Abstract
Bipolar disorder (BD) is a severe psychiatric illness with a poor prognosis and problematic, suboptimal, treatments. Treatments, borne of an understanding of the pathoetiologic mechanisms, need to be developed in order to improve outcomes. Dysregulation of cationic homeostasis is the most reproducible aspect of BD pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Endogenous sodium pump modulators (collectively known as endogenous cardiac steroids, ECS) are steroids which are synthesized in and released from the adrenal gland and brain. These compounds, by activating or inhibiting Na+, K+-ATPase activity and activating intracellular signaling cascades, have numerous effects on cell survival, vascular tone homeostasis, inflammation, and neuronal activity. For the past twenty years we have addressed the hypothesis that the Na+, K+-ATPase-ECS system may be involved in the etiology of BD. This is a focused review that presents a comprehensive model pertaining to the role of ECS in the etiology of BD. We propose that alterations in ECS metabolism in the brain cause numerous biochemical changes that underlie brain dysfunction and mood symptoms. This is based on both animal models and translational human results. There are data that demonstrate that excess ECS induce abnormal mood and activity in animals, while a specific removal of ECS with antibodies normalizes mood. There are also data indicating that circulating levels of ECS are lower in manic individuals, and that patients with BD are unable to upregulate synthesis of ECS under conditions that increase their elaboration in non-psychiatric controls. There is strong evidence for the involvement of ion dysregulation and ECS function in bipolar illness. Additional research is required to fully characterize these abnormalities and define future clinical directions.
Highlights
Introduction published maps and institutional affilType I bipolar disorder (BD) is a severe psychiatric illness that manifests as extreme variations in mood and energy, usually labelled as mania and depression, interspersed over a euthymic or dysthymic baseline [1]
Cardenolides, such as ouabain and digoxin, and bufadienolides, such as bufalin, are steroids originally identified in plants (Digitalis, Strophantus) and toads (Bufo), which have been used for hundreds of years in Western and Eastern medicine to treat heart failure, arrhythmias, and other maladies
These compounds, collectively termed endogenous cardiac steroids (ECS), are synthesized in the adrenal and hypothalamus of mammals [25,26,27], and they are considered a new class of hormones implicated in many physiological and pathophysiological mechanisms, including cell growth and cancer, vascular tone homeostasis, blood pressure, hypertension, natriuresis, heart contractility, and inflammation [22,24,28]
Summary
Type I bipolar disorder (BD) is a severe psychiatric illness that manifests as extreme variations in mood and energy, usually labelled as mania and depression, interspersed over a euthymic or dysthymic baseline [1]. The disorder afflicts approximately 1% of people [2,3], with documented suboptimal treatments and a host of undesirable outcomes related to both the disease and its treatment [4,5]. Despite over 60 years of directed effort, the pathoetiology of the illness remains unknown [3], but multiple clues have emerged that continue to inform ongoing research. The absence of a centralized unifying model contributes to the fragmented, siloed, fashion of current pathophysiologic research. We propose a mechanism of pathophysiology iations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
