Vasopressin Antagonists as Anxiolytics and Antidepressants: Recent Developments

Abstract

A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. The scientific bases for vasopressin antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not corticotrophin releasing factor (CRF), drives HPA function associated with chronic psychological stress, 3) the CNS localization of vasopressin V1a and V1b receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data showing efficacy in animal models employed as screens for anxiolytic and antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. In the United States alone, anxiety and depression affect some 40 million people each year and carry a conservatively estimated annual total economic burden of at least $125 billion. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through vasopressin receptor antagonism in the CNS may offer significant opportunities for improved outcomes. In this review, the development of compounds in this class since 2005 is considered. The most advanced clinical candidates and newer compounds described in recent patents are presented.

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats

“…Here we could repeatedly confirm more active behavioral response in AVP-deficient Brattleboro rats. This is in line with the assumption that central AVP signaling may play an important role in the development of depressive pathology You created this PDF from an application that is not licensed to print to novaPDF printer (http://www.novapdf.com) (Landgraf and Wigger, 2002, Scott and Dinan, 2002, Keck, 2006, Landgraf, 2006, Frank and Landgraf, 2008, Simon et al, 2008, Surget and Belzung, 2008, Ryckmans, 2010. Infusion of V1a and V1b antagonists not only into systemic circulation (Overstreet and Griebel, 2005) but also into the PVN , septum and the amygdala (Ebner et al, 2002) increased the active behavior during FS.…”

“…(Landgraf and Wigger, 2002, Scott and Dinan, 2002, Keck, 2006, Landgraf, 2006, Frank and Landgraf, 2008, Simon et al, 2008, Surget and Belzung, 2008, Ryckmans, 2010. As both psychiatric disorders are considered to be stress related and AVP has a regulatory role in the HPA axis (Engelmann et al, 2004, Makara et al, 2004, Murgatroyd and Spengler, 2011, this connection is reasonable to propose.…”

Effect of Parabolic Flight on Plasma Arginine Vasopressin as A Sensitive Marker for Psychophysiological Stress in Humans

“…These alterations are not found in control subjects (Peskind et al, 1998), suggesting an involvement of AVP in the pathophysiology of panic induction. Accordingly, dysregulation of the brain AVP system, especially the over-activity of AVP neurons, is likely to contribute to the etiology and symptomatology of anxiety-and depression-related disorders (Murgatroyd et al, 2004;Simon et al, 2008;Surget and Belzung, 2008). In addition, animal models of high anxiety are characterized by an overexpression of central AVP (Landgraf, 2006), and treatment with an antidepressant led to a gradual reduction of AVP hypersecretion (Keck et al, 2003 al., 2004).…”

Role of corticosteroids in the antidepressant response

“…169 V1a receptors are abundant in the cerebral cortex, limbic system, hypothalamus, and brain stem. 170 There are a number of antagonists of V1a, V1b, and V2 in development, particularly for the treatment of hyponatremia. The non-peptide V1b receptor antagonist, SSR149415, has demonstrated anxiolytic and antidepressant properties in animal models.…”