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THE BENEFITS IN ASSOCIATING THE MOOD STABILIZING THERAPY WITH ATYPICAL ANTIPSYCHOTIC THERAPY IN SCHIZOPHRENIA
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Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
controlled study. Aripiprazole was dosed at 15mg/day for the first 4 weeks then 30mg for thenext 4 weeks. The haloperidol dose remained fixed throughout the study. Serum haloperidol and aripiprazole levels were measured by LC-MS/MS and CYP2D6 genotyping was determined by allele specific PCR and restriction fragment length polymorphism. All statistical tests were two-tailed and significance was defined as an alpha < 0.05. Results: In the frequency of CYP2D6 genotype, *1/*10B type was a most frequent (37.7%) and *1/*1(30.2%), *10B/*10B (17.0%) types were followed. The mean dose of haloperidol was not significantly different between aripiprazole and placebo groups. In a repeated measures ANOVA design, plasma level of haloperidol and its metabolites did not demonstrate significant time effects and time-group interactions after adjunctive treatment of aripiprazole. Plasma levels of aripiprazole at week 8 were significantly higher than that at week 4 (102.0±60.8 nM/mg at week 4 and 183.2±79.2 nM/mg at week 8 (p=0. 0006). The concentration of haloperidol and aripiprazole were not significantly different among genotypes of CYP2D6. Cumulative side effects in the study for patients randomized to aripiprazole were as follows: insomnia, dry mouth, headache (23%). No significant correlation were found between adverse events and CYP2D6 genotypes. Conclusions: Genotypes of CYP2Dd did not affect drug interactions between both haloperidol and aripiprazole. Acknowledgement: This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health &Welfare, Republic of Korea (A040155) and no authors received any financial support from the pharmaceutical industry for this study. Joo-Cheol Shim, MD, PhD, Do-Un Jung, MD, Tae-Min Ha, MD. References [1] Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebocontrolled trial. Am J Psychiatry 2007;164(9):1404-1410. [2] Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequencebased CYP2D6 genotyping in the Korean population. Ther Drug Monit. 2006 Jun;28(3):382-7. 17. [3] de Leon J, Diaz FJ, Wedlund P, Josiassen RC, Cooper TB, Simpson GM. Haloperidol half-life after chronic dosing. J Clin Psychopharmacol 2004;24(6):656-660. [4] Molden E, Lunde H, Lunder N, Refsum H. Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients. Ther Drug Monit 2006; 28(6):744-749.
650 – THE BENEFITS IN ASSOCIATING THE MOOD STABILIZING THERAPY WITH ATYPICAL ANTIPSYCHOTIC THERAPY IN SCHIZOPHRENIA Alexandru Tiugan, Claudia Radut Military Emergency Clinical Hospital “Dr. Stefan Odobleja”, Dolj, Romania [email protected] Introduction: Negative symptoms in schizophrenia could be correlated with a diminished dopaminergic activity in the prefrontal cortex, associated with the dysfunction of NMDA glutamatergic receptors. Mood stabilizers act on the NMDA-glutamate receptors through competitively antagonizing the A1 adenosine receptors and mitigating the catecolaminic transmission at the level of the central nervous system, and it regulates the GABA neurotransmission in the glutamate-GABA balance. Methods: 126 patients fulfilling the DSM–IV-R criteria for schizophrenia were treated in the period 2002-2007. Out of these, 55 received treatment with atypical antipsychotic substances (SAA), in therapeutic doses, while the rest of 71 patients were treated with atypical antipsychotic substances and mood stabilizers Results: After the first 15 days of treatment with SAA and mood stabilizers, the patients’ aggressiveness was significantly reduced, and the psychomotor agitation lowered. In this lot of patients the rate
of relapses was much lower than for the others, and the positive symptomatology was quickly reduced, allowing for decreasing the SAA doses earlier. The efficiency parameters evaluated with PANSS total score and CGI highlighted lower values for the negative symptomatology for the patients also treated with mood stabilizers. Conclusions: The mood stabilizing substances represent a therapeutic possibility in association with SAA both in the acute schizophrenic episode, as well as in the maintenance phase, especially when the clinical board is dominated by aggressiveness and psychomotor agitation. In this therapeutic association, negative symptomatology and cognitive deterioration is emphasized more rarely and much later through the neuroprotective effect of associated substances.
