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P-4-67 Effect of olanzapine on deficit syndrome symptoms in chronic schizophrenia
347
P-4 Antipsychotics." basic and clinical studies minimal dystonic liability, which may translate into a low propensity to in duce EPS in man, In contrast to standard antipsychotics, SEROQUEL does not produce sustained elevations in plasma prolact~n Two hundred and eighty-six hospitalised patients with acute exacerba tion of chronic or subchronic schizophrenia {DSM-IIIR criteria} entered this international 6-week, multicentre, placebo-controlled double-blind study. Patients were randomised to placebo, low dose SEROQUEL (up to 250 mg/day) or high dose SEROQUEL(up to 750 mg/day} Study medications were titrated flexibly from an initial dose of 75 mg/day according to climcal response and tolerability Efficacy was assessed weekly using the BPRS, CGI and the SANS or PANSS (N), Safety was evaluated througn neurological assessments (AIMS, Simpson Scale, Barnes Akathisia Scale), adverse events monitoring, chnicol laboratory tests, ophthalmological examinations, ECGs, vital signs and
physical examinations These data demonstrate t~at: • SEROQUEL is effective ;n the treatment of the positive and negative symptoms of schizophrenia • SEROQUEL is well tolerated • SEROQUEL is not different from placebo m terms of emergent EPS • SEROQUEL does not produce sustained elevations of prolactin in man These clinical data support the atypical profile of SERQQUEL. SEROQUEL TM is a trademark, the property of ZENECA Limited
Time course for dopamine and serotonin receptor occupancy in the brain of schizophrenic patients following dosing with 150 mg Seroquel'" tld
Nordstrom A-L, Parde L, and Halldin C (1993) High 5HT2 receptor occupancy in clozapine treated patients demonstrated by PET P~ychopharmacology110, 36~367. SEROQUEL'" is a trademark, the property of ZENECA Limited
Olanzapine versus haloperidol therapy for chronic schizophrenia: impact on deficit syndrome D Revicki. L, Genduso. MEDTAP International, 2101 Wilson Blvd., Arlington, VA 22201, USA; Ully Research Laboratories, Indianapolis, IN 46285, USA Th~s clinical tria! evaluated the effect of olanzapine (OLZ} and haloperidol therapy on enduring negative symptoms, i.e., the deficit syndrome. A double-blind, randomized clinical trial evaluated deficit syndrome symptoms in 431 schizophrenics assigned to 1 mg to 17.5 mg OLZ or 10-20 mg haloperidol (HAL). The Quality of Life Scale (QLS) (Heinrichs et al.. 1984) was used to measure deficit syndrome symptoms. Patients were followed for 36 weeks if they responded to acute therapy at 6 weeks (based on BPRS scores). Statistically significant improvements in Total QLS scores were seen after 8 weeks in the OLZ-M group (p = 0.0009), OLZ-H group (p -= 0.005). HAL group (p = 0.015), and OLZ 1 mg group (p = 0.017). but net OLZ-L group (p ~ 0.935). Statistically significant improvements in Total QLS scores were observed for the 7.5-17.5 mg OLZ groups after 24 and 36 weeks of treatment (p < 0.001). No statistically significant differences in changes in Total QLS scores were observed between the OLZ and HAL cjroups at 12 or 24 weeks. The findings provide some support for the impact of OLZ on deficit syndrome symptoms. Large improvements in all domains except instrumental role function suggest that OLZ may improve quality of life in patients with qhronic schizophrenia
O. Gefvert 1, L.H. Lindstroml B Langstrom2. M Bergstrom2 T. Lundbergl R.A, Yates 3 . S D Larsson 4 , M . D Tuersley 3. t Depad'ment
References
of Psychmtry, Unlversity of Uppsala, Vasteras, Sweden, 2 University of Uppsala PET Centre, Uppsa/a, Sweden, 3 Zeneca Pharrnaceutzcals, Maeclesf~eld, UK; 4 Zeneca Pharrnaceutzeals, Gothenberg, Sweden
Helnnchs, D W Hanlon, TF_.. ~nd Carpenter, WT (1984) The quality of life scale: an ~nstrument lot rating the schizophrenic deficit syndrome Schizophrenia Bulletin 10, 388-398
