Abstracts from ASENT 2005 Annual Meeting

s from the ASENT 2005 Annual Meeting March 3–5, 2005 Dopamine D3 Receptor Gene and Olanzapine Response in Schizophrenia J. P. Houston, S. C. Kirkwood, D. J. Fu, D. H. Adams, M. Farmen, A. C. M. Downing, N. Mukhopadhyay, and A. Breier Eli Lilly and Company, Indianapolis, Indiana Introduction: Several single nucleotide polymorphisms (SNPs) for dopamine D3 receptor gene (DRD-3) have been associated with differential anti-psychotic response, including ser-9-gly (rs6280). Methods: We assessed response in 82 patients with schizophrenia retrospectively genotyped for SNPs of neuroreceptor genes associated with olanzapine activity. Baseline-to-endpoint reduction in Positive and Negative Syndrome Scale (PANSS)positive sub-scores over 6 weeks of olanzapine treatment was assessed by repeated measures ANOVA. Categorical response was an endpoint rating of mild or minimal or less on each PANSS-positive item. Results: PANSS-positive reduction for 3 DRD-3 SNPs differed significantly by allelic and genotypic analyses respectively at chromosome 3 positions rs1800828 (p 0.238 and 0.0130), rs6280 (p 0.022 and 0.0045), and rs3732790 (dbSNP) (p 0.0006 and 0.0130). For each SNP, one homozygous genotype was associated with greatest response (N 10, 24, and 42, respectively) compared with the rest of the 82 patients. Of patients homozygous for the more responsive ser-9-gly SNP vs. others, 45.8% vs. 17.24% (p 0.0116) had at most minimal PANSSpositive symptoms, and 79.2% vs. 58.6% (p 0.127) had at most mild PANSS-positive symptoms at endpoint. Conclusions: DRD-3 receptor gene SNPs predicted statistically and clinically significant acute positive symptom reduction with olanzapine in substantial subsets of patients with schizophrenia. Differential Rates of Clinical Trial Discontinuation as a Measure of Treatment Effectiveness among Antipsychotic Medications B. J. Kinon, H. Liu-Seifert, and D. H. Adams Eli Lilly and Company, Indianapolis, Indiana Objective: Antipsychotic treatment discontinuation may be used to measure overall treatment effectiveness. Few studies systematically assess early treatment discontinuation differences among antipsychotics. We investigate olanzapine discontinuation compared to other atypical antipsychotics. Methods: A post hoc, pooled analysis of 4 randomized, 24–28 week, double-blind clinical trials included 822 olanzapine-treated and 805 risperidone-, quetiapine-, or ziprasidonetreated patients. Discontinuation rates and the probability of staying in treatment were compared between olanzapine and the other atypicals combined. Results: Poor response/symptom worsening was the primary reason for discontinuation regardless of medication. There was a significant treatment difference in the rate of discontinuation due to poor response/symptom worsening (olanzapine 14.23% vs. other atypicals 24.60%, p 0.001). There was no treatment difference in the rate of discontinuation due to medication intolerability (olanzapine 5.60% vs. other atypicals 7.45%, p 0.13). Olanzapine-treated patients were significantly more likely to complete treatment (53.9% vs. 39.3%, p 0.001) and stayed in treatment longer (19.1 vs. 16.1 weeks, p 0.001) than other atypical-treated patients. Conclusions: The predominant reason for difference in early discontinuation between olanzapine and other antipsychotics was higher dropouts due to poor response/symptom worsening with other antipsychotics. Treatment discontinuation may be an important gauge of relative treatment effectiveness among antipsychotics. Oral Olanzapine Transition Dose Following Intramuscular Olanzapine Treatment J. Houston, C. Kaiser, and J. Ahl Eli Lilly and Company, Indianapolis, Indiana Background: Intramuscular (IM) antipsychotics are first line treatment for acute agitation in patients with schizophrenia. After stabilization, patients are transitioned to oral medication. Methods: This was a post-hoc analysis of transitional oral antipsychotic dose per IM group in a double-blind, randomized study. Over 24 hours, agitated inpatients received 1, 2, or 3 injections of IM olanzapine (OLZ) 10 mg (n 92, 26, 3, respectively), haloperidol (HAL) 7.5 mg (n 82, 32, 1, respectively), or placebo (PBO, n 24, 21, 2, respectively) followed by 4 days of oral treatment with 5–20 mg/d OLZ for IM OLZ and PBO groups and 5–20 mg/d HAL for IM HAL group. Agitation was assessed by the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC). Results: Median/means of mean oral doses in patients receiving 1, 2, and 3 injections, respectively, were 10.0/12.0 mg, 13.8/ 13.8 mg, and 20.0/18.3 mg OLZ for OLZ IM group; 10.0/9.9 mg, 11.3/11.8 mg, and 10.0/10.0 mg HAL for HAL IM group; and 10.0/10.6 mg, 11.3/12.5 mg, and 8.8/8.8 mg OLZ for PBO IM group. Reduction