1. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  Introduction to treatment-resistant depression (TRD).  Nonpharmacologic interventions for major depressive disorder and TRD, and which treatments are approved by the U.S. Food and Drug Administration (FDA) for TRD.  Systematic review methods.  The clinical questions addressed by the comparative effectiveness review (CER).  Results of studies and evidence-based conclusions about the effectiveness and harms of TRD treatments.  Gaps in knowledge and future research needs.  What to discuss with patients and their caregivers. Outline of Material

3.  Among patients who receive appropriate treatment for major depressive disorder (MDD), about 50% will not adequately respond.  Definitions of TRD have varied over time. For the purpose of this report, patients who do not respond to at least two adequate antidepressant trials are considered to have TRD.  Patients with TRD are significantly less likely to respond to subsequent medications and thus may require nonpharmacologic treatment. Background: Treatment-Resistant Depression Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

4.  Nonpharmacologic interventions for TRD include:  Psychotherapy (cognitive behavioral therapy [CBT] or interpersonal therapy [IPT]).  Electroconvulsive therapy (ECT).  Repetitive transcranial magnetic stimulation (rTMS)  Vagus nerve stimulation (VNS).  Use of rTMS as a treatment for TRD as defined in the report is not approved by the FDA, though off-label use has been studied in patients with this condition. Background: Nonpharmacologic Interventions Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

5. Background: Psychotherapies (CBT and IPT) DescriptionPsychotherapy to identify negative depressogenic cognitions or interpersonal behaviors Average durationWeekly sessions for 3 to 4 months AvailabilityWidely available Adverse effectsNo associated serious risks or adverse effects are commonly reported ContraindicationsShould not be used in patients with cognitive disorders Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm. Feldman G. Psychiatr Clin North Am 2007 Mar;30(1):39-50. PMID: 17362802. Schramm E, van Calker D, Dykierek P, et al. Am J Psychiatry 2007 May;164(5):768-77. PMID: 17475736.

6. Background: Electroconvulsive Therapy Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm. Lisanby SH. N Engl J Med 2007 Nov 8;357(19):1939-45. PMID: 17989386. Shapira B, Tubi N, Lerer B. J Ect 2000 Jun;16(2):97-109. PMID: 10868320. DescriptionPassing an electric current through the brain after administering anesthetic and muscle relaxants to produce a convulsion Common placement sites Bifrontal/bilateral or unilateral electrode placement Average durationAdministered 2 or 3 times a week for 3 to 4 weeks Usual dosageMillicoulombs of charge FDA approval for TRD Yes AvailabilityWidely available throughout the United States

7. Background: Repetitive Transcranial Magnetic Stimulation DescriptionFocal magnetic stimulation through the scalp without the use of anesthesia Common placement sites Dorsolateral prefrontal cortex Average duration40 minutes daily (usually weekdays) for 2 to 6 weeks Usual dosage<1–20 Hertz FDA approval for TRD No AvailabilityAccess is currently more limited for rTMS than for ECT, but availability is improving Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm. Fitzgerald PB, Benitez J, de Castella A, et al. Am J Psychiatry 2006 Jan;163(1):88-94. PMID: 16390894. Rossi S, Hallett M, Rossini PM, et al. Clin Neurophysiol 2009 Dec;120(12):2008-39. PMID: 19833552.

8. Background: Vagus Nerve Stimulation (VNS) DescriptionSurgically placed electrodes around the left vagus nerve to modulate mood and control seizures Common placement sites Left vagus nerve Average duration30 seconds every 5 minutes, generally for 10 weeks Usual dosageCurrent: >1 milliamperes; Frequency: 1–145 Hertz FDA approval for TRD Yes AvailabilityCurrently very limited Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm. Daban C, Martinez-Aran A, Cruz N, et al. J Affect Disord 2008 Sep;110(1-2):1-15. PMID: 18374988.