SERQQUEL'" (ICI 204,636)is an atypical dlbenzothiazepine antipsychotic agent in Phase III development by Zeneca Pharmaceuticals. Dosing of SERQQUEL in the Phase Illllt programme was TID and QID, based partly on preliminary pharmacekinetic data for the parent compound {Tmax approximately 15 h, plasma elimination half-life approximately 3 h) Given the importance of compliance with medication in schizophrenics, a more convenient dose regimen would be beneficial This was an open. non-randomised trial to determrne whether recap tor occupancy data is consistent with BID dosing Schizophrenic patients (DSM IIIR) were dosed with 150 mg SEROQUEL three times a day for fou, weeks and examined using Positron Emmision Tomographv (PET) at 2. 8, 12 and 24 hours after their final dose of 150 mg SEROQUEL. Plasma IC, 204,636 concentrations were measured PET scans used the radio-ligane [11C]-raclopride (RAC; a specific dopamme D2 antagonist) or [11C]-n-methyl spiperone (NMS: a less selective dopamlne D2/serotonin 5HT2 antagon,st) PET data analysis followed the methods of Nordstrom et al (1992). Eleven subchronic or chronic schizophrenic subiects/age 20-43 years, mean 33.9/ were entered and eight completed the PET assessments. There were no serious adverse events No extrapyramidal side effects (EPS) were reported during the dosing phase Time post 150 mg SEROQUEL {hi
2
8
12
26
Putamen D2 occupancy (n) Frontal Cortex 5HT2 occupancy {n) plasma IC1204.636 ng/ml (n)
44% !4/ 72% (4) 402 8 (8)
38% {4~ 65% (4) 102 2 (8)
27% ~4/ 58% (4) 47 O (8}
0% i3/ 50% (4) 7 2 (8i
D2 ligand binding at 26 h was similar to values for neuroleptlc-naive patients published by Nordstrom et al (1993), hence Seroquel D2 recep tor occupancy assumes zero occupancy at 26 h 5HT2 ligand b~nding at 26 h was 50% of published values for the drug naive state; SEROQUEL 5HT2 receptor occupancy calculation assumes the value from Nordstrom et al (1993), Mean plasma ehmination half-life was approximately 5.3 hours (range 2.7-93 hours). Once to twice daily dosing may therefore maintain sufficient 5HT2/D2 receptor occupancy for therapeutic beneht w~th a low incidence of ~PS in schizophrenic patients A large efficacy study in 622 patients (SAFARI) comparing BID and TID dosing regimens is in progress
References Nordstrom A-L., Farde L , Pauli S , Litter J-E , and Halldin C (1992) PET analysis of Ccntral [11Clraclopridc binding qnhealthy young adults and schizophrenic patients -- rehability and age effects Human psychopharmacology 7, 157-165
Effect of olanzapine on deficit syndrome symptoms in chronic schizophrenia D Revicki, L Genduso MEDTAP International, 2101 Wilson Blvd., Arlington, VA 22201, USA," Lilly Research Laboratories, Indianapolis, IN 46285, USA -he deficit syndrome ~s related to impaired function and less integration in the community. This study evaluated the impact of etanzapine (OLZ} therapy on enduring negative symptoms, i.e, the deficit syndrome. A double-blind. randomized clinical trial evaluated deficit syndrome symptoms in 335 schizophrenics assigned to three doses of OLZ {2.5-17,5 rag), haloperidol (HAL) or placebo ~PLA). The Quality of Life Scale (QLS) (Heinrichs et al., 1984) was used to measure deficit syndrome symptoms. Patients were followed for 24 weeks if they responded to acute therapy at 6 weeks, Statistically significant improvements in "[ota~ C)LS scores were observed in the OLZ-H and OLZ-M dose groups after 12 weeks (p < 001) and 24 weeks of treatment (p < 0 0 1 ) The OLZ-L group showed improvements at 12 weeks (p < 0,01), but not at 24 weeks. No changes were seen in the HAL or placebo groups. No differences in QLS scores were detected between the treatment groups at 12 or 24 weeks. The findings provide some support for the impact of OLZ on deficit syndrome symptoms. Large improvements in all domains except ~nstrumental role function suggest that OLZ may improve quality of life in patients with chronic schizophrenia.
