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Subchronic Effects Of Eszopiclone (Lunesta) On Pain Behavior And Circuitry In Primary Insomnia

The objective of this proposal is to use Functional Magnetic Resonance Imaging (fMRI) with an experimental pain paradigm in a group of chronic insomnia patients. These individuals will receive a baseline fMRI scan, will be treated subsequently with Lunesta, and will be compared to a placebo-treated group. To answer Question 1, we will compare brain activation in these subjects during mildly painful stimuli to determine the subchronic effects of Lunesta on the neural circuitry associated with vigilance, anticipation, pain perception and emotional pain processing. To that end, we will examine the following hypotheses: 1) Subchronic (1-week) administration of Lunesta will reduce brain activation in the insular cortex associated with anticipation and experience of pain, and will have no effect on brain activity associated with simple vigilance; 2) Greater reduction of activation during anticipation and experience of pain will be correlated with sleep improvement. To answer Question 2, we aim to compare psychophysical measures of pain perception and emotional pain processing in these subjects to determine the acute and subchronic effects of Lunesta on basic pain processes. We will examine the following hypotheses: 1) Subchronic administration of Lunesta will decrease subjective pain experience, especially associated with pain affect. 2) A greater decrease in experience of pain will be correlated with sleep improvement.

An fMRI Examination of Cognitive Deficits & Emotional Processing Dysfunction in Women with Posttraumatic Stress Disorder

To use fMRI to localize brain regions (or networks thereof) mediating the neuropsychological deficits seen in women with PTSD.  These studies will add to our understanding of the neural substrates involved in information processing in persons with PTSD.  The selection of functional tasks will be based on our evolving understanding of the nature of the cognitive deficits observed in PTSD. These include tests of working memory and attentional activity (both components of so-called “executive dysfunction”). Also included is an emotional facial presentation probe known to activate the amygdala. A subset of subjects will be re-tested following treatment with paroxetine [Paxil CR] to provide some early indications of regions and mechanisms) involved in response to treatment.

Randomized, Double-blind, Placebo-controlled, Parallel Design Study of the Effects of a Selective Serotonin Reuptake Inhibitor (escitalopram) and a Benzodiazepine (alprazolam) Versus Placebo on Functional Magnetic Resonance Imaging (fMRI) of the Brain, and on Behavioral/Clinical Measures in Patients with Generalized Anxiety Disorder

The hallmark of Generalized Anxiety Disorder (GAD), a highly prevalent disease, is excessive anxiety and worries (apprehensive expectation). Treatment options include benzodiazepines and selective serotonin reuptake inhibitors (SSRI), however the need for more efficacious and better tolerated treatment options persists.

Clinical development of novel treatments in GAD patients is difficult as they appear to represent a heterogeneous patient population and because the placebo response is commonly high. Consequently, the failure rate in these studies that typically are 6-8 weeks long, is estimated to be up to 80%. Hence, there is a need for identification and validation of a biomarker that can be used early in drug development to either successfully differentiate subpopulations within the clinically characterized GAD population (DSM-IV) or to measure anxiolytic drug effects in true drug responders more effectively than can be done with clinical scales.

Functional magnetic resonance imaging (fMRI) is a methodology that has emerged in the last 10 to 15 years. It allows (relative) quantification of brain activity by measuring the neurovascular response at rest and during a task stimulus non-invasively. Both blood-oxygenation level dependent (BOLD) and perfusion (ASL) imaging are believed to relate to neuronal activity. There is emerging fMRI data which shows great promise for both identifying brain structures and networks involved in anxiety and for visualizing the therapeutic and side effects of new drug candidates for these indications. In this study, the primary interest will be to detect drug-induced changes in activity of brain regions or circuits that are believed to be relevant for GAD and that have been shown to be reliably activated by the chosen stimulus/paradigm.

A randomized, placebo-controlled, double-dummy, four-way crossover design study to investigate the changes of fMRI BOLD activation induced by emotional activation paradigms following single doses of GW876008 and lorazepam (comparator) in healthy subjects

GW876008 is a selective corticotropin releasing factor 1 (CRF1) receptor antagonist that is being developed as a novel oral treatment for depression and anxiety. Preclinical data indicate that CRF1 antagonists produce rapid anxiolytic effects and attenuate response to negative emotional stimuli and stress. Presently, it is unknown if CRF1 antagonists can produce the same effects in humans. Recent findings indicate that fMRI can be used to study the effects of single dose anxiolytic-like drugs by measuring the attenuation of brain activation maps in limbic structures associated to the processing of negative emotions. The aim of this study is to use fMRI BOLD and ASL signals to investigate the effects of GW876008 (50 and 200 mg) and a standard anxiolytic (lorazepam 1 mg) on cerebral activation patterns induced by specific emotional negative tasks in healthy volunteers. To date, a total of 84 subjects have received at least a single dose of GW876008 in four studies (10mg, 25mg, 50mg, 100mg, 150mg, 200mg and 250mg); a total of 82 subjects have received a single dose of 100mg GW876008 to date. A total of 44 subjects have received repeated doses of GW876008 in the 28-day repeat dose study in healthy subjects [20mg (n=9 males); 50mg (n=9 males); 75mg (n=9 males); 125mg (n=9 males and n=8 females)]. No safety concerns have been identified clinically, and doses were generally well tolerated with no reports of serious or significant adverse events. If positive, this study will build confidence into the potential for GW876008 to show anxiolytic effects in patients with anxiety disorders, an effect showed to be associated with reduced amygdala activation in multiples previous fMRI studies. The study might also provide preliminary information about the exposure-response relationship to support the dose selection strategy for Phase II.

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last edited: 07/28/2007