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P.3.c.055 Asenapine: short-term tolerability, safety, and pharmacokinetic profile in older patients with psychosis
P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical) Conclusion: A significant number of patients treated with antipsychotic drugs switched treatment. The principal reason for switching was inadequate symptom control. Tolerability issues were also important reasons for switching, and these differed between first and second generation antipsychotic drugs. P.3.c.054 Effect of the DRD2 Taq 1A polymorphism on perospirone and aripiprazole efficacy for Japanese schizophrenia patients Y. Takekita1 ° , M. Kato1 , M. Wakeno1 , S. Nonen2 , S. Tetsuo2 , S. Sakai1 , A. Suwa1 , G. Okugawa1 , T. Kinoshita1 . 1 Kansai Medical University, Dept of Neuropsychiatry, Osaka, Japan; 2 Osaka University, Clinical Evaluation of Medicines and Therapeutics Graduate School of Pharmaceutical Sciences, Osaka, Japan Objective: Perospirone (PER) and aripiprazole (APZ), a second generation antipsychotics with similar effects on serotonergic receptors, partial agonistic activity at 5-HT1A receptor and antagonistic activity at 5-HT2A receptor as well as remarkably different effects on dopaminergic systems. PER acts as D2 antagonist, whereas APZ has partial agonistic activity on D2 receptor. We compared the therapeutic efficacy and tolerability, the effect by DRD2 Taq 1A polymorphism of PER and APZ in patients with schizophrenia. Subjects and Method: All patients were diagnosed as schizophrenia according to DSM-IV-TR. The patients who gave the informed consent to this 12-week and flexible-dose trial were randomly assigned to PER (8−48 mg/day, n = 28) or APZ (3−30 mg/day, n = 34). The patients were between 18 and 73 years (APZ groups: mean = 41.3±16.3, 15 males and 16 females; PER groups: mean = 47.5±16.1, 12 males and 13 females). The clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) before and every 4 weeks after treatment. The efficacy was assessed by changes from baseline for PANSS score. An intention-to-treat analysis was instead carried out for the 6 patients who underwent a baseline and at least 1 other PANSS assessments, out of 62 subjects. Genotyping for DRD2 Taq 1A polymorphism were analyzed by using polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP), and TaqMan® . Repeated measures analysis was performed with PANSS baseline included in the model as covariate. The study was approved by the Ethical Review Board of Kansai Medical University. Result: Both groups showed significant improvement during the study with reduction of total PANSS scores. As for treatment, there were no significant differences in PANSS total, positive and negative subscale score change overtime between PER and APZ treatment group. As for tolerability, PER treated patients reported more extrapyramidal symptoms (36%) than APZ treated patients (22%), especially rigidity. Furthermore more patients treated with APZ (71%) completed the 12-week study than those treated with PER (46%); time to discontinuation was significantly in favor of APZ (p = 0.03). The clinical efficacy of APZ and PER were almost the same, subsequently we combined these two drugs as dopamine modulator and evaluated the association between Taq1A polymorphism and APZ/PER in the combined sample. The patients with A1/A1 allele (n = 14) group showed significant improvement during the study with reduction of total PANSS scores (p = 0.05) and the negative subscale (p = 0.05) compared to A1/A2 and A2/A2 allele group (n = 42). When divided by each drug,
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no significant efficacy of Taq1A polymorphism could be seen in PANSS reduction, may be due to small sample size. There is no correlation between Taq1A polymorphism and discontinuation rate or frequency of side effects. Conclusion: Our findings suggest that PER and APZ exhibit similar efficacy in the treatment of Japanese schizophrenia patients. However there is difference between the two drugs in discontinuation rate with favorable continuity of APZ. In addition, our data could lead that DRD2 Taq 1A polymorphism play an important role in improvement of total symptom, among others negative symptom, of schizophrenia in PER and APZ treatment. P.3.c.055 Asenapine: short-term tolerability, safety, and pharmacokinetic profile in older patients with psychosis S. Dubovsky1 ° , C. Frobose2 , P. Phiri3 , J. Panagides4 . 