- Email: [email protected]
P.3.c.010 Asenapine safety and tolerability in acute schizophrenia: a placebo-and risperidone-controlled trial
P.3.c Psychotic disorders and antipsychotics – Antipsychotics (clinical) of our patients, suggesting that this intervention is worth trying. Further research in this area is needed to confirm these findings.
N appetite decrease 3 month vs baseline weight change (kg) std dev 95% CI t P 6 month vs baseline weight change (kg) std dev 95% CI t P 6 month vs 3 month t P
ALL
weight loss
weight gain
23 30.4%
17 35.3%
6 16.7%
−2.35 3.67 1.59 3.07 0.006
−3.60 3.14 1.61 4.74 0.0002
1.21 2.67 2.80 −1.11 0.318
−2.47 4.29 1.86 2.75 0.012
−4.38 2.86 1.47 6.32 0.00001
2.95 2.72 2.85 −2.66 0.045
0.14 0.886
0.77 0.4529
−1.64 0.163
S401
Results: All patients had a diagnosis of schizophrenia or schizoaffective disorder and were prescribed valproate for psychiatric purposes. The average dose of valproate was 1700 mg per day (range 100–5400 mg/d). All of the patients reviewed were taking one or more psychotropic medications in conjunction with valproate. 49% were taking three or more psychotropic drugs with valproate. Antipsychotics were the most frequently co-prescribed drug (in 96.5% of patients), followed by antidepressants (45.6%), benzodiazepines (19.3%), other psychotropics (15.8%) and mood stabilizers (12.3%). The average number of psychotropic drugs coprescribed with valproate was 2.5 (range 1−5). 54.4% of patients were taking at least one psychotropic drug which is known to share a common metabolic pathway with valproate and were therefore at risk of adverse effects due to potential drug interactions. Conclusions: These results are in concordance with previous studies, which have shown psychotropic polypharmacy to be a common phenomenon in the inpatient mental health setting. This is in part due to the frequency of psychiatric co-morbidity such as affective disorder and psychosis or dementia and delirium. The potential for psychotropic drug interactions in this context is high. Further investigation of the metabolic and clinical impact of these potential interactions is warranted, in light of the increasingly frequent practice of psychotropic co-prescribing. References
References [1] de Haan L., van Amelsvoort T., Rosien K., Linszen D., 2004, Weight loss after switching from conventional Olanzapine tablets to orally disintgrating Olanzapine tablets, Psychopharmacology, 175, 389–390.
P.3.c.009 Valproate and psychotropic drug interactions J. Glen1 ° , J. Fleming2 , M. Herman3 , M. Chetty2 . 1 Macquarie Hospital, Pharmacy Department, Sydney, Australia; 2 Sydney University, Faculty of Pharmacy, Sydney, Australia; 3 Macquarie Hospital, Psychology Department, Sydney, Australia Introduction: Valproate is a well-established anti-convulsant drug that is being used increasingly for the management of a range of psychiatric disorders, particularly mood disorder, and often in combination with other psychotropic drugs This practice is potentially problematic because valproate has a narrow therapeutic range and drug-drug interactions with valproate may render the relationship between dosage and serum level unpredictable, leading to an increased incidence of adverse effects and cases of potential toxicity or under-treatment. The aim of this study was to examine psychotropic co-prescription patterns with valproate in chronic schizophrenic patients and its association with potential psychotropic drug interactions. Methods: This was a retrospective analysis of medication charts from 57 chronic psychiatric in-patients of Macquarie Hospital, North Ryde. Psychotropic prescription use patterns with valproate in general, as well as of individual classes, specifically antidepressants, antipsychotics, benzodiazepines and mood stabilizers were examined. Assessment of potential drug interactions was conducted by a review of the common metabolic pathways shared by valproate and concomitantly administered drugs. These pathways include cytochrome P450 enzymes CYP2C9 and CYP2C19 as well as uridine diphosphoglucuronyltransferase (UDPGT). Statistical analysis was carried out using SPSS 11.5. The potential for psychotropic drug interactions with valproate, based on common enzyme pathways, was evaluated.