in agitation continued during transition to oral antipsychotic for HAL and PBO groups and for OLZ patients who received 1 IM dose. Reduction in agitation was maintained during transition for patients who received multiple OLZ IM doses. Conclusions: Reduction in agitation was maintained following transition from IM to oral therapy. Transitional oral doses increased with the number of OLZ injections. Topiramate Modulates Neuronal Excitability in the Basolateral Amygdala by Selectively Inhibiting GluR5 Kainate Receptors and Acting as a Positive Modulator of GABAA Receptors F. M. Braga, V. Aroniadou-Anderjaska, H. Li, and M. A. Rogawski Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland Topiramate is a novel antiepileptic drug that has also shown promise in the treatment of certain psychiatric illnesses. The NeuroRx : The Journal of the American Society for Experimental NeuroTherapeutics Vol. 2, 533–538, July 2005 © The American Society for Experimental NeuroTherapeutics, Inc. 533 mechanisms underlying the clinical therapeutic effects of topiramate are poorly understood. Recently, we reported that topiramate inhibits postsynaptic GluR5 kainate receptor-mediated responses in basolateral amygdala (BLA) principal neurons, suggesting that a reduction of GluR5 receptor-mediated excitation of pyramidal neurons is one mechanism responsible for the antiepileptic properties of topiramate. Since GABAergic inhibition plays a primary role in neuronal excitability, in the present study we examined whether topiramate 1) also inhibits GluR5 receptors on GABAergic interneurons in the BLA, and 2) directly influences GABAergic synaptic transmission. We have previously demonstrated that GluR5 receptors are present on both somatodendritic and presynaptic sites of BLA interneurons. Activation of these receptors enhances GABA release. However, when extracellular glutamate concentrations are high (as during epileptic seizures), activation of interneuronal, presynaptic GluR5 receptors inhibits GABAergic transmission, further contributing to hyperexcitability. Using whole-cell recordings in rat amygdala slices, we found that topiramate, in a dose-dependent manner (1–10 M), 1) suppressed excitatory postsynaptic currents (EPSCs) evoked in BLA interneurons by the selective GluR5 agonist, ATPA (10 M), 2) suppressed the ATPA-induced enhancement of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from pyramidal cells, and 3) prevented the ATPA-induced reduction of IPSCs evoked in pyramidal cells. Thus, by an effect on interneuronal GluR5 receptors, topiramate can suppress spontaneous release of GABA, but promote evoked GABA release during intense activation of GluR5 receptors. In addition, we found that topiramate enhances inhibitory transmission by a direct effect on postsynaptic GABAA receptors. Thus, topiramate increased the amplitude of evoked, spontaneous, and miniature IPSCs recorded from BLA pyramidal cells. These results indicate that topiramate, at clinically relevant concentrations, selectively inhibits GluR5 receptor-mediated responses of interneurons, and acts as a positive modulator of GABAA receptors. This work was supported by DAMD 17-00-1-0110-DoD. Duloxetine at Doses of 60 mg QD and 60 mg BID is Effective in Treatment of Diabetic Neuropathic Pain (DNP) J. Wernicke, Y. Lu, J. Hall, D. DeSouza, A. Waninger, and P. Tran Eli Lilly and Company, Indianapolis, Indiana Objective: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. This study assessed the efficacy of duloxetine, a potent, selective, and balanced inhibitor of 5-HT and NE reuptake, on the reduction of pain severity, in patients with DNP. Methods: Patients with DNP and without comorbid depression were randomized to treatment with duloxetine 60 mg QD, 60 mg BID, or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures included night and 24-hour worst pain severity, Brief Pain Inventory (BPI), Clinical Global Impression of Severity (CGI-Severity), Patient Global Impression of Improvement (PGI-Improvement), Short-form McGill Pain Questionnaire, Dynamic Allodynia, and Average Daily Intake of Acetaminophen. Results: Duloxetine 60 mg QD and 60 mg BID demonstrated significant improvement in the treatment of DNP and showed rapid onset of action, with separation from placebo occurring at week one on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed superiority of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Reduction in 24-hour average pain severity was caused by direct treatment effect. CGI and PGI evaluation also demonstrated greater improvement on duloxetineversus placebo-treated patients. Duloxetine showed no notable interference on diabetic control, and both doses were safely administered and well tolerated. Conclusion: This study