ p-?-Sl Olanzapine Versus Haloperidol: Long-Term Results of the Multi-Center International Trial C. Beasley, P.Tran,IN. Beuzen, R. Tamura,M.A. DelIva, J. Bailey, J. Krueger, G. Tollefson. Olanzapine Development Team, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, U.S.A.

This international, multicenter, double-blind, parallel trial compared the efficacy and safety of a single dose range of olanzapine, 5-20 mg/day, to a single dose range of haloperidol, 5-20 mg/day, in the treatment of 1,996 in- and out-patients with a DSM-III-R diagnosis of schizophrenia (83.1%), schizophreniform disorder (1.9%), or schizoaffective disorder (15.0%). After completing the acute phase (6 weeks), a total of 718 patients from the olanzapine treatment group and 215 patients from the haloperidol treatment group continued into the double-blind extension phase and received the same initial study drug at the same dose range. The results of the double-blind extension phase (up to February 14, 1995)are reported here. Survival analysis of relapse prevention indicated that statistically significantly fewer patients in the olanzapine treatment group experienced relapse at any given point in time than patients in the haloperidol treatment group. Patients who were outpatients by the end of the acute phase and were later hospitalized because of an exacerbation of psychotic psychopathology were classified as experiencing a relapse. There were statistically significantly less treatment emergent dystonia, parkinsonism, and akathisiaevents with olanzapinethan with haloperidol. Scoreson the Simpson Angus,Barnes, and AIMS indicated improvement in extrapyramidal symptoms for olanzapine treated patients. A statistically significantly lower percentage of olanzapine-treated patients met the symptomatic criteria for treatment-emergent diskinetic symptoms, as measured by the AIMS. than haloperidol-treated patients. In conclusion, olanzapinewas effective in maintaining reduction of psychotic symptoms achieved during acute pharmacology over a long-term period. Olanzapine was also well toleratedduring long-term extension therapy.

I p-?-?I Clinical Efficacy and Safety of Olanzapine in Japanese Schizophrenics

IP-7-51 Olanzapine Versus Haloperidol: Acute Results of the Multi-Center International Trial P. Tran, C. Beasley,J. Street, R. Tamura,M.A. DelIva, K. Graffeo, J. Krueger, G. Tollefson. Olanzapine Development Team, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, u.s.A.

This international, multicenter, double-blind, parallel trial compared the efficacy and safety of a single dose range of olanzapine, 5-20 mg/day, to a single dose range of haloperidol, 5-20 rug/day, in the treatmentof 1,996 in-and out-patientswith a DSM-III-Rdiagnosisof schizophrenia (83.I %), schizophreniform disorder (1.9%), or schizoaffective disorder (15.0%). The acute phase of the trial was 6 weeks in length and the results are reported here. To enter the trial, patients were either symptomatic (BPRS (k; ::: (8), with or without current therapy; or were intolerant of current therapy (other than haloperidol), with or without symptoms. 97.5% of patients with baseline and post-randomization BPRS scores began with baseline BPRS 0-6 ::: 18. On the primary analysis of overall efficacy, the difference in baseline to endpoint (LOCF) mean change on the BPRS, olanzapinewas statistically significantly superior to haloperidol(-10.89, -7.93; p = 0.015). Mean change on COl-S and response rate (> 40% improvement on BPRS with 3 or more weeks treatment)also significantly favored olanzapine as did improvement on BPRS-negative and PANSS-

J. Ishigooka I, S. Miura 2, M. Murasaki I, Y. Kudo 3.

I Department of Psychiatry, Kitasato University School ofMedicine, Sagamihara, Japan; 2 Kitasato University School ofAllied Health Science, Sagamihara, Japan; 3 Haruki Hospital, Kishiwada, Japan