1 University of Buffalo, Department of Psychiatry, Buffalo, USA; 2 Merck, Department of Global Clinical Trial Management, Summit, USA; 3 Merck, Department of Statistics, Summit, USA; 4 Merck, Department of Clinical Development, Summit, USA Purpose: Asenapine is an atypical antipsychotic indicated in the United States for the acute treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In this study, we report on the short-term tolerability, safety, and pharmacokinetic profile of asenapine in elderly patients with psychosis. Methods: This 6-week randomized, parallel-group, multidose, multicenter trial enrolled patients aged 65 years with psychotic symptoms that were not related to dementia. At screening, patients were required to have a Positive and Negative Syndrome Scale (PANSS) score 4 on 1 of 5 predefined items (delusions, hallucinatory behavior, excitement, hostility, poor impulse control), a PANSS total score >50, and a Clinical Global Impression-Severity of Illness score 3. After a washout period of 3 days, patients were randomized to 1 of 2 treatment groups. Patients in the first treatment group received sublingual asenapine 2 mg twice daily (BID) on days 1 and 2, asenapine 5 mg BID on days 3 and 4, and asenapine 10 mg BID thereafter. Patients in the second treatment group received asenapine 5 mg BID on days 1−4 and asenapine 10 mg BID thereafter. Drug treatment was conducted under double-blind conditions during the initial 6 days and was open-label for the remainder of the trial. Blood samples were collected on treatment days 3, 4, 7, 8, 21, and 42 (before the morning dose) and 0.5−12 hours after the morning dose on days 4 and 8. Pharmacokinetic parameters for asenapine were calculated based on plasma concentrations observed on days 4 and 8. Results: A total of 122 patients (n = 61 in each treatment group) were randomized and 76 (62.3%) completed the trial. In the overall population, the mean±SD age was 71.2±5.2 years, with most patients (77.9%) in the age range of 65−75 years. Baseline demographics and clinical characteristics were comparable between groups. Tolerability was comparable across treatment schedules. Adverse events reported by 5% of patients included hypertension (8.2%), headache (6.6%), and somnolence (6.6%). The incidence of extrapyramidal symptoms reported as adverse events was 5.7%. Mean weight change at endpoint was 0.4 kg; clinically significant weight gain was reported in 2 patients (1.7%). Median times to maximum asenapine concentration at 5 and 10 mg BID were 1.00 and 1.06 hours, respectively. Maximum asenapine concentrations
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P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical)
(Cmax ) at 5 and 10 mg BID, as measured by the geometric mean, were 4.73 and 7.93 ng/mL. Areas under the curve from 0−12 hours at 5 and 10 mg BID were 32.1 and 56.3 ng·h/mL. Conclusions: Compared with previous findings in patients aged <65 years (asenapine Cmax: 4.23 ng/mL at 5 mg BID, 6.56 ng/mL at 10 mg BID), exposure was 12−30% higher in elderly patients, indicating lower drug clearance in this population. Despite the increased exposure, short-term asenapine treatment was generally well tolerated in elderly patients with psychosis during rapid dosage escalation. Disclosure statement: Research support from Pfizer, Otsuka, Sumitomo Pharma, Biogen, and Tower Foundation. P.3.c.056 Prolactin elevation induced by antipsychotics in first episode psychotic patients R. Perez-Iglesias1 ° , I. Mata1 , M.T. Garcia-Unzueta2 , J.A. Amado3 , O. Martinez-Garcia1 , J.L. Vazquez-Barquero1 , 1 Hospital Universitario Marques de B. Crespo-Facorro1 . Valdecilla, Psiquiatria, Santander, Spain; 2 Hospital Universitario Marques de Valdecilla, Analisis clinicos, Santander, Spain; 3 Hospital Universitario Marques de Valdecilla, Endocrinolog´ıa, Santander, Spain Purpose: The prevalence rate of hyperprolactinemia in patients taking antipsychotic is considerably higher than the prevalence rate of general population. Although prolactin levels are not routinely obtained, this association may have long-term consequences in terms of menstrual disturbances, sexual dysfunction and lower bone mineral density. There are few data comparing the effect of low doses of antipsychotics on prolactin levels in first episode psychotic patients. The main objective of this study was to compare the effect of typical (haloperidol) an atypical (olanzapine and risperidone) antipsychotics on serum prolactin levels during the first 3 months of treatment. Method: A randomized, open-label, prospective clinical trial was conducted. Participants were 145 consecutive first episode psychotic patients included in a first episode program of Cantabria (Spain) from February 2002 to February 2005. Patients have not been previously exposed to antipsychotic medication. The rate of participation was 98.6% and the number of patients who remained adherent with the protocol after 12 weeks was 88.3%. Prolactin levels were measured by chemiluminiscent automathed assay in a Advia Centaur Chemistry System from Bayer Diagnostics (Bayer Corporation, Tarrytown, NY, USA), using the reagents supplied by Boehringer-Mannheim (Mannheim, Germany). Normal values were <12.5 ng/ml for men and <18.5 ng/ml for women. Results: Mean dose of antipsychotics at 3 months were: 4.2 mg/d haloperidol, 12.7 mg/d of olanzapine and 3.6 mg/d of risperidone. The mean prolactin levels at baseline were: 34.1 ng/ml for haloperidol group, 26.0 ng/ml for olanzapine and 35.7 ng/ml for risperidone. At 3 months the prolactin levels were: 22.8 ng/ml for haloperidol group, 23.1 ng/ml for olanzapine and 72.5 ng/ml for risperidone. Patients treated with risperidone experienced a significantly increase in prolactin levels compared with both olanzapine and haloperidol treatments (F = 39.1, df = 2, p < 0.001). The increment from baseline levels in risperidone group was 97% (65.4% in men and 133.9% in women) resulting in abnormal plasma prolactin levels at 3 months in 92.3% of men and 100% of women. It is noteworthy that although risperidone is the only treatment that produces increase in prolactin levels in our study, the three groups of treatment showed high levels of prolactin
at baseline and at 3 months. One possible explanation for the high prolactin levels, even at baseline, is that some patients had received their first dose of treatment the night before the blood test was performed. Another factor that could have influenced the prolactin levels is the stress experienced at the moment of admission. Despite the elevated percentage of patients with abnormal prolactin levels, few patients reported prolactin-related side effects: only 2 patients reported galacthorrea, both treated with risperidone, 4 patients reported amenorrhea (2 treated with haloperidol y 2 treated with risperidone) and 15 patients reported sexual side effects (6 treated with haloperidol, 3 treated with olanzapine and 6 treated with risperidone). Only 1 patient in risperidone treatment group needed change to a different treatment because the severity of sexual side effects. Conclusions: Serum prolactin levels should be monitored during risperidone treatment and sexual side effects should be inquired. References [1] Haddad, PM, Wieck, A (2004) Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs, 64(20): 2291–2314. [2] Melkersson, K (2005) Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry, 66(6): 761–767. [3] Volavka, J, Czobor, P, Cooper, TB, Sheitman, B, Lindenmayer, JP, Citrome, L, McEvoy, JP, Lieberman, JA (2004) Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry, 65(1): 57−61.
P.3.c.057 Which patients switch antipsychotic medication? Data from the international Antipsychotic Drug Substitution Registry P. Paterakis1 ° , B. Galinska-Skok2 , L. Pani3 , M. Bubrovszky4 , 1 “Dromokaitio” Psychiatric G. Perdriset5 , P. Thomas4 . General Hospital of Athens, Department of psychiatry, Athens, Greece; 2 Medical University of Bialystok, Department of psychiatry, Choroszcz, Poland; 3 Institute Biomedical Technologies PharmaNess Scarl, Neuropharmacology Section, Cagliari, Italy; 4 Hˆ opital Fontan − CHRU de Lille, Department of psychiatry, Lille, France; 5 sanofi-aventis, Medical Affairs Department, Paris, France Purpose of the study: Around one-third of patients treated with antipsychotic drugs change their medication every year. The frequency of switch varies among countries depending on the local medical practice and is likely to vary between different antipsychotic drug classes. A naturalistic, multinational observational survey (SWITCH) has been implemented to evaluate the dynamics of treatment discontinuation and substitution in the management of schizophrenia in everyday clinical practice. The primary objective of this study was to identify the frequency of switching antipsychotic treatments in patients with schizophrenia. A secondary objective was to identify reasons for switch to other antipsychotic. Methods used: This was a cross-sectional, observational study performed in eleven countries (Algeria, Greece, India, Jordan, Lithuania, Mexico, Philippines, Poland, Slovakia, Ukraine and Vietnam). All adult patients with schizophrenia consulting consecutively within one month (up to fifty per site) were included in the study. These patients constituted the Screening population. Data was collected on socio-demographics, psychiatric diagnosis
