Background Bipolar disorder is a severe psychiatric illness with poor prognosis and problematic and suboptimal treatments. Understanding the pathoetiologic mechanisms may improve treatment and outcomes. Discussion Dysregulation of cationic homeostasis is the most reproducible aspect of bipolar pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Recent discoveries of the role of endogenous sodium pump modulators (which include ‘endogenous ouabain’) in regulation of sodium and potassium distribution, inflammation, and activation of key cellular second messenger systems that are important in cell survival, and the demonstration that these stress-responsive chemicals may be dysregulated in bipolar patients, suggest that these compounds may be candidates for the coupling of environmental stressors and illness onset. Specifically, individuals with bipolar disorder appear to be unable to upregulate endogenous ouabain under conditions that require it, and therefore may experience a relative deficiency of this important regulatory hormone. In the absence of elevated endogenous ouabain, neurons are unable to maintain their normal resting potential, become relatively depolarized, and are then susceptible to inappropriate activation. Furthermore, sodium pump activity appears to be necessary to prevent inflammatory signals within the central nervous system. Nearly all available data currently support this model, but additional studies are required to solidify the role of this system. Conclusion Endogenous ouabain dysregulation appears to be a reasonable candidate for understanding the pathophysiology of bipolar disorder.
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