Major depressive disorder (MDD) is common and costly. Over the course of a year, between 13.1 million and 14.2 million people will experience MDD. Approximately half of these people seek help for this condition, and only 20% of those receive adequate treatment. For those who do initiate treatment for their depression, approximately 50% will not adequately respond following acute-phase treatment; this refractory group has considerable clinical and research interest. Patients with only one prior treatment failure are sometimes included in this group, but patients with two or more prior treatment failures are a particularly important and poorly understood group and are considered to have treatment-resistant depression (TRD). Patients with TRD incur the highest direct and indirect medical costs among those with MDD. These costs increase with the severity of TRD. Treatment-resistant patients are twice as likely to be hospitalized, and their cost of hospitalization is more than six times the mean total costs of depressed patients who are not treatment resistant. Given the burden of TRD generally, the uncertain prognosis of the disorder, and the high costs of therapy, clinicians and patients need clear evidence to guide their treatment decisions. The choices are wide ranging, include both pharmacologic and nonpharmacologic interventions, and are fraught with incomplete, potentially even conflicting, evidence. Somatic treatments, which may involve use of a pharmacologic intervention or a device, are commonly considered for patients with TRD. Antidepressant medications, which are the most commonly used intervention, have decreasing efficacy for producing remission after patients have experienced two failures. Such drugs also often have side effects, sometimes minor but sometimes quite serious. For these reasons, clinicians often look for alternative strategies for their TRD patients. This review is intended to help various decisionmakers come to informed choices about the use of nonpharmacologic interventions for TRD in adults. Our principal goal is to summarize comparative data on the efficacy, effectiveness, and harms of electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve stimulation, and cognitive behavioral therapy or interpersonal psychotherapy in patients with TRD. The following Key Questions are addressed: KQ1a. For adults with TRD, do nonpharmacologic interventions such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve stimulation, or demonstrated effective psychotherapy differ in efficacy or effectiveness in treating acute-phase depressive symptoms (e.g., response and remission), whether as a single treatment or part of a combination treatment? KQ1b. How do these nonpharmacologic treatments compare with pharmacological treatments in efficacy or effectiveness in treating acute-phase depressive symptoms after two or more failed adequate trials? KQ2. For adults with TRD, do nonpharmacologic interventions differ in their efficacy or effectiveness for maintaining response or remission, whether as a single treatment or part of a combination treatment? KQ3. Do nonpharmacologic interventions differ in their efficacy or effectiveness for treating TRD as a function of particular symptom subtypes (e.g., catatonic or psychotic symptoms)? KQ4. For adults with TRD, do nonpharmacologic interventions differ in safety, adverse events, or adherence? Adverse effects of interest include but are not limited to amnesia, memory loss, headaches, and postoperative complications. KQ5. How do the efficacy, effectiveness, or harms of treatment with nonpharmacologic treatments for TRD differ for the following subpopulations: Elderly or very elderly patients; other demographic groups (defined by age, ethnic or racial groups, and sex)? Patients with medical comorbidities? KQ6. For adults with TRD, do nonpharmacologic interventions differ in regard to other health-related outcomes?