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Gaynes BN, Lux LJ, Lloyd SW, et al. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. (Comparative Effectiveness Reviews, No. 33.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults

Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults [Internet].

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Introduction

Burden and Costs of Disease

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.1 Approximately half of these people seek help for this condition, and only 20 percent of those receive adequate treatment.2

Among people who do receive adequate treatment, the normal course of treatment consists of an acute phase lasting 6 to 12 weeks with the goal of remission, meaning a complete resolution of the depressive episode (Figure 1). This is followed by a continuation phase of treatment during which the treatment goal is continued absence of depressive symptoms (i.e., relapse prevention) for an additional 4 to 9 months such that the patient's episode can be considered completely resolved. A maintenance phase lasting an additional 1 or more years is recommended in patients who have had two or more previous episodes of depression to prevent the recurrence of a new depressive episode.3,4

Figure 1 displays the phases of treatment for major depression with response to initial treatment. This figure is described further in the section “Burden and Costs of Disease” as follows: “Among people who do receive adequate treatment, the normal course of treatment consists of an acute phase lasting 6 to 12 weeks with the goal of remission, meaning a complete resolution of the depressive episode. This is followed by a continuation phase of treatment during which the treatment goal is continued absence of depressive symptoms (i.e., relapse prevention) for an additional 4 to 9 months such that the patient's episode can be considered completely resolved. A maintenance phase lasting an additional 1 or more years is recommended in patients who have had two or more previous episodes of depression to prevent the recurrence of a new depressive episode.”

Figure 1

Phases of treatment for major depression with response to initial treatment. Source: Re-created based on Kupfer, 1991. Tx1 = treatment attempt 1. Dashed lines indicate hypothetical worsening of depressive severity, which could indicate failure of treatment, (more...)

Unfortunately, the course of treating patients with depression (especially MDD) often does not follow the idealized treatment phases of reaching, continuing, and maintaining remission as depicted in Figure 1. In the acute phase of treatment, only 30 percent of patients reach the treatment goal of remission. The remaining 70 percent will either obtain response (usually defined as at least a 50 percent reduction in depressive severity) without remitting (about 20 percent) or not respond at all (50 percent).6

This 50 percent of people whose depressive disorder does not adequately respond following acute-phase treatment appear to have a harder-to-treat depression,7 and this refractory group has generated considerable clinical and research interest.7 Patients with only one prior treatment failure are sometimes included in this group, but patients with two or more prior failed treatment attempts are a particularly important and poorly understood group8 and are considered to have treatment-resistant depression (TRD; see the section below on patient populations included) (Figure 2).8 Indeed, for patients whose depression does not remit after two adequate treatment attempts in the current episode, the likelihood of recovery with subsequent medication treatment decreases by half to approximately 15 percent.8 In contrast with Figure 1, which depicts the course of treatment for a patient responding to first-line treatment (i.e., Tx1), the treatment-resistant patients depicted in Figure 2 require additional treatments (i.e., Tx2, Tx3, or more) and thus have prolonged depressive symptoms during unsuccessful acute phase treatment. Patients with two or more treatment failures during the same depressive episode (i.e., those marked as having TRD at Tx3 in the figure) are also believed to have more resistant disease than patients with two or more prior treatment failures during their entire lifetime. The former group of patients seemingly has a more uncertain prognosis for their condition over time than do patients not seen as treatment-resistant (as defined here); by extension, they face longstanding and greater burden of disease.

Figure 2 displays the phases of treatment for resistant or treatment refractory depression. This figure is described further in the section “Burden and Costs of Disease” as follows: “In contrast with Figure 1, which depicts the course of treatment for a patient responding to first-line treatment, the treatment-resistant patients depicted in this figure require additional treatments (i.e., Tx2, Tx3, or more) and thus have prolonged depressive symptoms during unsuccessful acute phase treatment. Patients failing two or more treatments during the same depressive episode (i.e., those marked as having TRD at Tx3 in the figure) are also believed to have more resistant disease than patients failing two or more prior treatments during their entire lifetime. The former group of patients seemingly has a more uncertain prognosis for their condition over time than do patients not seen as treatment-resistant (as defined here); by extension, they face longstanding and greater burden of disease.”

Figure 2

Phases of treatment for resistant depression (treatment refractory). Source: Adopted from Kupfer, 1991 Tx1-3 = Treatment attempt 1, 2, and 3, respectively; TRD = treatment-resistant depression. Dashed lines indicate hypothetical worsening of depressive (more...)

