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Tuesday, December 14 Poster Session II Neuropsychopharmacology (2004) 29, S127-S182 © 2004 Nature Publishing Group All rights reserved 0893-133X/04 www.neuropsychopharmacology.org S127 Tuesday, December 14 that does not activate ganglion or muscle-type nicotinic acetylcholine Poster Session II - Tuesday receptors. It is orally active, has shown long lasting cognitive effects in animal models and neuroprotective effects in vitro. Methods: Four early placebo-controlled studies in humans have been completed and 1. Effect of Memantine on Behavioral Outcomes in Moderate to partial data from a fifth are available (N=124). The completed stud- Severe Alzheimer’s Disease ies include SRD, MRD, food interaction and a PK in the elderly. Sin- Jeffrey L Cummings*,Eugene Schneider, Pierre N Tariot and gle doses up to 320mg and multiple doses for 10 days up to 200mg, Stephen M Graham have been explored. An ongoing study in elderly subjects with age as- Department of Neurology, University of California Los Angeles, Los sociated memory impairment (AAMI) involves three-week dosing up Angeles, CA, USA to 150mg. Safety/Tolerability: The drug was well tolerated overall. No changes of clinical significance were detected on biochemistry Memantine is a low-moderate affinity, uncompetitive N- testing, urine analysis, vital signs, ECG or 24-hour Holter monitor- methyl-D-aspartate (NMDA) receptor antagonist approved for the ing. Adverse events (AEs) were mild to moderate in intensity. Severe treatment of moderate to severe Alzheimer’s disease (AD). Excitotox- AEs were only seen at MTD - identifed in these studies as 320mg in icity mediated by NMDA receptors is thought to play a role in the the young and 150mg in the elderly. Dose limiting AEs included pathogenesis of AD. Memantine blocks prolonged pathological acti- headache, dizziness, lightheadedness, and occasional nausea/vomit- vation of NMDA receptors while allowing normal receptor function. ing. Since no changes in CV variables accompanied these AEs, we This analysis of a 24-week double-blind, placebo-controlled trial con- have concluded they were due to the central pharmacology of TC- ducted in moderate to severe AD patients (N=404) assessed the effect 1734. Central Activity: Clear evidence of CNS penetration was found of memantine on behavioral symptoms in moderate to severe AD pa- after single dosing and multiple dosing (10 days). Pharmaco-EEG tients receiving stable donepezil treatment. The trial demonstrated showed acceleration type changes with power shift from the high significant benefits of memantine on functional, cognitive, and global theta, low alpha range to high alpha, low beta range. There was good measures. Behavioral symptoms were assessed using the Neuropsy- correlation between plasma levels of TC-1734 and pharmaco-EEG chiatric Inventory (NPI), administered at baseline, Week 12 and Week changes. Cognitive enhancement: Cognitive effects were evaluated 24. The statistical analysis (ANCOVA) was based on the ITT popula- using factors measured by the CDR cognitive test battery. In the tion using an LOCF approach. Baseline characteristics between the MRD study, a difference was seen between drug and placebo at day 10 placebo and memantine groups were comparable. At Week 24, there on the Power of Attention factor. In the elderly PK study, improve- was a statistically significant treatment difference (P=.002), with a re- ment was seen on the Quality of Episodic Memory factor. This effect duction in behavioral disturbances and psychiatric symptoms in me- was most pronounced in the period 36-48 hours (the last time points mantine-treated patients and worsening in placebo-treated patients. assessed) following a single 80mg dose. The long duration of action In addition, several NPI domains demonstrated statistically signifi- is similar to that seen in animal models and suggests dosing once cant treatment differences in favor of memantine at Week 24. These daily may be appropriate. In elderly AAMI subjects who received domains were agitation/aggression (P=.001), irritability/lability 50mg doses, there were robust differences between drug and placebo (P=.005) and appetite/eating change (P=.045). When patients on the Power of Attention and Continuity of Attention factors. A dif- asymptomatic at baseline were examined, significantly fewer meman- ference was also seen on the Speed of Memory factor. There were tine patients exhibited emergence of delusions (P=.011) and agita- some differences seen on the Quality of Episodic Memory factor, but tion/aggression (P=.032) at Week 12 and agitation/aggression none on the Quality of Working Memory factor. These 50mg results (P=.016), irritability/lability (P=.041) and nighttime behavioral dis- were statistically significant. Improvements in the 100mg cohort