Fast-Fail Trials in Mood and Anxiety Spectrum Disorders; Kappa Opioid Receptor Phase 2a

Overview

The available treatment for patients with mood and anxiety disorders have significant limitations (Rush, 2007; Denys and de Geus, 2005). There is a need to develop new treatments for people with these disorders. Many research studies carried out in animals and a few preliminary studies carried out in humans suggest that medications which block kappa opioid receptors (KOR) have potential for being effective new treatments for patients with mood and anxiety spectrum disorders. These medications have shown particular promise for improving one important type of difficulty experienced by many patients who suffer from mood and anxiety spectrum disorders referred to as anhedonia, which is an impairment in reward-related function. In this study we will test the hypothesis that KOR antagonism is a promising means of improving anhedonia in patients with mood and anxiety spectrum disorders. We will do so by evaluating whether we can establish Proof of Concept (POC) that a relatively selective KOR antagonist, CERC-501 (formerly known as LY2456302), engages neural circuits involved in mediating reward-related function in patients with mood and anxiety spectrum disorders with anhedonia. We are attempting to establish POC in this study in order to determine whether there is a sufficient basis for pursuing future work evaluating whether KOR antagonism has therapeutic effects on clinical and behavioral measures of reward-related functioning.

FAST-MAS addresses an important problem and critical barrier to progress in Mood and Anxiety Spectrum Disorders and if the aims of the project are achieved, FAST-MAS could shift scientific knowledge, technical capacity, and clinical practice in a positive direction. The Mood and Anxiety Spectrum disorders are both extremely common and associated with significant morbidity and mortality and, as such, represent an important public health problem in the United States. The mood disorders include the following diagnostic entities: major depressive disorder (MDD), bipolar disorder (including subtypes of mania, mixed state, and depressed, as well as types I and II), and dysthymic disorder. Available epidemiologic data suggest that the prevalence of these mood disorders is extremely high among adults in the United States, approaching 10%. Among the mood disorders, MDD has high lifetime prevalence, with recent estimates up to 16%. According to the World Health Organization (WHO), MDD is currently the leading cause of disability with the greatest burden of illness in developed countries and the third most common cause of disability worldwide. MDD is life shortening due to both suicide and its association with increased mortality from other medical conditions. It is also a highly recurrent condition with between 50% and 75% of persons diagnosed with MDD experiencing more than one episode. Bipolar Disorder is also a highly recurrent condition. The lifetime prevalence of bipolar disorder has been estimated to be approximately 3.4% in the World Health Survey Initiative. Approximately 60% of affected individuals experience severe or very severe role impairment based on the Sheehan Disability Scale and, like MDD, bipolar disorder is associated with significant suicide risk. The anxiety disorders are also very common and associated with significant adverse impact on affected individuals and society. These disorders include the following diagnostic entities: generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder, social phobia, specific phobias, and post-traumatic stress disorder (PTSD). As a group, these conditions affect approximately 18% of adults in a given year and they are associated with significant co-morbidities and adverse consequences. Of the anxiety disorders, GAD appears to be associated with the greatest per patient cost and disability with a degree of disability comparable to that of MDD and comparable to chronic medical conditions such as arthritis, diabetes, and peptic ulcer disease. It affects approximately 6.8 million adults in the U.S. and is a highly chronic condition. Panic disorder affects about 6 million American adults and is twice as common in women as men. Panic disorder is also highly disabling and often chronic and even mild forms of this disorder are linked to significantly increased impairment in function and quality of life as well as a number of comorbidities. Approximately 2.2 million adults in the U.S. are affected by obsessive-compulsive disorder and this disorder is often accompanied by psychiatric comorbidities. Roughly half of individuals with this condition have a chronic unremitting course which is associated with significant disability and morbidity. Social phobia, also known as social anxiety disorder, is seen in roughly 15 million adults in the U.S. and is often associated with MDD or other anxiety disorders. It is generally a chronic condition that leads to a great degree of disability due to substantial impairment in social, educational, and occupational function. Approximately 8 million adults in the U.S. experience PTSD and approximately 12% of the population have PTSD at some point in their lives and affected individuals frequently experience associated MDD, other anxiety disorders and substance use problems. The level of disability associated with this condition tends to be quite high and includes impairment in social and occupational function and quality of life. There are also substantial financial and social costs associated with PTSD due to increased hospitalization rates, suicidality, and substance use problem. Mood disorders and anxiety disorders are highly prevalent conditions, many of which are chronic, nearly all of which are associated with substantial comorbidities, disability and impairment and some are associated with an increased risk for mortality. Despite the availability of many pharmacologic, psychotherapeutic, brain stimulation, and combination treatment options available to clinicians, many patients with Mood and Anxiety Spectrum Disorders respond poorly to treatment. In light of the impairments, costs, and risks of these disorders, the limitations of the available treatments represents an enormous burden to public health and speak strongly to the need for new treatments for these conditions as well as novel methodologies of treatment development that are not only faster than existing methodologies but which also promote new ways of thinking about these disorders and their treatment and capitalize on recent and ongoing developments in basic science. This study will be a six-site randomized, double-blind, PBO (placebo) -controlled, parallel-group mono-therapy study to assess the effects of CERC-501 (formerly known as LY2456302) compared to PBO in adults age 21-65 years with mood and anxiety spectrum disorders. We will recruit a total of 90 subjects, of which 45 will be randomized to CERC-501 and 45 to placebo for 8 weeks of treatment