Treatment-resistant Depression, Study notes of Psychiatry

Download Treatment-resistant Depression and more Study notes Psychiatry in PDF only on Docsity! Scheduled presentations March 21, 2014 19-Mar-14 Order of Scheduled Presentations TOPIC: Treatment-resistant Depression Name Notes 1. John Neumaier, MD, PhD No slides. 2. Anna Borisovskaya, MD No slides. 3. Farrokh Farrokhi, MD Vice President, WA State Association of Neurological Surgeons 4. Mercy Yule, EAMP Health Technology Assessment Participant_disclosure Page 2 of 2 Disclosure Any unmarked topic will be considered a “Yes” Potential Conflict Type Yes No 1. Salary or payments such as consulting fees or honoraria in excess of $10,000. 2. Equity interests such as stocks, stock options or other ownership interests. 3. Status or position as an officer, board member, trustee, owner. 4. Loan or intellectual property rights. 5. Research funding. 6. Any other relationship, including travel arrangements. If yes, list name of organizations that relationship(s) are with and for #6, describe other relationship: _________________________________________________________________________________ _________________________________________________________________________________ ________________________________________________________________________________________ Potential Conflict Type Yes No 7. Representation: if representing a person or organization, include the name and funding sources (e.g. member dues, governmental/taxes, commercial products or services, grants from industry or government). If yes to #7, provide name and funding Sources: _________________________________________________ _________________________________________________________________________________ ________________________________________________________________________________________ ________________________________________________________________________________________ If you believe that you do not have a conflict but are concerned that it may appear that you do, you may attach additional sheets explaining why you believe that you should not be excluded. I certify that I have read and understand this Conflict of Interest Form and that the information I have provided is true, complete, and correct as of this date. X Signature Date Print Name For questions contact: Christine Masters Health Technology Assessment PO Box 42712 Olympia, WA 98504-2712 360-725-5126 x x x x x x x I am a faculty member of the University of Washington Department of Psychiatry but I am presenting my own professional opinions and am not representing the department, hospital or University formally but am stating this for clarity sake. John F Neumaier, MD, PhDFeb 20, 2014 Farrokh Farrokhi, M.D. March 21, 2014 WA ‐ Health Technology Clinical Committee 1 Comments on Deep Brain Stimulation for Treatment Resistant Depression Farrokh Farrokhi, MD Neurosurgery - Virginia Mason Vice President - Washington State Association of Neurological Surgeons March 21, 2014 Request on behalf of WSANS/AANS/CNS to: Defer decision of DBS for TRD Due to insufficient evidenced HTA Analysis: “The evidence was insufficient to allow conclusions.” “A single uncontrolled study evaluated certain response predictors.” “No controlled studies have been published.” “DBS can result in serious complications.” “narrative review article provided an estimate that hemorrhage can occur in up to 10% of patients (regardless of indication).” Farrokh Farrokhi, M.D. March 21, 2014 WA ‐ Health Technology Clinical Committee 2 Toronto: Continued Proof-of-Principle Testing Unblinded, safety and efficacy testing of chronic stimulation 0 5 10 15 20 25 Base 1 2 3 4 5 6 7 8 9 10 11 12 To ta l H AM -D 1 7 Sc or e All time points p < 0.001 Months Post-DBS Resp=60%; Resp=55% months after implant 20 patients: 1 Year Follow-up avg=42 mo Long Term f/u: 3-6 yrs, n=14 IT OC Resp 62.5% 46.2% 75% 64% Rem 18.8% 15.4% 50% 42% years after implant 2008 2011 