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P.4.e.008 The factors that influence the therapeutic response to paroxetine in patients with panic disorder: longitudinal study
P.4.e Anxiety disorders and anxiolytics - Other (clinical)
IP.4.e.ooal The
factors that influence the therapeutic response to paroxetine in patients with panic disorder: longitudinal study
M. Veda1 " T. Watanabe 1 , Y. Saeki", A. Saito/, K. Akiyama/, y. Inoue", S. Morita", G. Hirokane", N. Yamada", K. Shimoda1 . 1 Dokkyo Medical University, Department of Psychiatry, Tochigi, Japan; 2 Dokkyo Medical University, Department of Biological Psychiatry and Neuroscience, Tochigi, Japan; 3MP Technopharma, Analytical division, Fukuoka, Japan; 4 Shiga University ofMedical Science, Department of Psychiatry, Shiga, Japan Selective serotonin reuptake inhibitors (SSRIs) are thought to interact with serotonergic system and be effective for treatment of panic disorder (PD). Recent investigations have also been focused on the impact of genetic polymorphism of serotonin transporter (5-HTT) on the clinical effect of SSRIs in PD because 5-HTT is the primary target of action of SSRIs. The 5-HTT gene-linked polymorphic region (5-HTTLPR), located in the promoter region, has been identified as a functional polymorphism. In vitro, the basal activity of the long variant (L) was more than twice that of the short variant (S) in 5-HTT mRNA synthesis and 5-HTT expression. The objective of this study was to evaluate genetic and pharmacokinetic factors for pharmacotherapeutic effect of paroxetine (PAX) in patients with PD. In the present study, we investigated into therapeutic response to PAX in 2 and 4 weeks after the initiation of the treatment. Subjects were 38 Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of PD. Subjects were received lOmg/day of PAX for 4 weeks. Severity of PD was assessed with the Panic and Agoraphobia Scale (PAS). Plasma concentration of PAX was determined by high performance liquid chromatography. 5-HTTLPR gene variants were determined by polymerase chain reaction techniques. Multiple regression analysis was performed in order to analyze the relationship between demographic variables from the subjects and the clinical response to PAX (percentage reduction of PAS score). We used the plasma concentration of PAX, age, gender, body weight, comorbid physical illness, comorbid major depressive disorder, comorbid agoraphobia, smoking status, habitual use of alcohol, PAS score at baseline, frequency of panic attacks per week at baseline, 5-HTTLPR genotype (LIS or SIS), adverse effect of PAX, use of lorazepam and/or brotizolam as independent variables and the clinical response to PAX (percentage reduction of PAS score) as the dependent variable. Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype and comorbid physical illness were significant factors affecting clinical response to PAX (percentage reduction of PAS score), and indicated that these factors accounted for 52.4% (R 2 = 0.524) of the variability of the percentage reduction of PAS score at 2 weeks. The final model was described by the following equation (p=0.001): percentage reduction of PAS score (%) = 68.5 1.2 x (plasma concentration of PAX (ng/ml)) - 33.0x(L/S = 1, S/S=O) - 21.8x(with comorbid physical illness = 1, without comorbid physical illness=O) [1]. However, no significant clinical factor affecting clinical response to PAX was detected at 4 weeks after initiation of pharmacotherapy with PAX. Perna et al [2] investigated the relationship between allelic variation of 5-HTT and the clinical response to PAX in 92 PD patients who completed treatment with variable doses of PAX for 12 weeks. Both LIL genotype and LIS genotype showed a better response to PAX than SIS genotype (p < 0.03). This result was observed in the whole sample, but was related to only female patients (p < 0.02). From
S617
the results of the present study, determination of pharmacokinetic factor (i.e., plasma levels of PAX) and pharmacogenetic factor (i.e., 5-HTTLPR genotype) might be useful only for predicting the clinical response to PAX in patients with panic disorder in the early phase of pharmacotherapy with PAX. References [1] Saeki, Y., Watanabe, T., Veda, M., Saito, A., Akiyama, K., Inoue, Y., Hirokane, G., Morita, S., Yamada, N., & Shimoda, K. (2009). Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder. Eur J Clin Pharmacol.[Epub ahead of print] PMID: 19259652 DOl IO.I007/s0022S-009-0633-S [2] Perna, G., Favaron, E., Di Bella, D., Bussi, R., & Bellodi, L. (2005). Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology 30, 2230-5.