turbances (P=.027) at Week 24 compared to placebo patients. When were less prominent, suggesting a possible inverted U-dose response patients symptomatic at baseline were examined, there was signifi- curve. Again this is consistent with animal findings and with results cantly less worsening compared to placebo in symptoms of agita- seen with many drugs that enhance cognition. Conclusions: TC- tion/aggression (P=.018, Week 12; P=.021, Week 24) and 1734 was well tolerated in early studies in humans. Unlike other appetite/eating changes (P=.012, Week 12). Effective treatment of NNR agonists, it did not cause peripheral CV effects or, except at the these behaviors is important for this patient population with respect MTD, nausea/vomiting. At a dose of 50mg, TC-1734 enhanced atten- to both quality of life and the potential for reducing caregiver burden. tion, memory and speed of cognition in a group of elderly subjects Aging; Neurodegenerative disorders with AAMI. Cognition; Nicotine 2. TC-1734: A Neuronal Nicotinic Acetylcholine Receptor Partial Agonist that Demonstrated an Excellent Safety/Tolerabililty 3. Using The Tryptophan Depletion Paradigm to Examine The Profile and Cognitive Enhancement in Early Studies in Humans Relationship Between Estrogen and Serotonin In Modulating Geoffrey C Dunbar* Mood and Cognition in Menopausal Women Cynthia N Epperson*,Ralitza Gueorguieva, John H Krystal, Clinical Development and Regulatory Affairs, Targacept Inc, Winston George Heninger and Zenab Amin Salem, NC, USA Sponsor: Raymond Bartus Psychiatry, Yale University, New Haven, CT, USA; Obstetrics/Gynecology, Yale University, New Haven, CT, USA Background: Neuronal nicotinic acetylcholine receptor(NNR) agonists are believed capable of affecting various aspects of cognition, Sponsor: Stephanie O’Malley including attention, memory and learning, in both normal and cog- nitively impaired subjects. Previous NNR agonists have lacked suffi- Background: Changes in neuroendocrine function may predis- cient selectivity for the CNS and their development terminated due to pose menopausal women to psychological disturbances characterized peripheral side effects like nausea/vomiting and cardiovascular (CV) by depressed mood, anxiety, irritability, fatigue, insomnia, forgetful- changes. TC-1734 is a selective partial agonsit at the CNS α4β2 NNR ness and decline in libido. The acute tryptophan (TRP) depletion ACNP 2004 Annual Meeting S128 paradigm was employed to examine serotonergic contribution to problem. Methods:5focus groups (N=30) consisting of four to mood and cognitive function in menopausal women who were seven participants each were conducted at the Medical University of within four weeks of recovery from an episode of major depression South Carolina and community locations. A brief demographic and in healthy menopausal women pre and post treatment with es- survey was completed at the beginning of the focus groups. A trogen. Methods: Menopausal women with depression that was re- seven-item focus group discussion guide was developed and focus sponsive to treatment with estradiol 75 ug/d (N=4); the selective groups were conducted by a trained moderator. All sessions were serotonin reuptake inhibitor (SSRI) fluoxetine 20-40 mg/d (n=4); or tape-recorded and transcribed. Nonnumerical Unstructured Data estradiol 75 ug/d and fluoxetine 20 mg/d (N=3) and peri and post Indexing Search and Theory Building was utilized to code and ana- menopausal healthy controls (N=18) underwent active and sham lyze the transcripts. Results:All participants self-identified them- TRP depletion sessions. Healthy menopausal women underwent the selves as African American. Participants were 55 years of age and procedures both before and after estradiol 75 ug/d treatment (ET) for older. Analysis of transcripts revealed recurring focus groups 3 months. Mood and cognition were assessed using standard clinician themes that may influence the decision making process. Partici- administered tests before and 6 hours after administration of the pants expressed similar beliefs and thoughts about Alzheimer’s dis- amino acid mixture. Results: Although active TRP depletion re- ease symptoms. They expressed self-concerns about their own sulted in an 89% decline in total and free plasma TRP levels, neither memory often elaborating on their confusion about normal aging menopausal women who had recently recovered from an episode of versus dementia. They stressed concerns about the length of time major depressive disorder (MDD) or healthy menopausal women pre from awareness of symptoms to the physician’s diagnosis. They ap- or post estrogen administration experienced a worsening of their peared to lack the knowledge that there are medications indicated in mood during active tryptophan depletion. In contrast,
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