Emory Studies: Replication, Extension Entry Criteria Funding: Dana, Stanley, Woodruff Found’n , Emory Hosp Devices donated by St. Jude Medical , IDE: G060028/S002 10UP/7BP2; 10W/7M; age 42+9, MDE 5.3+4y Meds stable, 1 mo placebo, 6 mo open DBS First patient Jan 12, 2007 • time course, remission rate, similar to Toronto • modest sham effect; carryover from OR? • Continued improvement over time • if Remitter, no spont relapses, more resilient? Spain n=8 62% 1 yr SJM pilot n=21 48% 6 mo (3 centers) case reports (Argentina, GR, Calgary) b a se lin e sh a m 4 w ee ks 2 4 w e e ks 1 ye a r 2 ye a rs 0 6 1 2 1 8 2 4 H D R S Baseline sham 4 wks 24 wks 1 yr 2 yrs BP2 MDD Subgroups BP=MDD at all time point No induced mania/hypomania BL sh 1m 2 3 4 5 6 7 8 9 10 11 12 2y 24 18 12 6 0 ALL pts HDRS No change in meds for 6 months Response  Remission 6 mo        42%         18% 1 yr         36%         36% 2 yr          65%         58% Last f/u: 12/14 (80%R) T0=Jan07 3 explanted, 11 new cohort Farrokh Farrokhi, M.D. March 21, 2014 WA ‐ Health Technology Clinical Committee 3 One Source of Response Variability surgical precision Standardized to AC-PC mean MNI space Resp Non-R ACC th nAc mF10 mF nAc6m NR N=9 6m R N=6 mF10 ACC TAM-seed Probablistic Tractography mF nAc Th aTh nAc L ACCmF10Overlap ath nAc Voltage Field Modeling (TAM) Butson & McIntyre Brain Stim 2008 Location of Active Contacts Simple Localization is not adequate even when done ideally Need individual tract maps to ensure full coverage of critical White matter bundles for each patient. TO: Christine Masters FROM: Mercy Yule, EAMP DATE: 28 Feb 2014 RE: Participant disclosure for presentation March 21, 2014 | believe that | do not have any conflict of interest. However, | currently am a member of, and do committee work with the Washington East Asian Medicine Association, a professional group of which | was formerly president, to promote understanding of and access to acupuncture and East Asian Medicine services. Nes (16 fade Mercy Yule, EAMP 28 Feb 2014 Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 1 Mercy Yule, EAMP Acupuncture has a record of safety with few serious adverse events. Better research studies on acupuncture for many conditions are becoming available. Although more research is needed specifically on the population with conditions that resist current treatments, research shows that acupuncture is safe and effective for treatment of Major Depressive Disorder. Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 2 Roschke, J., et al (2000). The benefit from whole body acupuncture in major depressive disorder. Journal of Affective Disorders. 57: 73-81 Qu, Shan-shan, et al (2013). A 6-week randomized controlled trial with a 4-week follow-up of acupuncture combined with paroxetine in patients with major depressive disorder. Journal of Psychiatric Research. 47: 726-732 Song, C., Halbreich, U., Leonard, B., Luo, H. (2009). Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: The effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry. 42: 182-188 Zhang, Z., et al (2010) The effectiveness and safety of acupuncture therapy in depressive disorders: Systematic review and meta- analysis. Journal of Affective Disorders. 124 : 9-21 Single-blind placebo controlled study of 70 inpatients with major depressive disorder divided into three groups: Specific standardized acupuncture points Non-specific acupuncture points Pharmacological management Treatments were given for a period of 4 weeks Patients were evaluated 2 times a week for 8 weeks by judges who were blinded to the treatment. Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 5 Conclusion: “ Acupuncture did improve the course of depression more than pharmacological treatment…” Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 6 An RCT with 160 patients diagnosed with MDD assigned to one of three groups: Paroxetine alone Paroxetine combined with acupuncture Paroxetine combined with electroacupuncture This was a 6 week trial with a 4 week follow up, using the Hamilton Depression Rating Scale (HAMD-17), the Self-rating Depression Scale (SDS), and clinical evaluation (CGI-S). Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 7 Conclusion “Collectively, as most antidepressant agents have broad side effects, acupuncture in manual and electrical stimulation modes provides a safe and effective treatment in augmenting the antidepressant efficacy…” Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 10 Meta-analysis of 207 studies on acupuncture for depression; 133 were on MDD, 15 on PSD (Post-stroke depression).20 of the RCT’s on MDD were considered high quality according to JADAD scale. Mercy Yule, EAMP March 21, 2014 WA‐ Health Technology Clinical Committee 11 Conclusion: “The efficacy of acupuncture as a monotherapy was comparable to antidepressants alone in improving clinical response and alleviating symptom severity of MDD…” Although the nature of the present review is to consider specific non- pharmacological therapies for treatment resistant Major Depressive Disorder, acupuncture might also be considered. Acupuncture can treat MDD when used alone, and can reduce the medication burden when used in conjunction with pharmaceutical therapy. February, 2014 CURRICULUM VITAE DAVID HARTFORD AVERY PERSONAL DATA: Date of Birth: May 31, 1946 Birthplace: Gary, Indiana CURRENT ADDRESS: Psychiatric Medicine Associates 1505 Westlake Ave N. Suite 920 Seattle, WA 98109 EDUCATION: Wabash College, Crawfordsville, Indiana B.A., Religion, Chemistry, May 1968 Washington University School of Medicine, St. Louis, Missouri M.D., Medicine, May 1972 POST GRADUATE TRAINING: 7/1972-6/1973 Internship (Internal Medicine), University of Iowa Hospital, Iowa City, Iowa 7/1973-6/1976 Residency in Psychiatry, University of Iowa Hospital, Iowa City, Iowa 8/1976-7/1977 Fellowship in Psychopharmacology with Dr. Leo Hollister at the Palo Alto VA Hospital 8/1977-12/1977 Post-Doctoral Scholar in Psychiatry, Stanford University School of Medicine 1/1978-1/1980 NIMH Post-Doctoral Fellow with Dr. Ole Rafaelsen at the Psychochemistry Institute, University of Copenhagen, Copenhagen, Denmark FACULTY POSITIONS HELD: 4/1980-6/1984 Assistant Professor of Psychiatry, University of Washington School of Medicine, Seattle, WA 7/1984-6/1999 Associate Professor, University of Washington School of Medicine, Seattle, WA 7/1999-9/2012 Professor, University of Washington School of Medicine 10/2012- Present Professor Emeritus, University of Washington School of Medicine David H. Avery, M.D. Curriculum Vitae February, 2014 Page 2 HOSPITAL POSITIONS HELD: 4/1980-present Attending Psychiatrist, Harborview Medical Center 7/1982-6/1987 Director of Inpatient Psychiatry, Harborview Medical Center 7/1993-2/2011 Director of Inpatient Psychiatry, Harborview Medical Center CURRENT AFFLIATION: Psychiatric Medicine Associates Medical Staff, Swedish Medical Center HONORS: Phi Beta Kappa; Summa Cum Laude, American Psychiatric Association Distinguished Fellow BOARD CERTIFICATIONS: National Board of Medical Examiners, Parts I, II, III, 1973 American Board of Psychiatry and Neurology, January, 1981 CURRENT LICENSE: State of Washington - #025209 MD00018099 PROFESSIONAL ORGANIZATIONS: 1977-1985 Collegium Internationale Neuro-Psychopharmacologicum 1981-1987 American Psychopathological Association 1981-2011 Society of Biological Psychiatry George M. Thompson Award Committee Member, 1995-97 1983-present American Psychiatric Association 1984-2001 West Coast College of Biological Psychiatry, (President, 1992-1993) 1989-1995 Sleep Research Society 1989-1999 Society for Light Treatment and Biological Rhythms, (Chair, DSM-IV Committee, 1990; Chair, Publications Committee, 1996- 98.) (Chair, Federal Industrial Relations Committee, 1992-98); Board Member, 1995-1998 1997-present International Society for Transcranial Simulation (ISTS), now renamed The International Society for ECT and Neurostimulation. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 3 TEACHING RESPONSIBILITIES: Course 665 (Third Year Medical Student Psychiatry Clinical Clerkship) over the past 30 years. Supervision of second year medical students in Human Biology 560 (1981-1985). Lectures to Residents in their R-1, R-2, and R-3 years. I have been in charge of the Mood Disorders Module of the R-2 Residents since 2005. Mentor for 8 medical students in their research projects. Mentor of two Ph.D. graduate students in physiological psychology. Mentor for three Senior Fellows for training in transcranial magnetic stimulation. EDITORIAL RESPONSIBILITIES: Editorial Advisory Board for Clinical Advances in the Treatment of Psychiatric Disorders. JOURNAL REFEREE: Acta Psychiatric Scandinavica American Journal of Physiology American Journal of Psychiatry Archives of General Psychiatry Biological Psychiatry Bipolar Disorders Chronobiology International Comprehensive Psychiatry Convulsive Therapy General Hospital Psychiatry International Journal of Neuropsychopharmacology Journal of Alternative and Complementary Medicine Journal of Abnormal Psychology Journal of Affective Disorders Journal of Clinical Psychiatry Journal of ECT Journal of Nervous and Mental Disease Journal of Psychiatric Research Journal of Psychosomatic Research Journal of Sleep Research Neuropsychopharmacology Progress in Neuro-Psychopharmacology and Biological Psychiatry Psychiatry Research Psychosomatic Medicine Sleep Women’s Health in Primary Care David H. Avery, M.D. Curriculum Vitae February, 2014 Page 6 BIBLIOGRAPHY: Original Investigations: 1. Noyes, R., Brunk, S.F., Avery, D.H., and Cantor, A.: The analgesic properties of delta-9 tetrahydrocannabinol and codeine. Clin.Pharmocol. Therapy 18(1):84, 1975. 2. Noyes, R., Jr., Brunk, S.F., Avery, D.H., and Cantor, A.: Psychological effects of oral delta-9-tetrahydrocannabinol in advanced cancer patients. Comprehensive Psychiatry 17:641-646, 1976. 3. Avery, D.H. and Winokur, G.: Mortality in depressed patients treated with electro- convulsive therapy and antidepressants. Arch. Gen. Psych. 33:1029-37, 1976. 4. Avery, D.H. and Finn, R.: Succinylcholine-prolonged apnea associated with clindamycin and abnormal liver function tests. Dis. Nerv. Syst. 38(6):473-475, 1977. 5. Avery, D.H. and Winokur, G.: The efficacy of electroconvulsive therapy and antidepressants in depression. Biol. Psychiatry 12(4):507-21, 1977. 6. Avery, D.H. and Winokur, G.: Suicide, attempted suicide, and relapse rates in depression following ECT and antidepressant therapy. Arch. Gen. Psych. 35:749-753, 1978. 7. Avery, D.H. and Lubrano, A.: Depression treated with imipramine and ECT: The decarolis study reconsidered. Am. J. Psych. 136(4B):559-562, 1979. 8. Calil, H.M., Avery, D.H., Hollister, L.E., Creese, L., and Snyder, S.H.: Serum levels of neuroleptics measured by dopamine radio-receptor assay and some clinical observations. Psychiatry Research 1:39-44, 1979. 9. Dealy, R.S., Ishiki, D.M., Avery, D.H., Wilson, L.G., and Dunner, D.L.: Secondary depression in anxiety disorders. Comp. Psych. 22:612-618, 1981. 10. Avery, D.H., Wildschiodtz, G., and Rafaelsen, O.J.: REM latency and temperature in affective disorder before and after treatment. Biol. Psychiatry 17(4):463-470, 982. 11. Avery, D.H., Wildschiodtz, G., and Rafaelsen, O.J.: Nocturnal temperature in affective disorder. J. Affect. Dis. 4:61-71, 1982. 12. Avery, D.H., Overall, J.E., Calil, H.M., and Hollister, L.E.: Alcohol-induced euphoria: alcoholics compared to non-alcoholics. International J. Addictions 17(5): 823 845, 1982. 13. Avery, D.H., Overall, J., Calil, H., and Hollister, L.E.: Plasma calcium phosphate during alcohol intoxication: alcoholics compared to nonalcoholics. J. Studies on Alcohol 44(2):205-214, 1983. 14. Avery, D.H. and Silverman, J.: Psychomotor retardation and agitation in depression: relationship to age, sex, and response to treatment. J. Affect. Dis. 7:67-76, 1984. 