New approaches to managing difficult-to-treat depressions.

In a sense, all depression is difficult to treat. Most depressions are episodic conditions that, not infrequently, are slow to fully remit. Most also are complicated by comorbid psychiatric and general medical disorders. However, a minority of such difficult-to-treat depressions are treatment resistant. The most common cause of initial treatment failure is not resistance but undertreatment-that is, an insufficient duration of treatment, a subtherapeutic dosage of antidepressant, and/or poor adherence to the prescribed regimen. Complicating factors such as undiagnosed hypothyroidism or substance abuse can result in apparent treatment resistance unless addressed. Challenging subtypes of illness, including psychotic and bipolar subtypes of depression, are not necessarily inherently refractory but must be met with modified treatment approaches.