Executive Summary – Sept. 23, 2011
Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults
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BackgroundMajor 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 percent of those receive adequate treatment. For those who do initiate treatment for their depression, approximately 50 percent 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).
These TRD patients represent a complex population with a disease that is difficult to manage.
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. After considering both medical and disability claims from an employer’s perspective, one study found that TRD employees cost $14,490 per employee per year, whereas the cost for non-TRD employees was $6,665 per employee per year.
Given the burden of TRD generally, the uncertain prognosis of the disorder, and the high costs of therapy, clinicians and patients alike 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 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 treatment 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 from the RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center (EPC) provides a comprehensive summary of the available data addressing the comparative effectiveness of four nonpharmacologic treatments as therapies for patients with TRD: electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), and cognitive behavioral therapy or interpersonal psychotherapy (CBT or IPT).
The core patient population of interest was patients with MDD who met our definition of TRD: failure to respond following two or more adequate antidepressant treatments. We also included TRD studies in which the patient population could include a “mix” of up to 20 percent of patients with bipolar disorder (i.e., 80 percent or more of patients had only MDD), assuming that this small mix would not substantially alter outcomes seen with MDD-only populations.
We structured our review to maintain our focus on study populations meeting our TRD definition (≥2 antidepressant failures) while not excluding potentially relevant evidence. We identified different tiers of TRD-related studies to use in our analytic strategy:
- Tier 1 evidence (TRD as defined in this report): studies in which patients specifically had two or more prior treatment failures with medications.
- Tier 2 evidence: studies in which patients had one or more prior treatment failures.
- Tier 3 evidence: studies in which the number of prior failed treatments was not specified but the clinical situation suggested a high probability of patients having two or more prior antidepressant treatment failures; these data have probable relevance to TRD. Studies that did not specify the number of failed treatments but noted that all subjects were referred for ECT were included in this tier.
- KQ 1a. For adults with TRD (defined as two or more failed adequate trials of a biologic [i.e., pharmacologic] intervention), do nonpharmacologic interventions such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), or demonstrated effective psychotherapy (e.g., cognitive therapy [CBT or IPT]) 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?
- KQ 1b. 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?
- KQ 2. For adults with TRD, do nonpharmacologic interventions differ in their efficacy or effectiveness for maintaining response or remission (e.g., preventing relapse or recurrence), whether as a single treatment or part of a combination treatment?
- KQ 3. Do nonpharmacologic interventions (single or combination) differ in their efficacy or effectiveness for treating TRD as a function of particular symptom subtypes (e.g., catatonic [frozen or hyper] or psychotic symptoms)?
- KQ 4. 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.
- KQ 5. 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 (e.g., seizure history, stroke, diabetes, dementia, perinatal depression, ischemic heart disease, cancer)?
- KQ 6. For adults with TRD, do nonpharmacologic interventions differ in regard to other health-related outcomes (e.g., quality of life)?
We searched MEDLINE, Embase, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts. We searched for systematic reviews, clinical controlled trials, meta-analyses, and nonexperimental studies in which the investigator did not assign group allocation. Sources were searched from 1980 through November 18, 2010. AHRQ Scientific Resource Center (SRC) staff contacted device manufacturers and invited them to submit dossiers, including citations. The SRC also provided our EPC with other relevant data that may not have been captured in the literature search.
For efficacy and effectiveness (KQs 1 and 2), we first focused on head-to-head randomized controlled trials (RCTs) comparing one intervention with another. When sufficient head-to-head evidence was unavailable, we evaluated indirect evidence: nonpharmacologic interventions versus placebo- or sham-controlled evidence or “treatment as usual” controls. For KQs 3, 4, 5, and 6, we examined data from both experimental and observational studies (generally prospective cohort studies). We did not formally distinguish efficacy from effectiveness trials.
We rated the quality of individual studies as good, fair, or poor; only good or fair studies are included in these analyses. We evaluated the strength of the various bodies of evidence using principles stated in the AHRQ Methods Guide for Comparative Effectiveness Reviews, which grades strength as high, moderate, low, or insufficient. We evaluated the applicability of the body of evidence using a qualitative assessment of the population, intervention/treatment, comparator, outcomes measured, timing of followup, and setting.
Throughout this report we synthesized the literature qualitatively. If data were sufficient, we conducted meta-analyses of data for comparisons involving trials that were fairly homogenous in study populations, treatment intervention, and outcome assessments. Given our focus on Tier 1 (TRD) studies, for each KQ we first present an overview of the particular comparison, including the strength of evidence findings for the Tier 1 studies. This summary does not present detailed findings from the Tier 2 and Tier 3 studies. The results chapter of the full report presents those data in greater detail.
Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults - Executive Summary AHRQ Effective Health Care Program