Clinical trials of olanzapine, a putative "atypical" antipsychotic agent, are now being conducted in Japan. The result of an early Phase II study demonstrated the 58% efficacy as the final global improvement rate and only 5% of patients were discontinued by the adverse events. Following this study, the late Phase II study, multicenter open label study was conducted in 158 schizophrenics diagnosed with the ICD-IO criteria. Olanzapine was administered in a dose range of 2.5-15 mg/day. The symptoms of these patients were evaluated according to BPRS and PANSS. BPRS-totaJ score was reduced significantly from baseline to endpoint. Both BANSS-positive and -negative score were also reduced significantly from baseline to endpoint. The results, in terms of final global improvement rate, showedthat 58% patients achieved moderate or remarkable improvement. With regards to adverse drug events, insomnia, tremor, somnolence, malaise, dry mouth and amenorrhea were common (» 10%). AIMS scores were all reduced, and significantly in the following regions; lips and perioral, tongue and facial/oral movement total score, lowerextremity movements, and severityof abnormal movements. Patients received olanzapine experienced no acute dystonic reaction.

P Poster Presentations

60 Olanzapine is effective in treating both positive and negative symptoms of schizophrenia and well tolerated.

I p-?-Sl

The Efficacy of Zuclopenthixol Acetate in the Treatment of Psychtic Patients N. Dilbaz. H. Guz, G. Boyam. Department of Psychiatry. Numune Hospital. Ankara, TURKEY

24 psychotic, 7 acute manic and 7 exacerbated patients were included in the study to evaluate the clinical effect of zuclopenthixol acetate in viscoleo. Each patient received 50-200 mg of the drug for the first injection. If necessary, the injection could be repeated twice. At the end of the 7 days %78 of the patients had a moderate to marked effect of the treatment. One day after the injection the reduction of the mean total BPRS scores were not statistically significant, but two and three days after the injection the deduction was statistically significant. Statistically significant reductions of (activation) factor scores were seen one day after the injection whereas the anxiety/depression anergia scores remained almost the same. Statistically significant reductions of delusions. activation, hostility and suspiciousness were seen two and three days after the injection. The frequency of side effects was in general low and most often the symptoms were of mild degree.

IP-?-91 Clinical Experience with Zuclopentixol in Twenty-Five Acute Schizofrenic Patients

J. Vilaprifio, R. Galena, S. Kotlik, E. Gris. C. Guzzo, A. Daneo, Neuropsychiatric Hospital Dr. Carlos Pereyra. Mendoza. Argentina The purpose of the study is to verify the efficiency and the tolerance of zuclopentixol used in 25 schizofrenic patients (men and women, ages 18 or older). with positive symptoms, agitation and a few negative symptoms. The diagnostic was made according to DSM-IV criteria. There was a first interview at the moment of hospitalization and periodical controls the Ist. 2nd. 3rd. 4th. 6th and 8th weeks using the Clinical Global the Brief Psychiatries Rating Scale (bprs) and Clinical Global Impression (CGI). The adverse side effects were valoreted according to the UKU side effect rating scale. The results of the treatment were: 75% of the patients presented agitation. which disappeared absolutely in 100% of the cases, between the 12th and 48th hours with zuciopentixol acuphase (50 to 200 mg/day). All the patients of the present study presented positive symptoms (delusions, hallucinations. etc.) which remitted in 85% of the cases between the 6th and 10th day with zuclopentixol depot (200 to 500 mg each JO to 21 days). In two cases treated with zuclopentixol (75 to 100 rug/day) taken orally. the results were the same. The 60% of the patients presents significants adverse side effects and were treated with biperideno or trihexifenidllo clorhidrate; the interruption of the treatment was not necessary, in conclusion, zuclopentixol has demonstrated to be a very good option in treatment of acute schizofrenic patients with agitation and positive symptoms, which remitted promptly. beside the safety of continuity provided by the differents presentations.

IP-7-10 I AAcetate Controlled Double BlindStudyof Zuclopenthixol Compared with Clothiapine in Acute Psychosis Including Maniaand Exacerbation of Chronic Psychosis H. Uys, M. Berk. Department of Psychiatry. Wits Medical School. 7 York Road. Parktown ; 2193 This was a double blind 6 day controlled randomized study to compare the parenteral use of zuclopenthixol acetate and an aqueous solution of clothiapine administered parenterally in the initial phase of treatment of acute psychosis. The sample included 42 patients with mania, exacerbation of schizophrenia and acute psychosis who required acute neuroleptic treatment. There was no significant difference between the two prcparations in efficacy using the Brief Psychiatric Rating Scale or the Clinical Global impression Scale. The groups did not differ significantly regarding side effects. the onset of sedation, number of injections and achievement of behavioural control. The patients in the zuclopenthixol group received

more anticholinergic medications than the clothiapine group (p = 0.028. chi-square with Yates correction). Zuclopenthixol and clothiapine were equally effective in achieving behavioural control in acute psychosis.