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no significant efficacy of Taq1A polymorphism could be seen in PANSS reduction, may be due to small sample size. There is no correlation between Taq1A polymorphism and discontinuation rate or frequency of side effects. Conclusion: Our findings suggest that PER and APZ exhibit similar efficacy in the treatment of Japanese schizophrenia patients. However there is difference between the two drugs in discontinuation rate with favorable continuity of APZ. In addition, our data could lead that DRD2 Taq 1A polymorphism play an important role in improvement of total symptom, among others negative symptom, of schizophrenia in PER and APZ treatment. P.3.c.055 Asenapine: short-term tolerability, safety, and pharmacokinetic profile in older patients with psychosis S. Dubovsky1 ° , C. Frobose2 , P. Phiri3 , J. Panagides4 . 1 University of Buffalo, Department of Psychiatry, Buffalo, USA; 2 Merck, Department of Global Clinical Trial Management, Summit, USA; 3 Merck, Department of Statistics, Summit, USA; 4 Merck, Department of Clinical Development, Summit, USA Purpose: Asenapine is an atypical antipsychotic indicated in the United States for the acute treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In this study, we report on the short-term tolerability, safety, and pharmacokinetic profile of asenapine in elderly patients with psychosis. Methods: This 6-week randomized, parallel-group, multidose, multicenter trial enrolled patients aged 65 years with psychotic symptoms that were not related to dementia. At screening, patients were required to have a Positive and Negative Syndrome Scale (PANSS) score 4 on 1 of 5 predefined items (delusions, hallucinatory behavior, excitement, hostility, poor impulse control), a PANSS total score >50, and a Clinical Global Impression-Severity of Illness score 3. After a washout period of 3 days, patients were randomized to 1 of 2 treatment groups. Patients in the first treatment group received sublingual asenapine 2 mg twice daily (BID) on days 1 and 2, asenapine 5 mg BID on days 3 and 4, and asenapine 10 mg BID thereafter. Patients in the second treatment group received asenapine 5 mg BID on days 1−4 and asenapine 10 mg BID thereafter. Drug treatment was conducted under double-blind conditions during the initial 6 days and was open-label for the remainder of the trial. Blood samples were collected on treatment days 3, 4, 7, 8, 21, and 42 (before the morning dose) and 0.5−12 hours after the morning dose on days 4 and 8. Pharmacokinetic parameters for asenapine were calculated based on plasma concentrations observed on days 4 and 8. Results: A total of 122 patients (n = 61 in each treatment group) were randomized and 76 (62.3%) completed the trial. In the overall population, the mean±SD age was 71.2±5.2 years, with most patients (77.9%) in the age range of 65−75 years. Baseline demographics and clinical characteristics were comparable between groups. Tolerability was comparable across treatment schedules. Adverse events reported by 5% of patients included hypertension (8.2%), headache (6.6%), and somnolence (6.6%). The incidence of extrapyramidal symptoms reported as adverse events was 5.7%. Mean weight change at endpoint was 0.4 kg; clinically significant weight gain was reported in 2 patients (1.7%). Median times to maximum asenapine concentration at 5 and 10 mg BID were 1.00 and 1.06 hours, respectively. Maximum asenapine concentrations
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P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical)
(Cmax ) at 5 and 10 mg BID, as measured by the geometric mean, were 4.73 and 7.93 ng/mL. Areas under the curve from 0−12 hours at 5 and 10 mg BID were 32.1 and 56.3 ng·h/mL. Conclusions: Compared with previous findings in patients aged <65 years (asenapine Cmax: 4.23 ng/mL at 5 mg BID, 6.56 ng/mL at 10 mg BID), exposure was 12−30% higher in elderly patients, indicating lower drug clearance in this population. Despite the increased exposure, short-term asenapine treatment was generally well tolerated in elderly patients with psychosis during rapid dosage escalation. Disclosure statement: Research support from Pfizer, Otsuka, Sumitomo Pharma, Biogen, and Tower Foundation. P.3.c.056 Prolactin elevation induced by antipsychotics in first episode psychotic patients R. Perez-Iglesias1 ° , I. Mata1 , M.T. Garcia-Unzueta2 , J.A. Amado3 , O. Martinez-Garcia1 , J.L. Vazquez-Barquero1 , 1 Hospital Universitario Marques de B. Crespo-Facorro1 . Valdecilla, Psiquiatria, Santander, Spain; 2 Hospital Universitario Marques de Valdecilla, Analisis clinicos, Santander, Spain; 3 Hospital Universitario Marques de Valdecilla, Endocrinolog´ıa, Santander, Spain Purpose: The prevalence rate of hyperprolactinemia in patients taking antipsychotic is considerably higher than the prevalence rate of general population. Although prolactin levels are not routinely obtained, this association may have long-term consequences in terms of menstrual disturbances, sexual dysfunction and lower bone mineral density. There are few data comparing the effect of low doses of antipsychotics on prolactin levels in first episode psychotic patients. The main objective of this study was to compare the effect of typical (haloperidol) an atypical (olanzapine and risperidone) antipsychotics on serum prolactin levels during the first 3 months of treatment. Method: A randomized, open-label, prospective