The Role of Chronic Stress in Anxious Depression.

Depression is a heterogeneous disease with many different subtypes. Patients with the anxious depression-a common subtype of major depression-are at an increased risk for treatment-resistance to standard antidepressants, with resultant increases in morbidity. However, the underlying pathophysiology of anxious depression remains unknown. Without such knowledge, the development of targeted treatments towards this specific depression subtype will likely remain elusive. One method by which research into the neurobiology of anxious depression may prove fruitful is with the research domain criteria (RDoC). RDoC provides a framework for investigation into the underlying pathophysiology of mental illness. By studying disorders in terms of RDoC constructs-such as the sustained threat construct of the negative valence system-new insights may be gained into neurobiological mechanisms of disease. These mechanisms may be useful for the development of novel antidepressants that are based on specific brain targets. Specifically, we review the impact that sustained threat-or chronic stress-has on the eventual development of depression (especially anxious depression) through pathological changes to molecules, cells, neurocircuitry, physiology, and behavior.