Although TRD broadly is defined as inadequate response following adequate antidepressant therapy in MDD, treatment resistance is a complex phenomenon that is influenced by heterogeneity in depressive subtypes, psychiatric comorbidity, and comorbid medical illnesses.9 As described in Figure 2, major depression is usually considered treatment resistant when at least two antidepressant attempts have failed.10 However, criteria for treatment resistance have been variably defined in clinical research and practice. Important factors related to the definition of TRD include the number of failed treatments, the time between treatment attempts, and the adequacy of the dose and duration of antidepressant treatment. The term “pseudo-resistance” has been used to describe patients classified as treatment resistant even though they never actually received an adequate treatment course; pseudo-resistance may account for as many as 60 percent of patients initially classified as TRD.9

Patients with TRD incur the highest direct and indirect medical costs among those with MDD. These costs increase with the severity of TRD.11 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.12 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 (1996–1998).13

Purpose of This Report

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,8 sometimes minor but sometimes quite serious.14 For these reasons, clinicians often look for alternative strategies for their TRD patients.

This comparative effectiveness review (CER) 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 (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), and cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT) in patients with TRD. Comparisons between two or more nonpharmacologic interventions are our main interest; however, because patients with TRD and their clinicians often decide between another medication treatment and a nonpharmacologic option, we also compare nonpharmacologic options with pharmacologic ones, both directly and indirectly. The goal is to produce a rough estimate of how these strategies compare for this patient population.

Included Interventions

Nonpharmacologic somatic treatments and nonsomatic psychotherapy treatments offer alternatives to antidepressant medications, although the evidence base for many of these treatments is limited. At the time the protocol for this review was developed, only four types of interventions had an evidence base sufficient to establish their efficacy and therefore be considered appropriate for a CER. Interventions that offer promising options for patients with TRD include ECT, rTMS, VNS, and evidence-based psychotherapy (e.g., cognitive therapy, such as cognitive behavioral therapy [CBT or IPT]). In some cases, these therapies or procedures can be used in combination (e.g., ECT and rTMS). Table 1 provides a summary of these principal nonpharmacologic interventions, including their uses, technical parameters, common side effects, and contraindications. They are described in more detail below. Generally, although these interventions may be safe and effective options for TRD, little evidence exists to guide decisions about their comparative efficacy. Further, how the nonpharmacologic options compare with pharmacologic treatments remains unclear.

Table 1. Summary of nonpharmacologic interventions covered in this report.

Table 1

Summary of nonpharmacologic interventions covered in this report.

Electroconvulsive Therapy (ECT)

ECT has been available for use in the United States since the 1930s. Current evidence indicates that ECT has a role in the treatment of people with depression and in certain subgroups of people with schizophrenia, catatonia, and mania.15,16 Its primary current role in depression is for treatment resistance or intolerance.17 Because ECT was introduced prior to U.S. Food and Drug Administration (FDA) device regulation, it was not subjected to formal review and approval as a device. It has since been classified as a class III device, which means that “insufficient information exists to determine that general controls are sufficient to provide reasonable assurance of its safety and effectiveness.” (21 CFR860.3) The FDA is reconsidering how it classifies ECT.26

ECT involves passing an electric current through the brain to produce a convulsion. Electrodes are usually placed at the bifrontal, bilateral, or right unilateral position. It is not commonly used as a first-line therapy or in primary care practice. The exceptions are uses in an emergency in which the person's life is at risk because of refusing to eat or drink or being in a catatonic state or in cases of attempted suicide. The effectiveness of ECT may be related to the stimulus parameters used, including position of electrodes, dosage, and waveform of electricity.

ECT is covered by major insurance plans, Medicaid, and Medicare. Reimbursement is approximately $275 per treatment,27 independent of the costs of inpatient hospitalization, should it be required. ECT usually consists of two to three treatments per week for 3 to 4 weeks.

ECT shows greater improvement in patients with suicidal intent than other antidepressant treatments; thus, it may be used as an early therapeutic option in suicidal patients.28 Research also indicates that despite physical illness, coexisting diseases, or cognitive impairment, older patients tolerate ECT as well as younger patients and may demonstrate better response.29,30 Because ECT is a procedure that involves anesthesia, it also poses slight risks to patients from the procedure itself. Other potential risks include seizure and adverse cognitive effects.17

Repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS involves magnetic focal stimulation through the scalp. The current elicited by the electromagnetic coil stimulates nerve cells in the region of the brain involved in mood regulation and depression. It can be administered in an office setting without the use of anesthesia. Patients may perceive it as less threatening than ECT.31 Patients having conductive, ferromagnetic, or other magnetic-sensitive metals in the head or within 30cm of the treatment coil should not undergo this procedure.25 Sessions are usually 40 minutes in length, administered daily (usually only weekdays) for 2 to 6 weeks. rTMS costs between $100 and $300 per session.31,32 Medicare does not cover rTMS, although some private insurance plans cover it under limited circumstances.

