Refractory bipolar disorder and neuroprogression.

Immune activation and failure of physiologic compensatory mechanisms over time have been implicated in the pathophysiology of illness progression in bipolar disorder. Recent evidence suggests that such changes are important contributors to neuroprogression and may mediate the cross-sensitization of episode recurrence, trauma exposure and substance use. The present review aims to discuss the potential factors related to bipolar disorder refractoriness and neuroprogression. In addition, we will discuss the possible impacts of early therapeutic interventions as well as the alternative approaches in late stages of the disorder.