1p.4.e.0091 Efficacy of trazodone in patients diagnosed
with generalised anxiety disorder and benzodiazepine dependence M. Zavoianu1 " A. Luchian1, C. Tudor 1, G. Grigorescu1, D. Vasile 1 . 1 Central Clinic Military Hospital, Psychiatry, Bucharest, Romania Background: Generalized anxiety disorder (GAD) is a common chronic condition characterized by a pattern of frequent, longlasting and difficult to control anxiety that is not focused on anyone object or situation. Neurobiological hypothesis in GAD is an abnormal regulation of serotoninergic system. Trazodone, a serotonine antagonistlreuptake inhibitor, is an effective antidepressant drug with anxiolytic and hypnotic activity. Recent studies indicated that trazodone might due its anxiolytic action to a partial agonist effect at 5HTIA receptors. Objective:To assess the efficacy of trazodone in improving anxiety and benzodiazepine dependence severity. Methods: A group of 21 patients, 9 male and 12 female, 3560 years of age (mean age 45.7), diagnosed with GAD according to DSM IV-TR criteria and benzodiazepine dependence also according to DSM IV-TR criteria were evaluated for 6 months. All patient were evaluated using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impressions (CGI)-severity and improvement every week during the first month, then every month to endpoint. Inclusion criteria: male or female between 18 and 65 years of age meeting DSM IV-TR criteria for general anxiety disorder and benzodiazepine dependence, CGI-severity score ~4, HAM-A score ~ 25 with at least moderate symptoms of anxious mood, tension and poor sleep quality (a score ~ 2 on items 1, 2 and 4). Exclusion criteria: persoual history of Axis I disorders, other than generalized anxiety disorder, axis II comorbidity, somatic comorbidity, pregnancy or breast feeding. Each subject was gradually weaned from benzodiazepines over a 14 day period using a tapering dose schedule and received a progressive dose of trazodone (mean dose 225 mg/day) from the beginning of the weaning period. Benzodiazepine dependence was evaluated using the Severity of Dependence Scale (SDS) at baseline and 4 weeks from baseline. Benzodiazepine withdrawal symptoms were evaluated using Physician Withdrawal Checklist (pWC). Results: Patients significantly improved during the first 4 weeks of treatment; HAM-A decreased with 53.8% after 4 weeks and the long term efficacy was also good, as HAM-A scores declined gradually throughout the study (~73.6% decrease at the endpoint)
IP.4.e.ooal The
factors that influence the therapeutic response to paroxetine in patients with panic disorder: longitudinal study
M. Veda1 " T. Watanabe 1 , Y. Saeki", A. Saito/, K. Akiyama/, y. Inoue", S. Morita", G. Hirokane", N. Yamada", K. Shimoda1 . 1 Dokkyo Medical University, Department of Psychiatry, Tochigi, Japan; 2 Dokkyo Medical University, Department of Biological Psychiatry and Neuroscience, Tochigi, Japan; 3MP Technopharma, Analytical division, Fukuoka, Japan; 4 Shiga University ofMedical Science, Department of Psychiatry, Shiga, Japan Selective serotonin reuptake inhibitors (SSRIs) are thought to interact with serotonergic system and be effective for treatment of panic disorder (PD). Recent investigations have also been focused on the impact of genetic polymorphism of serotonin transporter (5-HTT) on the clinical effect of SSRIs in PD because 5-HTT is the primary target of action of SSRIs. The 5-HTT gene-linked polymorphic region (5-HTTLPR), located in the promoter region, has been identified as a functional polymorphism. In vitro, the basal activity of the long variant (L) was more than twice that of the short variant (S) in 5-HTT mRNA synthesis and 5-HTT expression. The objective of this study was to evaluate genetic and pharmacokinetic factors for pharmacotherapeutic effect of paroxetine (PAX) in patients with PD. In the present study, we investigated into therapeutic response to PAX in 2 and 4 weeks after the initiation of the treatment. Subjects were 38 Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of PD. Subjects were received lOmg/day of PAX for 4 weeks. Severity of PD was assessed with the Panic and Agoraphobia Scale (PAS). Plasma concentration of PAX was determined by high performance liquid chromatography. 5-HTTLPR gene variants were determined by polymerase chain reaction techniques. Multiple regression analysis was performed in order to analyze the relationship between demographic variables from the subjects and the clinical response to PAX (percentage reduction of PAS score). We used the plasma concentration of PAX, age, gender, body weight, comorbid physical illness, comorbid major depressive disorder, comorbid agoraphobia, smoking status, habitual use of alcohol, PAS score at baseline, frequency of panic attacks per week at baseline, 5-HTTLPR genotype (LIS or SIS), adverse effect of PAX, use of lorazepam and/or brotizolam as independent variables and the clinical response to PAX (percentage reduction of PAS score) as the dependent variable. Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype and comorbid physical illness were significant factors affecting clinical response to PAX (percentage reduction of PAS score), and indicated that these factors accounted for 52.4% (R 2 = 0.524) of the variability of the percentage reduction of PAS score at 2 weeks. The final model was described by the following equation (p=0.001): percentage reduction of PAS score (%) = 68.5 1.2 x (plasma concentration of PAX (ng/ml)) - 33.0x(L/S = 1, S/S=O) - 21.8x(with comorbid physical illness = 1, without comorbid physical illness=O) [1]. However, no significant clinical factor affecting clinical response to PAX was detected at 4 weeks after initiation of pharmacotherapy with PAX. Perna et al [2] investigated the relationship between allelic variation of 5-HTT and the clinical response to PAX in 92 PD patients who completed treatment with variable doses of PAX for 12 weeks. Both LIL genotype and LIS genotype showed a better response to PAX than SIS genotype (p < 0.03). This result was observed in the whole sample, but was related to only female patients (p < 0.02). From
S617
the results of the present study, determination of pharmacokinetic factor (i.e., plasma levels of PAX) and pharmacogenetic factor (i.e., 5-HTTLPR genotype) might be useful only for predicting the clinical response to PAX in patients with panic disorder in the early phase of pharmacotherapy with PAX. References [1] Saeki, Y., Watanabe, T., Veda, M., Saito, A., Akiyama, K., Inoue, Y., Hirokane, G., Morita, S., Yamada, N., & Shimoda, K. (2009). Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder. Eur J Clin Pharmacol.[Epub ahead of print] PMID: 19259652 DOl IO.I007/s0022S-009-0633-S [2] Perna, G., Favaron, E., Di Bella, D., Bussi, R., & Bellodi, L. (2005). Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology 30, 2230-5.
1p.4.e.0091 Efficacy of trazodone in patients diagnosed
with generalised anxiety disorder and benzodiazepine dependence M. Zavoianu1 " A. Luchian1, C. Tudor 1, G. Grigorescu1, D. Vasile 1 . 1 Central Clinic Military Hospital, Psychiatry, Bucharest, Romania Background: Generalized anxiety disorder (GAD) is a common chronic condition characterized by a pattern of frequent, longlasting and difficult to control anxiety that is not focused on anyone object or situation. Neurobiological hypothesis in GAD is an abnormal regulation of serotoninergic system. Trazodone, a serotonine antagonistlreuptake inhibitor, is an effective antidepressant drug with anxiolytic and hypnotic activity. Recent studies indicated that trazodone might due its anxiolytic action to a partial agonist effect at 5HTIA receptors. Objective:To assess the efficacy of trazodone in improving anxiety and benzodiazepine dependence severity. Methods: A group of 21 patients, 9 male and 12 female, 3560 years of age (mean age 45.7), diagnosed with GAD according to DSM IV-TR criteria and benzodiazepine dependence also according to DSM IV-TR criteria were evaluated for 6 months. All patient were evaluated using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impressions (CGI)-severity and improvement every week during the first month, then every month to endpoint. Inclusion criteria: male or female between 18 and 65 years of age meeting DSM IV-TR criteria for general anxiety disorder and benzodiazepine dependence, CGI-severity score ~4, HAM-A score ~ 25 with at least moderate symptoms of anxious mood, tension and poor sleep quality (a score ~ 2 on items 1, 2 and 4). Exclusion criteria: persoual history of Axis I disorders, other than generalized anxiety disorder, axis II comorbidity, somatic comorbidity, pregnancy or breast feeding. Each subject was gradually weaned from benzodiazepines over a 14 day period using a tapering dose schedule and received a progressive dose of trazodone (mean dose 225 mg/day) from the beginning of the weaning period. Benzodiazepine dependence was evaluated using the Severity of Dependence Scale (SDS) at baseline and 4 weeks from baseline. Benzodiazepine withdrawal symptoms were evaluated using Physician Withdrawal Checklist (pWC). Results: Patients significantly improved during the first 4 weeks of treatment; HAM-A decreased with 53.8% after 4 weeks and the long term efficacy was also good, as HAM-A scores declined gradually throughout the study (~73.6% decrease at the endpoint)