[1] [2] [3] [4]
Karow K, et al., 2003, Current Opinion in Psychiatry, 16(6),713−18. Ketter TA, et al., 1995, J Clin Psychopharmacology, 15(6), 387−98. Liston HL, et al., 2001, J Clin Psychopharmacology, 21(5), 500−15. Tanaka E., 1999, J Clin Pharmacy and Therapeutics, 24(2), 87−92.
P.3.c.010 Asenapine safety and tolerability in acute schizophrenia: a placebo- and risperidone-controlled trial S.G. Potkin1 ° , M. Cohen2 , J. Panagides3 , A. Jina4 . 1 University of California, Irvine, Psychiatry, Orange, USA; 2 Organon Pharmaceuticals USA Inc., Neuroscience, Roseland, USA; 3 Organon International Inc, Neuroscience, Roseland, USA; 4 Pfizer Inc, Psychiatry, New York, USA Purpose: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. In a double-blind trial, we evaluated the safety and tolerability of asenapine versus placebo and risperidone in patients with an acute exacerbation of schizophrenia. Methods: Patients were eligible for the study if they had a Positive and Negative Syndrome Scale (PANSS) score of at least 60 at screening and baseline, a score of 4 or higher on 2 or more of the 5 items of the PANSS positive subscale at screening and baseline, and a Clinical Global Impression score of 4 or higher (moderately ill) at baseline. Patients meeting the inclusion criteria were randomly assigned to treatment with sublingual asenapine 5 mg twice daily with oral placebo, oral risperidone 3 mg twice daily with sublingual placebo, or double placebo for 6 weeks. Adverse events and extrapyramidal symptoms were assessed weekly and 30 days after study exit. Results: Of the 180 patients who received study medication (asenapine, n = 59; risperidone, n = 59; placebo, n = 62), 151 patients (84%) had 1 or more adverse events. The most frequently reported events were headache and agitation (placebo and risperidone), followed by transient sleep disturbances (active medications). Although there were no significant between-group differences on formal ratings of extrapyramidal symptoms, hypertonia
S402
P.3.c Psychotic disorders and antipsychotics – Antipsychotics (clinical)
and hyperkinesia were more frequent with risperidone (12% and 7%, respectively) than with placebo (3%, 0%) or asenapine (0%, 0%), and concomitant use of antiparkinsonian drugs was more frequent with risperidone (31%) than with asenapine (17%). Clinically significant weight gain (7% increase in body weight) occurred more often with risperidone (17%) than with asenapine or placebo (4% and 2%; both P < 0.05 vs risperidone). Mean weight gain was similar in all 3 treatment groups among normal-weight patients but greater with risperidone among overweight patients. The incidence of hyperprolactinemia was higher with risperidone (79%) than with asenapine or placebo (9% and 2%). Mean total cholesterol levels decreased from baseline to endpoint 0.4 mmol/L for asenapine and 1.7 mmol/L for placebo but increased from baseline to endpoint 2.3 mmol/L for risperidone. Mean fasting glucose increased from baseline to endpoint 0.2 mmol/L for asenapine, 0.09 mmol/L for placebo, and 0.4 mmol/L for risperidone. Changes in blood pressure and heart rate were comparably small in all 3 treatment groups, and there were no cases of QTc prolongation >500 milliseconds in any group. Completion rates were higher in the asenapine and risperidone groups (46% and 42%, respectively) than in the placebo group (34%). Withdrawal rates because of lack of efficacy and adverse events were, respectively, 15% and 10% with asenapine, 29% and 11% with placebo, and 27% and 7% with risperidone. Conclusions: Asenapine appears to be well tolerated by patients with acute schizophrenia, with little effect on total cholesterol or fasting glucose, and a low incidence of extrapyramidal symptoms, hyperprolactinemia, and clinically significant weight gain.