651 – EFFICACY AND SAFETY WITH LONG-ACTING INJECTABLE RISPERIDONE IN SCHIZOPHRENIA: TWO YEARS FOLLOW UP STUDY Miguel Vega 1 , A. Chinchilla 1 , D. Crespo 1 , R. Yánez 2 , F. Pando 1 , E. Benítez 1 1 Psychiatry Service, Hospital Ramón y Cajal, Madrid, Spain; 2 University of Alcalá de Henares, Madrid, Spain [email protected] Introduction: We present the results of a two years follow up with 107 patients with schizophrenia (DSM-IV Diagnostic Criteria), treated with long-acting injectable risperidone, the efficacy and safety of this risperidone formulation was the focus of our study. Methods: All patients were previously treated with oral antipsychotics between three and six months and moved to long acting risperidone at a regimen dose of 50-100mg every two weeks. Evaluations at day 0 and at 6, 12, 24 months were performed. We used as parameters of efficacy: the PANSS, and the CGI, and secondary effects, relapses and hospitalizations were registered during follow up. Results: 10 patients (9.3%) were lost in the first year follow up, and 5 more (4.8%) during the second year, 14% of the whole sample. At the end of the study 66.3% received a 50mg IM dose and 3.2% of those, needed a supplementary oral dose between 3-6mg of risperidone. 9,7% were receiving 75mg IM at the end of the study, and 20.6% were in the higher dose range of 100mg IM, every two weeks. Total mean PANSS score decreased from 64 (mean basal score), to 30 in the group of 50mg to 36 in the 75mg dose group and to 36 in the 100mg dose group, at 24 months evaluation. The mean CGI basal score decreased from 2.8, to 1.4 (risperidone 50mg IM); to 1.6 (risperidone 75 mg IM), and to 1.6 (risperidone 100 mg IM.) at the end of follow up. 15% of the patients relapsed during these 24 months, and 14 (13%) were hospitalized. Compliance was 90% during the first year, and 85% at the end of the study. Secondary effects were rated as weak, and tolerable, and were not cause for abandoning the study. Conclusions: We conclude that long-acting injectable risperidone, is an iousefficacy and well tolerated treatment option, for schizophrenia patients, in acute and maintenance phases of the illness, in a range dose of 50-100mg every two weeks, that facilitates adherence and efficacy. References [1] Kane, J.M. et al.: Long acting injectable risperidone: efficacy and safety of the first long acting atypical antipsichotic. Am. J. Psychiatry, 2003, 160, 6, 1125-1132. [2] Kissling, W. et al.: Direct transition to long-acting risperidoneanalysis of long-term efficacy. J.Psychopharm, 19, 5, supp 1 (2005), 15-21.
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
controlled study. Aripiprazole was dosed at 15mg/day for the first 4 weeks then 30mg for thenext 4 weeks. The haloperidol dose remained fixed throughout the study. Serum haloperidol and aripiprazole levels were measured by LC-MS/MS and CYP2D6 genotyping was determined by allele specific PCR and restriction fragment length polymorphism. All statistical tests were two-tailed and significance was defined as an alpha < 0.05. Results: In the frequency of CYP2D6 genotype, *1/*10B type was a most frequent (37.7%) and *1/*1(30.2%), *10B/*10B (17.0%) types were followed. The mean dose of haloperidol was not significantly different between aripiprazole and placebo groups. In a repeated measures ANOVA design, plasma level of haloperidol and its metabolites did not demonstrate significant time effects and time-group interactions after adjunctive treatment of aripiprazole. Plasma levels of aripiprazole at week 8 were significantly higher than that at week 4 (102.0±60.8 nM/mg at week 4 and 183.2±79.2 nM/mg at week 8 (p=0. 0006). The concentration of haloperidol and aripiprazole were not significantly different among genotypes of CYP2D6. Cumulative side effects in the study for patients randomized to aripiprazole were as follows: insomnia, dry mouth, headache (23%). No significant correlation were found between adverse events and CYP2D6 genotypes. Conclusions: Genotypes of CYP2Dd did not affect drug interactions between both haloperidol and aripiprazole. Acknowledgement: This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health &Welfare, Republic of Korea (A040155) and no authors received any financial support from the pharmaceutical industry for this study. Joo-Cheol Shim, MD, PhD, Do-Un Jung, MD, Tae-Min Ha, MD. References [1] Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebocontrolled trial. Am J Psychiatry 2007;164(9):1404-1410. [2] Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequencebased CYP2D6 genotyping in the Korean population. Ther Drug Monit. 2006 Jun;28(3):382-7. 17. [3] de Leon J, Diaz FJ, Wedlund P, Josiassen RC, Cooper TB, Simpson GM. Haloperidol half-life after chronic dosing. J Clin Psychopharmacol 2004;24(6):656-660. [4] Molden E, Lunde H, Lunder N, Refsum H. Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients. Ther Drug Monit 2006; 28(6):744-749.