rTMS is usually considered a reasonable option for acute treatment of TRD as opposed to VNS and pharmacotherapy, which are predominantly used as long-term treatments for TRD.33 The FDA first approved this device in October 2008. The FDA states that rTMS is “indicated for the treatment of Major Depressive Disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.”34 Possible side effects with rTMS include mild headaches, syncope, and transient hearing changes.23 Although rTMS does pose a risk of seizure,35 it reportedly does not have the cognitive risks of ECT.23

Vagus Nerve Stimulation (VNS)

VNS involves surgically placed electrodes around the left vagus nerve. The VNS device consists of a round battery-powered generator that is implanted into the chest wall and attached to wires threaded along the vagus nerve. The therapy includes minor surgery, lasting approximately 30 to 60 minutes. Once implanted, the generator pulses the nerve for 30 seconds once every 5 minutes.36 The total duration of this intervention is generally 10 weeks, although the stimulation can be extended for longer intervals.24

VNS was first used in patients with epilepsy; it was also found simultaneously to improve mood.37 The FDA approved VNS for TRD in July 2005, with labeled indication for “adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.”38 The Centers for Medicare and Medicaid Services decided not to cover VNS in February 2007, citing lack of evidence.36 VNS devices cost approximately $10,000 to $20,000, not including the cost of surgery and hospital fees. Although the initial cost of VNS is very high, it may save money for TRD patients in the long run. One study reported long-term savings with VNS compared with usual TRD care, estimating savings of $2,974 and $23,539 per patient per year at 5 and 8 years of device life, respectively.39

The place in therapy for VNS may be for patients who have four or more adequate antidepressant treatment failures.40 Considerations also include a longer onset of antidepressant action than other treatments, as VNS benefits for TRD may not be fully realized for 6 to 12 months.41 Further, VNS poses surgical risks and is associated with several side effects such as voice alteration, cough, neck pain, paresthesia, and dyspnea.42

Cognitive Behavioral Therapy (CBT) or Interpersonal Psychotherapy (IPT)

Use of CBT began in the 1960s. It is a type of psychotherapy that aims to modify distorted, maladaptive, and depressogenic cognitions and related behavioral dysfunction.19 The therapist first introduces the patient to the cognitive model. Agendas, feedback, and psychoeducational procedures are used to structure sessions. To treat depressed patients with CBT, therapists emphasize negatively distorted thinking and deficits in learning and memory functioning.

Developed in the 1970s, IPT helps patients explore social and interpersonal issues that relate to depressive symptoms. Depressive symptoms identified are related to one of the four key problem areas: grief, disputes, transitions, and deficits.20 After selecting a focus area, later sessions help the patient develop strategies to deal with the problem.43

Both CBT and IPT have been studied extensively for depression, eating disorders, anxiety, and personality disorders, but understanding of their role in the treatment of TRD is more limited. Both therapies involve weekly sessions with the therapist, which last for 30 to 60 minutes. CBT may be carried out in a group setting if deemed beneficial for the patient. The therapy generally lasts from 3 to 4 months for acute phase treatment, although treatment duration may be for longer periods. Costs of CBT and IPT depend on the facility and the therapist; on average, these interventions cost around $150 per session. Medicare currently covers CBT and IPT. FDA approval is not required for CBT or IPT since they do not include drugs or devices.

CBT and IPT do not have any risks or side effects associated with them. Patients need to have normal cognitive functioning to comprehend the therapist's questions. CBT and IPT are comparable psychotherapies for major depression and appear to be as effective as antidepressant medication treatment,44-46 although CBT may be more effective in patients with severe depression.43

Pharmacologic Interventions

For many patients with TRD, the consideration of another pharmacologic intervention (whether a single agent or combination) remains the next decision step. To place the comparative effectiveness of nonpharmacologic treatments within the context of pharmacologic considerations, we also consider clinical outcomes for a next step pharmacologic treatment based on augmentation and combination medications commonly used in clinical practice.47 Given the limited evidence base addressing this topic for TRD, we only consider pharmacologic information for clinical outcomes during acute phase treatment for our main population of interest (see Key Question [KQ] 1b below).