Rates of specific adverse effects were low but this may reflect the fact that data were derived from documentation of adverse effects in the clinical notes. Mirror image analysis was restricted to patients in whom readmission rates could be analysed i.e. patients who commenced RLAI in the community or who were discharged on RLAI after starting treatment in hospital. There were 74 such patients. Within this group RLAI was associated with a reduction in the number of admissions (63 v 33 p < 0.005) and in total inpatient days (4550 v 2188 days, p < 0.005). The mean reduction in in-patient care per patient per year of treatment with RLAI was 29 days which represents a net financial saving over the acquisition and administration costs of RLAI of £1528. The assumptions used in this cost-effectiveness analysis were designed to provide a conservative estimate of any financial savings that could be attributed to RLAI. Benefits were greater for patients who were not treatment resistant. Conclusions: RLAI was cost-effective and associated with reduced in-patient care. As such RLAI can offer considerable benefits to some patients. These results require replication in other services. The main weakness of the data is that it derives from a mirror-image design and not a randomised controlled trial (RCT). However this has to be balanced against the fact that RCTs are unlikely to recruit patients who are representative of those who benefit most from a long acting injection i.e. those who comply poorly with treatment. For this reason mirror image studies remain an important part of the evidence base for long acting injections.
P.3.c.012 Discontinuation rate of antipsychotic drugs in the treatment of first treated schizophrenia P.3.c.011 Three years of experience of risperidone long acting injection in a UK psychiatric service including a mirror-image analysis of in-patient care O.S. Niaz1 , P.M. Haddad2 ° . 1 Sheffield Care Trust, Department of Psychiatry, Sheffield, UK; 2 University of Manchester, Neuroscience and Psychiatry Unit, Manchester, UK Purpose of the study: To assess the use of risperidone long acting injection (RLAI) in a UK psychiatry service. The specific aims were to describe (i) the characteristics of patients prescribed RLAI, (ii) the reasons for initiation of treatment, (iii) the reasons for discontinuation of treatment and (iv) to assess the effectiveness of RLAI using mirror image analysis of admission rates and the total number of in-patient days. Methods used: Retrospective case note audit of all patients prescribed RLAI over nearly three years in a general psychiatric service. Mirror image analysis compared treatment on RLAI with an equal period prior to initiation for each patient. Summary of results: During the audit period (December 2002 to September 2005) 92 patients were prescribed RLAI. The notes of 90 of these patients were available for review. Nearly all suffered from schizophrenia or schizoaffective disorder. The average duration of illness prior to starting RLAI was 11.7 years. Baseline rates of drug and alcohol misuse, unemployment and forensic markers were all significantly higher than in a control group of patients prescribed oral antipsychotics. The most common reason for starting RLAI was non-concordance with oral antipsychotic treatment. The median duration of treatment with RLAI was 9.5 months with 51% continuing treatment at the audit point. Among those who stopped treatment inefficacy accounted for approximately twice as many discontinuations as intolerability.
J.C. Shim1 ° , B.M. Choe2 , Y.M. Jae3 , J.G. Kim4 , H.C. Kim5 , S.G. Kim6 . 1 Inje University, Busan Paik Hospital, Psychiatry, Busan, Republic of Korea; 2 Dong-A University Hospital, Psychiatry, Busan, Republic of Korea; 3 Bongseng Hospital, Psychiatry, Busan, Republic of Korea; 4 Maryknoll Hospital, Psychiatry, Busan, Republic of Korea; 5 Kosin University Hospital, Psychiatry, Busan, Republic of Korea; 6 Busan National University University Hospital, Psychiatry, Busan, Republic of Korea Purpose: Time to discontinuation of antipsychotic drug may reflect the effectiveness of drugs. We investigated the discontinuation rate of antipsychotic drugs in treatment of first treated schizophrenia. Methods: This study was done by retrospective chart review in six sites, 3 university and 3 private clinics, located in Busan, Korea. First, 3600 patients who were treated as a schizophrenia and schizoaffective disorder between January 1, 2002 and June 30, 2004 were screened by using data base system at each site. Among them, 550 patients who satisfied inclusion criteria were enrolled into this study finally. Inclusion criteria included patients with schizophrenia and schizoaffective disorder fulfilled by DSM-IV criteria for schizophrenia and schizoaffective disorder, with no, or less than 1 month, antipsychotic drug treatment in the past. Chart review was done by two experienced psychiatry independently. Data was evaluated at every 3 month interval from date of starting antipsychotic drug. Primary objective was to evaluate whether chosen medication was continued or not at each point. With regarding to discontinuation, the reason was classified into 4 categories: lack of efficacy, adverse event, patient’s demand and unknown. All cases that could not define cause of discontinuation definitely were classified into unknown. CGI was rated by two