15. Avery, D.H., et al: Dexamethasone suppression test in psychiatric outpatients with generalized anxiety disorder, panic disorder, and primary affective disorder. Am. J Psych. l42(7):844-848, l985. 16. Vitiello, M.V., Smallwood, R.G., Avery, D.H., Pascualy, R.A., Martin, D.C. and Prinz, P.N.: Circadian temperature rhythms in young adult and aged men. Neurobiology of Aging 7:97-l00, l986. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 7 BIBLIOGRAPHY: (Continued) Original Investigations: (continued) l7. Khan, A., Lee, E., Dager, S., Hyde, T., Raisys, Avery, D.H. and Dunner, D.L.: Platelet MAO-B activity in anxiety and depression. Biol. Psychiatry 2l:847-848, l986. l8. Dunner, D.L., Ishiki, D., Avery, D.H., Wilson, L.G. and Hyde, T.S.: Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: A Controlled study. J. Clin. Psych. 47:458-460, l986. 19. Avery, D.H., Wildschiodtz, G., Smallwood, R.G., Martin, D., Rafaelsen, O.J.: REM latency and core temperature relationships in primary depression. Acta Psychiatrica Scandinavica 74:269-80, 1986. 20. Dwersteg, J.F. and Avery, D.H.: Electroconvulsive therapy in a patient post burn. Convulsive Therapy 3(1):49-53, 1987 21. Khan, A., Cohen, S., Stowell, M., Capwell, R., Avery, D.H., Dunner, D.L.: Treatment options in severe psychotic depression. Convulsive Therapy 3(2):93-99, 1987. 22. Dunner, D., Myers, J., Khan, A., Avery, D.H., Ishiki, D., Pyke, R.,: Adinazolam-a new antidepressant: findings of a placebo-controlled, double-blind study in outpatients with major depression. J. Clin. Psychopharmacol 7(3):170-172, 1987. 23. Solan, W.J., Khan, A., Avery, D.H. and Cohen, S.: Psychotic and non-psychotic depression: comparison of response to ECT. J. Clin. Psych. 49:97-99, 1988. 24. Khan, A., Johnson, F., Avery, D.H., Cohen, S., Scherzo, B., Dunner, D.L.: DST in nonpsychotic depressed outpatients. Am. J. Psych. 145(9):1153-1156, 1988. 25. Khan, A., Cohen, S., Dager, S.R., Avery, D.H., and Dunner, D.L.: Onset of response in relation to outcome in depressed outpatients with placebo and imipramine. J. Affect dis. 17:33-38, 1989. 26. Viteillo, M.V., Prinz, P.N., Avery, D.H., Williams, D.E., Ries, R.K., Bokan, J.A., and Khan, A.: Sleep is undisturbed in elderly, depressed individuals who have not sought health care. Biol. Psychiatry 27:431-440, 1990. 27. Avery, D.H., Khan, A., Dager, S.R., Cox, G.B., Dunner, D.L.: Bright light treatment of winter depression: AM compared to PM light. Acta Psychiatrica Scandinavica 82:335-338, 1990. 28. Avery, D.H., Khan, A. Dager, S.R., Cohen, S., Cox, G.B. and Dunner, D.L.: Is morning light superior to evening light in treating seasonal affective disorder? Psychopharmacology Bulletin 26:521-524, 1990. 29. Dager, S.R., Khan, A., Cowley, D., Avery, D.H., Elder, J., Roy-Byrne, P.P. and Dunner, D.L.: Characteristics of placebo responses during long-term treatment of panic disorder. Psychopharmacology Bulletin 26(3):273-278, 1990. 30. Avery, D.H., Khan, A., Dager, S.R., Cohen, S., Cox, G.B., and Dunner, D.L.: AM or PM bright light treatment of winter depression? The significance of hypersomnia. Biol. Psychiatry 29:117-126, 1991. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 8 BIBLIOGRAPHY: (Continued) Original Investigations: (continued) 31. Khan, A., Dager, S.R., Cohen, S., Avery, D.H., Scherzo, B., and Dunner, D.L.: Chronicity of depressive episode in relation to antidepressant-placebo response. Neuropsychopharmacology 4(21):125-139, 1991. 32. Ward, N., Whitney, C., Avery D.H. and Dunner, D.L.: The analgesic effects of caffeine in headache. Pain 44:151-155, 1991. 33. Cowley, D.S., Dager, S.R., Roy-Byrne, P.P., Avery, D.H. and Dunner, D.L.: Lactate vulnerability after alprazolam versus placebo treatment of panic disorder. Biol. Psychiatry 30:49-56, 1991. 