Patient Populations Included

Treatment resistance defined by prior treatment failures. The primary focus of this review is on patients with MDD who have had two or more failed prior treatment attempts within the current episode. Definitions of TRD vary considerably and controversially, most often by the number of treatment failures (e.g., one failure, or one or more failures, or two or more failures), whether the treatment failures occur during the current episode, and whether treatment failures required different classes of antidepressants; no universally accepted definition of TRD currently exists.7,48-51 This variability is reflected in the differing operational definitions and selection criteria used for TRD trials. Nevertheless, a consensus appears to be forming around a definition of two or more treatment failures in the current episode.9,48 We view the most applicable evidence to be derived from patients with two or more failures of treatment attempts that are of adequate dose and duration during the current depressive episode. This population represents a group with known treatment resistance, and we believe these studies are most relevant to our KQs concerning efficacy, effectiveness, safety, and tolerability. However, given the evolving nature of the TRD definition, studies have often not clarified the number of failures within the current episode. Consequently, for the purposes of this report, we will define TRD as an episode of MDD that has not recovered following two or more adequate antidepressant medication treatments, regardless of the class of antidepressant used or whether the treatment failures were required to be in the current episode.

The variance of the TRD classification makes interpretation of the available data involving our interventions of interest challenging. Studies addressing TRD and these nonpharmacologic interventions are not always designed with the above specifications in mind. Rather, some studies focus more broadly on the efficacy and/or safety of the interventions in populations of patients with poorly specified characteristics with respect to treatment failures. In particular, they may require patients to have only one previous treatment failure rather than two, or they may be conducted in samples of patients for whom the investigators have not been completely clear about failures but still give enough information to regard the subjects as “probable” failures (e.g., patients referred for ECT). In such studies, baseline characteristics may provide data indicating that a subset of these patients have two or more treatment failures; however, it is often unclear what proportion of the sample would fit the TRD definition of two or more failures selected for this report. Although these study populations do not involve homogenous TRD populations, their samples likely include a substantial proportion of TRD patients, and hence can provide data relevant to TRD. Consequently, although we will focus on studies strictly meeting our TRD definition, we will secondarily consider how data from two other groups of studies—those requiring one or more treatment failures (which involve patients with only one treatment failure as well as those with TRD) and those with probable TRD—may enhance our results.

Treatment-resistant depression defined for two classes of mood disorder. Studies of treatment resistance often consider patients with bipolar disorder in addition to patients with MDD. Our primary focus is evidence about TRD in study patients who clearly have MDD and not any another mood disorder. However, clinical trials of TRD patients frequently allow a mixture of MDD and bipolar disorder in their samples. Given that depressive episodes in MDD may have a different prognosis than those in bipolar disorder,52 such a mixture may distort the true effect seen in MDD-only patients. At the same time, studies in which a small fraction of the patient population has bipolar disorder rather than purely MDD are still likely to produce some information on the main topic (i.e., MDD alone). We attempted to select a threshold that would allow inclusion of studies with a proportion of bipolar disease that would not change the likelihood of response. No evidence exists that indicates a proper threshold for such a mixture. After conferring with a Technical Expert Panel, we chose to include trials in our synthesis when the patient population as a whole consists of no more than 20 percent bipolar patients, assuming that such a mix would not substantially alter outcomes from what one would see with MDD alone. The type of bipolar diagnosis could include Type 1 (with manic episodes) or Type 2 (with hypomanic episodes).

Scope and Key Questions (KQs)

This review compares the efficacy, effectiveness, and harms of nonpharmacologic interventions for TRD in adults. To that end, we address the following six KQs. “Trials” in these KQs refers to treatment attempts, not experimental studies.

  • KQ 1a. For adults with treatment-resistant depression (TRD, defined as two or more failed adequate trials of a biologic1 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)?

Organization of the Report

The remainder of this report describes our methods, presents the results of our synthesis of the literature, discusses our conclusions, and provides other information relevant to the interpretation of this work. The Methods chapter describes our scientific approach for this comparative effectiveness review in detail. The Results chapter presents our findings for all the KQs and subquestions; it includes summary tables as well. In the Discussion chapter, we summarize the findings, present the strength of evidence for critical comparisons or outcomes, and discuss the implications for practice and further research. A complete list of references is located immediately following the discussion chapter.

This report also contains the following appendices. Appendix A contains the exact search strings we used in our literature searches. Appendix B documents all the data abstraction forms and our quality rating criteria. Our excluded studies with reasons for exclusion are presented in Appendix C. Evidence tables appear in Appendix D. Appendix E is our table of scales used for measuring neurocognitive and other adverse effects. Appendix F lists our poor-quality studies and reasons for exclusion from relevant KQ analyses. Appendix G lists all sources from which we identified all of the studies for this review. Finally, Appendix H provides a listing of studies recommended for inclusion by peer and public reviewers of the prior draft version of the report. It is added here to help current readers of this report understand why well-known studies did not meet the inclusion criteria for this comparative effectiveness review.

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