N appetite decrease 3 month vs baseline weight change (kg) std dev 95% CI t P 6 month vs baseline weight change (kg) std dev 95% CI t P 6 month vs 3 month t P
ALL
weight loss
weight gain
23 30.4%
17 35.3%
6 16.7%
−2.35 3.67 1.59 3.07 0.006
−3.60 3.14 1.61 4.74 0.0002
1.21 2.67 2.80 −1.11 0.318
−2.47 4.29 1.86 2.75 0.012
−4.38 2.86 1.47 6.32 0.00001
2.95 2.72 2.85 −2.66 0.045
0.14 0.886
0.77 0.4529
−1.64 0.163
S401
Results: All patients had a diagnosis of schizophrenia or schizoaffective disorder and were prescribed valproate for psychiatric purposes. The average dose of valproate was 1700 mg per day (range 100–5400 mg/d). All of the patients reviewed were taking one or more psychotropic medications in conjunction with valproate. 49% were taking three or more psychotropic drugs with valproate. Antipsychotics were the most frequently co-prescribed drug (in 96.5% of patients), followed by antidepressants (45.6%), benzodiazepines (19.3%), other psychotropics (15.8%) and mood stabilizers (12.3%). The average number of psychotropic drugs coprescribed with valproate was 2.5 (range 1−5). 54.4% of patients were taking at least one psychotropic drug which is known to share a common metabolic pathway with valproate and were therefore at risk of adverse effects due to potential drug interactions. Conclusions: These results are in concordance with previous studies, which have shown psychotropic polypharmacy to be a common phenomenon in the inpatient mental health setting. This is in part due to the frequency of psychiatric co-morbidity such as affective disorder and psychosis or dementia and delirium. The potential for psychotropic drug interactions in this context is high. Further investigation of the metabolic and clinical impact of these potential interactions is warranted, in light of the increasingly frequent practice of psychotropic co-prescribing. References
References [1] de Haan L., van Amelsvoort T., Rosien K., Linszen D., 2004, Weight loss after switching from conventional Olanzapine tablets to orally disintgrating Olanzapine tablets, Psychopharmacology, 175, 389–390.
P.3.c.009 Valproate and psychotropic drug interactions J. Glen1 ° , J. Fleming2 , M. Herman3 , M. Chetty2 . 1 Macquarie Hospital, Pharmacy Department, Sydney, Australia; 2 Sydney University, Faculty of Pharmacy, Sydney, Australia; 3 Macquarie Hospital, Psychology Department, Sydney, Australia Introduction: Valproate is a well-established anti-convulsant drug that is being used increasingly for the management of a range of psychiatric disorders, particularly mood disorder, and often in combination with other psychotropic drugs This practice is potentially problematic because valproate has a narrow therapeutic range and drug-drug interactions with valproate may render the relationship between dosage and serum level unpredictable, leading to an increased incidence of adverse effects and cases of potential toxicity or under-treatment. The aim of this study was to examine psychotropic co-prescription patterns with valproate in chronic schizophrenic patients and its association with potential psychotropic drug interactions. Methods: This was a retrospective analysis of medication charts from 57 chronic psychiatric in-patients of Macquarie Hospital, North Ryde. Psychotropic prescription use patterns with valproate in general, as well as of individual classes, specifically antidepressants, antipsychotics, benzodiazepines and mood stabilizers were examined. Assessment of potential drug interactions was conducted by a review of the common metabolic pathways shared by valproate and concomitantly administered drugs. These pathways include cytochrome P450 enzymes CYP2C9 and CYP2C19 as well as uridine diphosphoglucuronyltransferase (UDPGT). Statistical analysis was carried out using SPSS 11.5. The potential for psychotropic drug interactions with valproate, based on common enzyme pathways, was evaluated.
[1] [2] [3] [4]
Karow K, et al., 2003, Current Opinion in Psychiatry, 16(6),713−18. Ketter TA, et al., 1995, J Clin Psychopharmacology, 15(6), 387−98. Liston HL, et al., 2001, J Clin Psychopharmacology, 21(5), 500−15. Tanaka E., 1999, J Clin Pharmacy and Therapeutics, 24(2), 87−92.