9. Background: Commonly Reported Adverse Effects and Contraindications Treatment Common adverse effects or contraindications ECTPotential risks: seizure, adverse cognitive effects, and anesthesia-related complications. Increased risk of complications in patients with unstable cardiac disease, ischemia, arrhythmias, hemorrhage, or increased intracranial pressure. rTMSPotential adverse effects: mild headache, scalp pain, syncope, and transient hearing changes. Should not be used in patients with a high risk of seizure or who have metal objects anywhere in the body except the mouth. VNSPotential adverse effects: voice alteration, cough, neck pain, paresthesia, and dyspnea. Should not be used in patients with bilateral or left cervical vagotomy. Patients with implants should not receive shortwave, microwave, or ultrasound diathermy. Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm. Lisanby SH. N Engl J Med 2007 Nov 8;357(19):1939-45. PMID: 17989386. Neuronetics. NeuroStar TMS System TM User Manual. 2006. Available at: http://www.fda.gov/ohrms/DOCKETS/ac/07/briefing/2007-4273b1_15-NeuroStarUserManualRevision.pdf

10. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issues. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients.

11.  KQ 1a. For adults with TRD, do nonpharmacologic interventions 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?  Operational definition of TRD = two or more failed adequate trials of a biologic intervention.  Nonpharmacologic interventions include ECT, rTMS, VNS, and psychotherapy demonstrated to be effective. Clinical Questions Addressed by the CER (1 of 4) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

12.  KQ 1b. How do these nonpharmacologic treatments compare with pharmacologic 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, whether as a single treatment or part of a combination treatment? Clinical Questions Addressed by the CER (2 of 4) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

13.  KQ 3. Do nonpharmacologic interventions (single or combination) differ in their efficacy or effectiveness for treating TRD as a function of particular symptom subtypes?  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. Clinical Questions Addressed by the CER (3 of 4) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

14.  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?  Patients with medical comorbidities?  KQ 6. For adults with TRD, do nonpharmacologic interventions differ in regard to other health-related outcomes? Clinical Questions Addressed by the CER (4 of 4) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

15.  Depression severity  Response rates  Remission rates  Maintenance of remission  Cognitive functioning (improvements and deleterious effects)  Adverse events  Withdrawals (overall and those due to adverse events)  Health-related outcomes (e.g., health status and daily functioning) Outcomes Evaluated by the CER Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

16. Comparisons Reported by the CER  The CER sought to evaluate all potential comparisons between the relevant interventions, but the available literature only allowed an assessment of some of these comparisons:  ECT vs. sham treatment  rTMS vs. sham treatment  VNS vs. sham treatment  Psychotherapy vs. control  CBT vs. usual care  ECT vs. rTMS  ECT + rTMS vs. ECT  ECT vs. pharmacotherapy  Psychotherapy vs. pharmacotherapy Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

17.  Studies considered applicable to TRD included the following patient populations:  Adults only  Patients with an episode of MDD who had not recovered after two or more adequate antidepressant medication treatments  Mixed populations, including studies in which up to 20% of patients had bipolar disorder rather than MDD  Evaluated studies included both randomized controlled trials and observational studies. Comparative Effectiveness Review Study Criteria Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

18.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the CER HighFurther research is very unlikely to change the confidence in the estimate of effect. ModerateFurther research may change the confidence in the estimate of effect and may change the estimate. LowFurther research is likely to change the confidence in the estimate of effect and is likely to change the estimate. InsufficientEvidence either is unavailable or does not permit estimation of an effect. Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

19.  Benefits:  When compared with paroxetine, ECT produced a greater improvement in depression severity and treatment response. Strength of Evidence = Low  No other studies evaluating other pharmacotherapies were included in the systematic review.  Harms:  The adverse event rates of ECT versus pharmacotherapy were not compared in studies. Findings of the Comparative Effectiveness Review: ECT Versus Pharmacotherapy Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