References Hcinrichs. OW, Hanlon. TE.. and Carpenter, WT (1984). The quality of life scale: an instrument for rating the schizophrenic deficit syndrome Schizophrenia Bulletin 10, 388-398
Acute and long-term results of the North American double-blind olanzapine trial PV Tran, C M . Beasley, G.D. Tollefson. J.N. Beuzen, M.A. Dellva, T.M Sanger, S Paul. Eh D//y and Company, LIlly Corporate Center, DC
2128, Indianapolis. IN 46285 Olanzapine. structurally a thienobenzodiazepine, is a putative "atypical" antlpsychotic agent. In vitro studies have indicated that olanzapine has high affinity for 5-HT2A, 5-HT2c, 0 2, D 1 , muscarinic (particularly M 1), ~1, and H 1 receptors. In rive binding studies, neuroendocrine studies (ratio of blockade of quipazine-stimuiated serum corticosterone elevation to blockade
P-4 Antipsychotics." basic and clinical studies minimal dystonic liability, which may translate into a low propensity to in duce EPS in man, In contrast to standard antipsychotics, SEROQUEL does not produce sustained elevations in plasma prolact~n Two hundred and eighty-six hospitalised patients with acute exacerba tion of chronic or subchronic schizophrenia {DSM-IIIR criteria} entered this international 6-week, multicentre, placebo-controlled double-blind study. Patients were randomised to placebo, low dose SEROQUEL (up to 250 mg/day) or high dose SEROQUEL(up to 750 mg/day} Study medications were titrated flexibly from an initial dose of 75 mg/day according to climcal response and tolerability Efficacy was assessed weekly using the BPRS, CGI and the SANS or PANSS (N), Safety was evaluated througn neurological assessments (AIMS, Simpson Scale, Barnes Akathisia Scale), adverse events monitoring, chnicol laboratory tests, ophthalmological examinations, ECGs, vital signs and
physical examinations These data demonstrate t~at: • SEROQUEL is effective ;n the treatment of the positive and negative symptoms of schizophrenia • SEROQUEL is well tolerated • SEROQUEL is not different from placebo m terms of emergent EPS • SEROQUEL does not produce sustained elevations of prolactin in man These clinical data support the atypical profile of SERQQUEL. SEROQUEL TM is a trademark, the property of ZENECA Limited
Time course for dopamine and serotonin receptor occupancy in the brain of schizophrenic patients following dosing with 150 mg Seroquel'" tld
Nordstrom A-L, Parde L, and Halldin C (1993) High 5HT2 receptor occupancy in clozapine treated patients demonstrated by PET P~ychopharmacology110, 36~367. SEROQUEL'" is a trademark, the property of ZENECA Limited
Olanzapine versus haloperidol therapy for chronic schizophrenia: impact on deficit syndrome D Revicki. L, Genduso. MEDTAP International, 2101 Wilson Blvd., Arlington, VA 22201, USA; Ully Research Laboratories, Indianapolis, IN 46285, USA Th~s clinical tria! evaluated the effect of olanzapine (OLZ} and haloperidol therapy on enduring negative symptoms, i.e., the deficit syndrome. A double-blind, randomized clinical trial evaluated deficit syndrome symptoms in 431 schizophrenics assigned to 1 mg to 17.5 mg OLZ or 10-20 mg haloperidol (HAL). The Quality of Life Scale (QLS) (Heinrichs et al.. 1984) was used to measure deficit syndrome symptoms. Patients were followed for 36 weeks if they responded to acute therapy at 6 weeks (based on BPRS scores). Statistically significant improvements in Total QLS scores were seen after 8 weeks in the OLZ-M group (p = 0.0009), OLZ-H group (p -= 0.005). HAL group (p = 0.015), and OLZ 1 mg group (p = 0.017). but net OLZ-L group (p ~ 0.935). Statistically significant improvements in Total QLS scores were observed for the 7.5-17.5 mg OLZ groups after 24 and 36 weeks of treatment (p < 0.001). No statistically significant differences in changes in Total QLS scores were observed between the OLZ and HAL cjroups at 12 or 24 weeks. The findings provide some support for the impact of OLZ on deficit syndrome symptoms. Large improvements in all domains except instrumental role function suggest that OLZ may improve quality of life in patients with qhronic schizophrenia
O. Gefvert 1, L.H. Lindstroml B Langstrom2. M Bergstrom2 T. Lundbergl R.A, Yates 3 . S D Larsson 4 , M . D Tuersley 3. t Depad'ment
References
of Psychmtry, Unlversity of Uppsala, Vasteras, Sweden, 2 University of Uppsala PET Centre, Uppsa/a, Sweden, 3 Zeneca Pharrnaceutzcals, Maeclesf~eld, UK; 4 Zeneca Pharrnaceutzeals, Gothenberg, Sweden
Helnnchs, D W Hanlon, TF_.. ~nd Carpenter, WT (1984) The quality of life scale: an ~nstrument lot rating the schizophrenic deficit syndrome Schizophrenia Bulletin 10, 388-398