P.3.c.010 Asenapine safety and tolerability in acute schizophrenia: a placebo- and risperidone-controlled trial S.G. Potkin1 ° , M. Cohen2 , J. Panagides3 , A. Jina4 . 1 University of California, Irvine, Psychiatry, Orange, USA; 2 Organon Pharmaceuticals USA Inc., Neuroscience, Roseland, USA; 3 Organon International Inc, Neuroscience, Roseland, USA; 4 Pfizer Inc, Psychiatry, New York, USA Purpose: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. In a double-blind trial, we evaluated the safety and tolerability of asenapine versus placebo and risperidone in patients with an acute exacerbation of schizophrenia. Methods: Patients were eligible for the study if they had a Positive and Negative Syndrome Scale (PANSS) score of at least 60 at screening and baseline, a score of 4 or higher on 2 or more of the 5 items of the PANSS positive subscale at screening and baseline, and a Clinical Global Impression score of 4 or higher (moderately ill) at baseline. Patients meeting the inclusion criteria were randomly assigned to treatment with sublingual asenapine 5 mg twice daily with oral placebo, oral risperidone 3 mg twice daily with sublingual placebo, or double placebo for 6 weeks. Adverse events and extrapyramidal symptoms were assessed weekly and 30 days after study exit. Results: Of the 180 patients who received study medication (asenapine, n = 59; risperidone, n = 59; placebo, n = 62), 151 patients (84%) had 1 or more adverse events. The most frequently reported events were headache and agitation (placebo and risperidone), followed by transient sleep disturbances (active medications). Although there were no significant between-group differences on formal ratings of extrapyramidal symptoms, hypertonia
S402
P.3.c Psychotic disorders and antipsychotics – Antipsychotics (clinical)
and hyperkinesia were more frequent with risperidone (12% and 7%, respectively) than with placebo (3%, 0%) or asenapine (0%, 0%), and concomitant use of antiparkinsonian drugs was more frequent with risperidone (31%) than with asenapine (17%). Clinically significant weight gain (7% increase in body weight) occurred more often with risperidone (17%) than with asenapine or placebo (4% and 2%; both P < 0.05 vs risperidone). Mean weight gain was similar in all 3 treatment groups among normal-weight patients but greater with risperidone among overweight patients. The incidence of hyperprolactinemia was higher with risperidone (79%) than with asenapine or placebo (9% and 2%). Mean total cholesterol levels decreased from baseline to endpoint 0.4 mmol/L for asenapine and 1.7 mmol/L for placebo but increased from baseline to endpoint 2.3 mmol/L for risperidone. Mean fasting glucose increased from baseline to endpoint 0.2 mmol/L for asenapine, 0.09 mmol/L for placebo, and 0.4 mmol/L for risperidone. Changes in blood pressure and heart rate were comparably small in all 3 treatment groups, and there were no cases of QTc prolongation >500 milliseconds in any group. Completion rates were higher in the asenapine and risperidone groups (46% and 42%, respectively) than in the placebo group (34%). Withdrawal rates because of lack of efficacy and adverse events were, respectively, 15% and 10% with asenapine, 29% and 11% with placebo, and 27% and 7% with risperidone. Conclusions: Asenapine appears to be well tolerated by patients with acute schizophrenia, with little effect on total cholesterol or fasting glucose, and a low incidence of extrapyramidal symptoms, hyperprolactinemia, and clinically significant weight gain.