20.  Benefits:  rTMS does not clearly differ from ECT. Strength of Evidence = Low  Harms:  ECT and rTMS may not differ in withdrawals due to adverse events, but overall withdrawal rates were lower with rTMS. Strength of Evidence = Low  Evidence is insufficient to evaluate ECT versus rTMS with respect to adverse events and effects on cognitive/daily functioning.  Treatment interventions combining ECT with rTMS do not clearly differ from treatment with ECT alone. Strength of Evidence = Low Findings of the Comparative Effectiveness Review: rTMS ± ECT Versus ECT Alone Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

21.  Benefits: VNS does not clearly differ from sham treatment with respect to improvements in depression severity, response rates, or daily functioning. Strength of Evidence = Low  Harms: VNS may produce increased rates of some specific adverse effects and may result in a greater number of withdrawals attributed to adverse events (vs. sham treatment). Strength of Evidence = Low Findings of the Comparative Effectiveness Review: VNS Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at http://www.effectivehealthcare.ahrq.gov/trd.cfm.

22.  Benefits: When compared to sham treatment, rTMS:  Produced a greater decrease in depression severity. Strength of Evidence = High  Was three times as likely to produce a response. Strength of Evidence = High  Was six times as likely to achieve remission. Strength of Evidence = Moderate  Produced a greater improvement in health status and daily functioning. Strength of Evidence = Low  Evidence is insufficient to evaluate the ability of rTMS to maintain response or remission. Findings of the Comparative Effectiveness Review: rTMS (1 of 3) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

23.  Benefits: When compared to sham treatment, rTMS:  Produced better outcomes for depression severity and response rates for young adults. Strength of Evidence = Low  Produced better outcomes for depression severity in older adults with poststroke depression. Strength of Evidence = Low Findings of the Comparative Effectiveness Review: rTMS (2 of 3) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

24.  Harms:  rTMS produces more scalp pain at the stimulation site than sham treatment. Strength of Evidence = Low  Evidence is insufficient to permit conclusions about withdrawals because of adverse events or because of patient nonadherence to rTMS versus sham treatment. Findings of the Comparative Effectiveness Review: rTMS (3 of 3) Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

25.  Evidence is insufficient to evaluate the comparative effectiveness or adverse effects between the following comparators:  ECT versus sham treatment  rTMS + pharmacotherapy versus pharmacotherapy alone or sham treatment  Psychotherapy versus control treatment or pharmacotherapy Findings of the Comparative Effectiveness Review: Insufficient Evidence Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

26.  Comparative outcomes for ECT and rTMS are similar, with no synergistic effect derived from combining these therapies.  Regarding efficacy, indirect evidence suggests that rTMS is effective in response and remission over sham treatment.  The effectiveness of ECT was not addressed in the review.  No benefit was seen for VNS over sham treatment.  Evidence regarding adverse effects is limited. Conclusions Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.

27. Knowledge Gaps and Future Research Needs Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.  Information about health-related outcomes that concern quality of life or levels of functional impairment is sparse.  Few studies compare nonpharmacologic interventions with each other or with pharmacologic interventions.  Evidence is lacking about efficacy in subgroups defined by sociodemographic characteristics or by coexisting medical conditions.  Study shortcomings:  Inconsistent definitions of TRD  Inconsistent reporting of measured outcomes  Short followup periods  Limited, short-term, variable, and inconsistent adverse event reporting

28.  The definition of TRD and why it may need different forms of treatment  The potential benefits and adverse events associated with nonpharmacologic treatment options  The patient’s values and preferences regarding the trade- offs between the benefits and harms of the various treatment options  The availability of nonpharmacologic treatment options What To Discuss With Your Patients Gaynes BN, Lux L, Lloyd S, et al. AHRQ Comparative Effectiveness Review No. 33. September 2011. Available at www.effectivehealthcare.ahrq.gov/trd.cfm.