SERQQUEL'" (ICI 204,636)is an atypical dlbenzothiazepine antipsychotic agent in Phase III development by Zeneca Pharmaceuticals. Dosing of SERQQUEL in the Phase Illllt programme was TID and QID, based partly on preliminary pharmacekinetic data for the parent compound {Tmax approximately 15 h, plasma elimination half-life approximately 3 h) Given the importance of compliance with medication in schizophrenics, a more convenient dose regimen would be beneficial This was an open. non-randomised trial to determrne whether recap tor occupancy data is consistent with BID dosing Schizophrenic patients (DSM IIIR) were dosed with 150 mg SEROQUEL three times a day for fou, weeks and examined using Positron Emmision Tomographv (PET) at 2. 8, 12 and 24 hours after their final dose of 150 mg SEROQUEL. Plasma IC, 204,636 concentrations were measured PET scans used the radio-ligane [11C]-raclopride (RAC; a specific dopamme D2 antagonist) or [11C]-n-methyl spiperone (NMS: a less selective dopamlne D2/serotonin 5HT2 antagon,st) PET data analysis followed the methods of Nordstrom et al (1992). Eleven subchronic or chronic schizophrenic subiects/age 20-43 years, mean 33.9/ were entered and eight completed the PET assessments. There were no serious adverse events No extrapyramidal side effects (EPS) were reported during the dosing phase Time post 150 mg SEROQUEL {hi
2
8
12
26
Putamen D2 occupancy (n) Frontal Cortex 5HT2 occupancy {n) plasma IC1204.636 ng/ml (n)
44% !4/ 72% (4) 402 8 (8)
38% {4~ 65% (4) 102 2 (8)
27% ~4/ 58% (4) 47 O (8}
0% i3/ 50% (4) 7 2 (8i
D2 ligand binding at 26 h was similar to values for neuroleptlc-naive patients published by Nordstrom et al (1993), hence Seroquel D2 recep tor occupancy assumes zero occupancy at 26 h 5HT2 ligand b~nding at 26 h was 50% of published values for the drug naive state; SEROQUEL 5HT2 receptor occupancy calculation assumes the value from Nordstrom et al (1993), Mean plasma ehmination half-life was approximately 5.3 hours (range 2.7-93 hours). Once to twice daily dosing may therefore maintain sufficient 5HT2/D2 receptor occupancy for therapeutic beneht w~th a low incidence of ~PS in schizophrenic patients A large efficacy study in 622 patients (SAFARI) comparing BID and TID dosing regimens is in progress
References Nordstrom A-L., Farde L , Pauli S , Litter J-E , and Halldin C (1992) PET analysis of Ccntral [11Clraclopridc binding qnhealthy young adults and schizophrenic patients -- rehability and age effects Human psychopharmacology 7, 157-165
Effect of olanzapine on deficit syndrome symptoms in chronic schizophrenia D Revicki, L Genduso MEDTAP International, 2101 Wilson Blvd., Arlington, VA 22201, USA," Lilly Research Laboratories, Indianapolis, IN 46285, USA -he deficit syndrome ~s related to impaired function and less integration in the community. This study evaluated the impact of etanzapine (OLZ} therapy on enduring negative symptoms, i.e, the deficit syndrome. A double-blind. randomized clinical trial evaluated deficit syndrome symptoms in 335 schizophrenics assigned to three doses of OLZ {2.5-17,5 rag), haloperidol (HAL) or placebo ~PLA). The Quality of Life Scale (QLS) (Heinrichs et al., 1984) was used to measure deficit syndrome symptoms. Patients were followed for 24 weeks if they responded to acute therapy at 6 weeks, Statistically significant improvements in "[ota~ C)LS scores were observed in the OLZ-H and OLZ-M dose groups after 12 weeks (p < 001) and 24 weeks of treatment (p < 0 0 1 ) The OLZ-L group showed improvements at 12 weeks (p < 0,01), but not at 24 weeks. No changes were seen in the HAL or placebo groups. No differences in QLS scores were detected between the treatment groups at 12 or 24 weeks. The findings provide some support for the impact of OLZ on deficit syndrome symptoms. Large improvements in all domains except ~nstrumental role function suggest that OLZ may improve quality of life in patients with chronic schizophrenia.
References Hcinrichs. OW, Hanlon. TE.. and Carpenter, WT (1984). The quality of life scale: an instrument for rating the schizophrenic deficit syndrome Schizophrenia Bulletin 10, 388-398
Acute and long-term results of the North American double-blind olanzapine trial PV Tran, C M . Beasley, G.D. Tollefson. J.N. Beuzen, M.A. Dellva, T.M Sanger, S Paul. Eh D//y and Company, LIlly Corporate Center, DC
2128, Indianapolis. IN 46285 Olanzapine. structurally a thienobenzodiazepine, is a putative "atypical" antlpsychotic agent. In vitro studies have indicated that olanzapine has high affinity for 5-HT2A, 5-HT2c, 0 2, D 1 , muscarinic (particularly M 1), ~1, and H 1 receptors. In rive binding studies, neuroendocrine studies (ratio of blockade of quipazine-stimuiated serum corticosterone elevation to blockade