IP-?-11 I Efficacy ofL-Sulpiride in the Treatment of Disorganization in Acutely Relapsed Schizophrenics

M. Guazzelli, A. Gemignani. P. Pietrini, S. Starnini, A. Bertolino I , AI. Bertolino I, M. Casacchia 2. L. Fiori 3 . I Pisa, Bisceglie (BA) ; 2 L'Aquila ; 3 Torino, Italy Clinical effects of l-sulpiride 600- 800 mglday in comparison with haloperidol 15- 20 mg/day were assessed in 102 acutely relapsed hospitalized schizophrenics (DSM-III-R criteria; illness duration 17 ± II yrs). After random assignment to either drug group, Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) were administered blindly at recruitment (TO) and after I, 2, and 4 weeks of treatment. L-sulpiride treated pts (group A) and haloperidol pts (group B) did not differ in demographic and clinical characteristics at TO. Drop-outs were 4 in group A and II in group B. Both drugs significantly reduced BPRS, SAPS and SANS scores since the first follow-up evaluation. Haloperidol effects were grater on items Hallucinations and Delusions, whereas l-sulpiride prevailed on the Formal Thought Disorder cluster. Good responders (~ 50% BPRS total score reduction) were 6 in group A and 4 in group B, moderate responders (25- 50%) were 19 and 18. respectively and poor responders (less than 25%) were 21 and 19, respectively. Side effects were similar in both groups. and required treatment discontinuation in 2 group A pts and in 7 group B pts. The results of this study indicate that l-sulpiride 600-800 mg/day successfully controlled acute relapses in schizophrenia in a comparable way to equivalent doses of haloperidol. These findings also indicate that l-sulpiride may have a grater efficacy on the psychopathological dimension of disorganization in schizophrenia. In conclusion therapeutic efficacy on both positive and negative symptoms and clinical safety make I-sulpiride one of the drugs of choice in the treatment of schizophrenia.

Ip.7-12 1 Schizophrenia: Amisulpride in theTreatment of Acute A Double-Blind Comparison with Haloperidol P.Boyer I , S. Turjanski 2, O. Fleurot 2, and the Amisulpride Study Group. I Inserm U302, Pitie-Salpetriere, 75013 Paris, France; 2 Svnthelabo, 92350 Le Plessis-Robinson, France Amisulpride, a substituted benzamide with specific antidopaminergic (D2 and D3) activity. and selectivity for limbic dopaminergic receptors is an "atypical" antipsychotic, which has been shown to be effective in ameliorating productive and delict schizophrenia. The aim of this study was to compared the efficacy of amisulpride versus haloperidol in the treatment of an acute episode of schizophrenia. Preliminary results will be presented. One hundred and ninety one hospitalised patients with subchronic or chronic schizophrenia with acute exacerbations (DSM IIl-R criteria) entered this 6-week. multicentre. international, randomized, haloperidolcontrolled, double-blind study. After 7 days of wash-out period, patients were treated with fixed doses of 800 mg/d for amisulpride and 20 mg/d for haloperidol with the possibility to reduce the dose to 600 mgld or 15 mgld respectively, if required. Outcome were assessed primarily by the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (COl) for the effi cacy parameters and Simpson Angus scale (SAs) for neurological tolerance. Ninety five patients were randomised in the amisulpride group and 96 in the haloperidol group. 77% of the patients fulfill criteria of chronic schizophrenia and 23% of subchronic schizophrenia. Demographic characteristics were similar for both groups. A total of 188 patients could be analysed in the ITT analysis. Sixty four (33.5%) of patients discontinued the treatment, 25 (26%) in the amisulpride group and 39 (41%) in the haloperidol group (ns). Both groups showed improvement on BPRS total score at the end of the