Rates of specific adverse effects were low but this may reflect the fact that data were derived from documentation of adverse effects in the clinical notes. Mirror image analysis was restricted to patients in whom readmission rates could be analysed i.e. patients who commenced RLAI in the community or who were discharged on RLAI after starting treatment in hospital. There were 74 such patients. Within this group RLAI was associated with a reduction in the number of admissions (63 v 33 p < 0.005) and in total inpatient days (4550 v 2188 days, p < 0.005). The mean reduction in in-patient care per patient per year of treatment with RLAI was 29 days which represents a net financial saving over the acquisition and administration costs of RLAI of £1528. The assumptions used in this cost-effectiveness analysis were designed to provide a conservative estimate of any financial savings that could be attributed to RLAI. Benefits were greater for patients who were not treatment resistant. Conclusions: RLAI was cost-effective and associated with reduced in-patient care. As such RLAI can offer considerable benefits to some patients. These results require replication in other services. The main weakness of the data is that it derives from a mirror-image design and not a randomised controlled trial (RCT). However this has to be balanced against the fact that RCTs are unlikely to recruit patients who are representative of those who benefit most from a long acting injection i.e. those who comply poorly with treatment. For this reason mirror image studies remain an important part of the evidence base for long acting injections.
P.3.c.012 Discontinuation rate of antipsychotic drugs in the treatment of first treated schizophrenia P.3.c.011 Three years of experience of risperidone long acting injection in a UK psychiatric service including a mirror-image analysis of in-patient care O.S. Niaz1 , P.M. Haddad2 ° . 1 Sheffield Care Trust, Department of Psychiatry, Sheffield, UK; 2 University of Manchester, Neuroscience and Psychiatry Unit, Manchester, UK Purpose of the study: To assess the use of risperidone long acting injection (RLAI) in a UK psychiatry service. The specific aims were to describe (i) the characteristics of patients prescribed RLAI, (ii) the reasons for initiation of treatment, (iii) the reasons for discontinuation of treatment and (iv) to assess the effectiveness of RLAI using mirror image analysis of admission rates and the total number of in-patient days. Methods used: Retrospective case note audit of all patients prescribed RLAI over nearly three years in a general psychiatric service. Mirror image analysis compared treatment on RLAI with an equal period prior to initiation for each patient. Summary of results: During the audit period (December 2002 to September 2005) 92 patients were prescribed RLAI. The notes of 90 of these patients were available for review. Nearly all suffered from schizophrenia or schizoaffective disorder. The average duration of illness prior to starting RLAI was 11.7 years. Baseline rates of drug and alcohol misuse, unemployment and forensic markers were all significantly higher than in a control group of patients prescribed oral antipsychotics. The most common reason for starting RLAI was non-concordance with oral antipsychotic treatment. The median duration of treatment with RLAI was 9.5 months with 51% continuing treatment at the audit point. Among those who stopped treatment inefficacy accounted for approximately twice as many discontinuations as intolerability.
J.C. Shim1 ° , B.M. Choe2 , Y.M. Jae3 , J.G. Kim4 , H.C. Kim5 , S.G. Kim6 . 1 Inje University, Busan Paik Hospital, Psychiatry, Busan, Republic of Korea; 2 Dong-A University Hospital, Psychiatry, Busan, Republic of Korea; 3 Bongseng Hospital, Psychiatry, Busan, Republic of Korea; 4 Maryknoll Hospital, Psychiatry, Busan, Republic of Korea; 5 Kosin University Hospital, Psychiatry, Busan, Republic of Korea; 6 Busan National University University Hospital, Psychiatry, Busan, Republic of Korea Purpose: Time to discontinuation of antipsychotic drug may reflect the effectiveness of drugs. We investigated the discontinuation rate of antipsychotic drugs in treatment of first treated schizophrenia. Methods: This study was done by retrospective chart review in six sites, 3 university and 3 private clinics, located in Busan, Korea. First, 3600 patients who were treated as a schizophrenia and schizoaffective disorder between January 1, 2002 and June 30, 2004 were screened by using data base system at each site. Among them, 550 patients who satisfied inclusion criteria were enrolled into this study finally. Inclusion criteria included patients with schizophrenia and schizoaffective disorder fulfilled by DSM-IV criteria for schizophrenia and schizoaffective disorder, with no, or less than 1 month, antipsychotic drug treatment in the past. Chart review was done by two experienced psychiatry independently. Data was evaluated at every 3 month interval from date of starting antipsychotic drug. Primary objective was to evaluate whether chosen medication was continued or not at each point. With regarding to discontinuation, the reason was classified into 4 categories: lack of efficacy, adverse event, patient’s demand and unknown. All cases that could not define cause of discontinuation definitely were classified into unknown. CGI was rated by two