clinical trial was conducted. Participants were 145 consecutive first episode psychotic patients included in a first episode program of Cantabria (Spain) from February 2002 to February 2005. Patients have not been previously exposed to antipsychotic medication. The rate of participation was 98.6% and the number of patients who remained adherent with the protocol after 12 weeks was 88.3%. Prolactin levels were measured by chemiluminiscent automathed assay in a Advia Centaur Chemistry System from Bayer Diagnostics (Bayer Corporation, Tarrytown, NY, USA), using the reagents supplied by Boehringer-Mannheim (Mannheim, Germany). Normal values were <12.5 ng/ml for men and <18.5 ng/ml for women. Results: Mean dose of antipsychotics at 3 months were: 4.2 mg/d haloperidol, 12.7 mg/d of olanzapine and 3.6 mg/d of risperidone. The mean prolactin levels at baseline were: 34.1 ng/ml for haloperidol group, 26.0 ng/ml for olanzapine and 35.7 ng/ml for risperidone. At 3 months the prolactin levels were: 22.8 ng/ml for haloperidol group, 23.1 ng/ml for olanzapine and 72.5 ng/ml for risperidone. Patients treated with risperidone experienced a significantly increase in prolactin levels compared with both olanzapine and haloperidol treatments (F = 39.1, df = 2, p < 0.001). The increment from baseline levels in risperidone group was 97% (65.4% in men and 133.9% in women) resulting in abnormal plasma prolactin levels at 3 months in 92.3% of men and 100% of women. It is noteworthy that although risperidone is the only treatment that produces increase in prolactin levels in our study, the three groups of treatment showed high levels of prolactin
at baseline and at 3 months. One possible explanation for the high prolactin levels, even at baseline, is that some patients had received their first dose of treatment the night before the blood test was performed. Another factor that could have influenced the prolactin levels is the stress experienced at the moment of admission. Despite the elevated percentage of patients with abnormal prolactin levels, few patients reported prolactin-related side effects: only 2 patients reported galacthorrea, both treated with risperidone, 4 patients reported amenorrhea (2 treated with haloperidol y 2 treated with risperidone) and 15 patients reported sexual side effects (6 treated with haloperidol, 3 treated with olanzapine and 6 treated with risperidone). Only 1 patient in risperidone treatment group needed change to a different treatment because the severity of sexual side effects. Conclusions: Serum prolactin levels should be monitored during risperidone treatment and sexual side effects should be inquired. References [1] Haddad, PM, Wieck, A (2004) Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs, 64(20): 2291–2314. [2] Melkersson, K (2005) Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry, 66(6): 761–767. [3] Volavka, J, Czobor, P, Cooper, TB, Sheitman, B, Lindenmayer, JP, Citrome, L, McEvoy, JP, Lieberman, JA (2004) Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry, 65(1): 57−61.
P.3.c.057 Which patients switch antipsychotic medication? Data from the international Antipsychotic Drug Substitution Registry P. Paterakis1 ° , B. Galinska-Skok2 , L. Pani3 , M. Bubrovszky4 , 1 “Dromokaitio” Psychiatric G. Perdriset5 , P. Thomas4 . General Hospital of Athens, Department of psychiatry, Athens, Greece; 2 Medical University of Bialystok, Department of psychiatry, Choroszcz, Poland; 3 Institute Biomedical Technologies PharmaNess Scarl, Neuropharmacology Section, Cagliari, Italy; 4 Hˆ opital Fontan − CHRU de Lille, Department of psychiatry, Lille, France; 5 sanofi-aventis, Medical Affairs Department, Paris, France Purpose of the study: Around one-third of patients treated with antipsychotic drugs change their medication every year. The frequency of switch varies among countries depending on the local medical practice and is likely to vary between different antipsychotic drug classes. A naturalistic, multinational observational survey (SWITCH) has been implemented to evaluate the dynamics of treatment discontinuation and substitution in the management of schizophrenia in everyday clinical practice. The primary objective of this study was to identify the frequency of switching antipsychotic treatments in patients with schizophrenia. A secondary objective was to identify reasons for switch to other antipsychotic. Methods used: This was a cross-sectional, observational study performed in eleven countries (Algeria, Greece, India, Jordan, Lithuania, Mexico, Philippines, Poland, Slovakia, Ukraine and Vietnam). All adult patients with schizophrenia consulting consecutively within one month (up to fifty per site) were included in the study. These patients constituted the Screening population. Data was collected on socio-demographics, psychiatric diagnosis