650 – THE BENEFITS IN ASSOCIATING THE MOOD STABILIZING THERAPY WITH ATYPICAL ANTIPSYCHOTIC THERAPY IN SCHIZOPHRENIA Alexandru Tiugan, Claudia Radut Military Emergency Clinical Hospital “Dr. Stefan Odobleja”, Dolj, Romania [email protected] Introduction: Negative symptoms in schizophrenia could be correlated with a diminished dopaminergic activity in the prefrontal cortex, associated with the dysfunction of NMDA glutamatergic receptors. Mood stabilizers act on the NMDA-glutamate receptors through competitively antagonizing the A1 adenosine receptors and mitigating the catecolaminic transmission at the level of the central nervous system, and it regulates the GABA neurotransmission in the glutamate-GABA balance. Methods: 126 patients fulfilling the DSM–IV-R criteria for schizophrenia were treated in the period 2002-2007. Out of these, 55 received treatment with atypical antipsychotic substances (SAA), in therapeutic doses, while the rest of 71 patients were treated with atypical antipsychotic substances and mood stabilizers Results: After the first 15 days of treatment with SAA and mood stabilizers, the patients’ aggressiveness was significantly reduced, and the psychomotor agitation lowered. In this lot of patients the rate
of relapses was much lower than for the others, and the positive symptomatology was quickly reduced, allowing for decreasing the SAA doses earlier. The efficiency parameters evaluated with PANSS total score and CGI highlighted lower values for the negative symptomatology for the patients also treated with mood stabilizers. Conclusions: The mood stabilizing substances represent a therapeutic possibility in association with SAA both in the acute schizophrenic episode, as well as in the maintenance phase, especially when the clinical board is dominated by aggressiveness and psychomotor agitation. In this therapeutic association, negative symptomatology and cognitive deterioration is emphasized more rarely and much later through the neuroprotective effect of associated substances.
651 – EFFICACY AND SAFETY WITH LONG-ACTING INJECTABLE RISPERIDONE IN SCHIZOPHRENIA: TWO YEARS FOLLOW UP STUDY Miguel Vega 1 , A. Chinchilla 1 , D. Crespo 1 , R. Yánez 2 , F. Pando 1 , E. Benítez 1 1 Psychiatry Service, Hospital Ramón y Cajal, Madrid, Spain; 2 University of Alcalá de Henares, Madrid, Spain [email protected] Introduction: We present the results of a two years follow up with 107 patients with schizophrenia (DSM-IV Diagnostic Criteria), treated with long-acting injectable risperidone, the efficacy and safety of this risperidone formulation was the focus of our study. Methods: All patients were previously treated with oral antipsychotics between three and six months and moved to long acting risperidone at a regimen dose of 50-100mg every two weeks. Evaluations at day 0 and at 6, 12, 24 months were performed. We used as parameters of efficacy: the PANSS, and the CGI, and secondary effects, relapses and hospitalizations were registered during follow up. Results: 10 patients (9.3%) were lost in the first year follow up, and 5 more (4.8%) during the second year, 14% of the whole sample. At the end of the study 66.3% received a 50mg IM dose and 3.2% of those, needed a supplementary oral dose between 3-6mg of risperidone. 9,7% were receiving 75mg IM at the end of the study, and 20.6% were in the higher dose range of 100mg IM, every two weeks. Total mean PANSS score decreased from 64 (mean basal score), to 30 in the group of 50mg to 36 in the 75mg dose group and to 36 in the 100mg dose group, at 24 months evaluation. The mean CGI basal score decreased from 2.8, to 1.4 (risperidone 50mg IM); to 1.6 (risperidone 75 mg IM), and to 1.6 (risperidone 100 mg IM.) at the end of follow up. 15% of the patients relapsed during these 24 months, and 14 (13%) were hospitalized. Compliance was 90% during the first year, and 85% at the end of the study. Secondary effects were rated as weak, and tolerable, and were not cause for abandoning the study. Conclusions: We conclude that long-acting injectable risperidone, is an iousefficacy and well tolerated treatment option, for schizophrenia patients, in acute and maintenance phases of the illness, in a range dose of 50-100mg every two weeks, that facilitates adherence and efficacy. References [1] Kane, J.M. et al.: Long acting injectable risperidone: efficacy and safety of the first long acting atypical antipsichotic. Am. J. Psychiatry, 2003, 160, 6, 1125-1132. [2] Kissling, W. et al.: Direct transition to long-acting risperidoneanalysis of long-term efficacy. J.Psychopharm, 19, 5, supp 1 (2005), 15-21.