Patients with either major depressive disorder (MDD) or bipolar disorder can manifest depressive episodes. In 2015, 6.7 percent of adults in the United States (16.1 million people) experienced a depressive episode in the past year, with the great majority being a part of MDD. Treatment for MDD can be inadequate because either patients do not seek it or the care they receive is substandard. Even for patients receiving adequate treatment, only 30 percent (3% of patients with MDD) reach the treatment goal of full recovery or remission. The remaining 70 percent of MDD patients will either respond without remission (about 20%) or not respond at all (50%).
Patients whose depressive disorder does not respond satisfactorily to adequate treatment clearly have harder-to-treat depression, generally referred to as treatment-resistant depression (TRD). TRD is a complex phenomenon influenced by variety in depressive subtypes, psychiatric comorbidity, and coexisting medical illnesses. It poses a common, challenging presentation to psychiatric and primary care clinicians.
Although TRD episodes are most commonly associated with MDD, they are also seen in the depressed phase of bipolar disorder. More than 30 percent of those suffering from bipolar disorder and receiving treatment do not experience sustained remission of depressive symptoms.
TRD has substantial effects on patients, their families, communities, and society at large. TRD represents the highest direct and indirect medical costs among those with MDD.9 Individuals with TRD are twice as likely to be hospitalized; the cost of this hospitalization is more than six times the mean total cost for depressed patients who are not treatment resistant. TRD can nearly double both direct and indirect 2-year employer medical expenditures relative to expenditures for patients whose MDD responds to treatment.
TRD is especially relevant for Medicare beneficiaries. Mood disorders (mainly MDD and bipolar disorder) are the second leading cause of disability in Medicare patients under the age of 65. Depression in the elderly is associated with suicide more than at any other age; adults 65 or older constitute 16 percent of all suicide deaths. The decrease in average life expectancy for those with depressive illness, including Medicare beneficiaries, is 7 to 11 years. Depression is a major predictor of the onset of stroke, diabetes, and heart disease; it raises patients’ risk of developing coronary heart disease16 and the risk of dying from a heart attack nearly threefold.
No universally accepted operational definition of TRD exists. Definitional dilemmas limit the ability of systematic reviewers or other experts to synthesize information and generalize the TRD findings to the array of patient populations encountered in daily practice. Moreover, varying conceptualizations of TRD have made translating research findings or systematic reviews into clinical practice guidelines challenging and inconsistent. Indeed, guideline definitions of TRD differ, agreement on what constitutes prior treatment adequacy is lacking, and recommended “next step” interventions can diverge.
This systematic review was proposed as a large Technology Assessment by the Centers for Medicare & Medicaid Services and conducted for the Agency for Healthcare Research and Quality (AHRQ). We reviewed definitional and other aspects of TRD in clinical research. One aim is to inform future discussions and decisions about how to define the condition and specify the important outcomes measured in research studies. A second aim is to clarify how researchers might best design and conduct trials or observational to guide clinical practice and health policy.