Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy.

Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions.

Biological hypotheses and biomarkers of bipolar disorder.

The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state.