Targeting mitochondrially mediated plasticity to develop improved therapeutics for bipolar disorder

• Published in: Expert opinion on therapeutic targets Vol. 18; no. 10; p. 1131
• Main Authors: de Sousa, Rafael T, Machado-Vieira, Rodrigo, Zarate, Jr, Carlos A, Manji, Husseini K
• Format: Journal Article
• Language: English
• Published: England 01-10-2014
• Subjects: Antimanic Agents - pharmacology; Apoptosis - drug effects; Bipolar Disorder - drug therapy; Bipolar Disorder - genetics; Bipolar Disorder - physiopathology; Calcium - metabolism; Cell Survival - drug effects; Drug Design; Energy Metabolism - drug effects; Humans; Mitochondria - drug effects; Mitochondria - pathology; Molecular Targeted Therapy; Neuronal Plasticity - drug effects; Polymorphism, Genetic; Risk Factors; apoptosis; bipolar disorder; mood stabilizer; calcium; mitochondria; oxidative stress
• ISSN: 1744-7631
• DOI: 10.1517/14728222.2014.940893

Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology.
This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca²⁺) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca²⁺ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients.
Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.