34. Avery, D.H., Bolte, M.A., Millet, M.: Bright dawn simulation compared with bright morning light in the treatment of winter depression. Acta Psychiatrica Scandinavica 85:430-434, 1992 35. Avery, D.H., Bolte, M.A., Cohen, S., Millet, M.: Dawn simulation treatment of winter depression: Gradual versus rapid dawn. Journal of Clinical Psychiatry 53:359- 1363,1992. 36. Dager, SR, Roy-Byrne P, Hendrickson H, Cowley DS, Avery DH, Hall KC and Dunner DL: Long-Term outcome of panic states during double-blind treatment and after withdrawal of alprazolam and placebo. Annals of Clin Psychiatry 4:251-258, 1992. 37. Avery, D.H., Bolte, M.A., Dager, S.R., Wilson, L.G., Weyer, M., Cox G.B., Dunner, D.L.: Dawn simulation treatment of winter depression: A controlled study. Am J Psychiatry 150:113-117, 1993. 38. Bolte, M.A., Avery, D.H.: Case of fluoxetine-induced remission of Raynaud's phenomenon. Angiology 44(2):161-162, 1993. 39. Elmore, S.K., Dahl, K., Avery, D.H., Savage, M., Brengelmann, G.L.: Body temperature and diurnal type in women with Seasonal Affective Disorder. Health Care for Women International 14(1):17-26, 1993. 40. Dahl, K., Avery, D.H., Lewy, A.J., Savage, M., Brengelmann, G., Larsen, L., Vitiello, M.V., Prinz, P.N.: Dim light melatonin onset and circadian temperature during a constant routine in hypersomnic winter depression. Acta Psychiatrica Scandinavica 88:60-66, 1993. 41. Norden, M.M., Avery, D.H.: A controlled study of dawn simulation in subsyndromal winter depression. Acta Psychiatrica Scandinavica 88: 67-71, 1993 42. Avery, D.H., Bolte, M.A., Wolfson, J.K., Kazaras, A.L.: Dawn simulation compared with a dim red signal in the treatment of winter depression. Biological Psychiatry 36:181-188, 1994. 43. Brengelmann GL, Savage MV, Avery DH: Reproducibility of core temperature threshold for sweating onset in humans. Journal of Applied Physiology 77:1671-7, 1994. 44. Maiuro, R.D., Avery, D.H. Psychopharmacological treatment of aggressive behavior: Implications for domestically violent men. Violence and Victims 11(3):239-261, 1996. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 11 75. Anderson BS, Kavanagh K, Borckardt JJ, Nahas ZH, Kose S, Lisanby SH, McDonald WM, Avery D, Sackeim HA, George MS. Decreasing Procedural Pain Over Time of Left Prefrontal rTMS for Depression: Initial Results from the Open-Label Phase of a Multi-site Trial (OPT-TMS). Brain Stimulat. 2009 Apr 1;2(2):88-92. 76. Zarkowski P, Navarro R, Pavlicova M, George MS, Avery D. The Effect of Daily Prefrontal Repetitive Transcranial Magnetic Stimulation Over Several Weeks on Resting Motor Threshold. Brain Stimulat. 2009 Jul 1;2(3):163-167. 77. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer P, Schwartz T, Sackeim HA Daily Left Prefrontal TMS For Major Depression: A Sham-Controlled Multi- site Randomized Trial (NIH Optimization of TMS for Depression Study, OPT-TMS) Archives of General Psychiatry 67(5):507-516,2010. 78. Polley KH, Navarro R, Avery DH, George MS, Holtzheimer PE. 2010 Updated Avery- George-Holtzheimer Database of rTMS Depression Studies. Brain Stimul. 2011 Apr;4(2):115-6. (http://www.brainstimjrnl.com/content/mmc_library). 79. Edwardson M, Fetz E, Avery DH: Seizure produced by 20Hz transcranial magnetic stimulation during isometric muscle contraction in a healthy subject. Clinical Neurophysiology 2011 Nov;122(11):2326-7 80. McDonald WM, Durkalski V, Ball ER, Holtzheimer PE, Pavlicova M, Lisanby SH, Avery D, Anderson BS, Nahas Z, Zarkowski P, Sackeim HA, George MS Improving the antidepressant efficacy of transcranial magnetic stimulation: maximizing the number of stimulations and treatment location in treatment-resistant depression. Depress Anxiety. 2011 Nov;28(11):973-80. 81. Johnson KA, Baig M, Ramsey D, Lisanby SH, Avery D, McDonald WM, Li X, Bernhardt ER, Haynor DR, Holtzheimer PE 3rd, Sackeim HA, George MS, Nahas Z. Prefrontal rTMS for treating depression: Location and intensity results from the OPT-TMS multi-site clinical trial. Brain Stimul. 2012 Mar 14. [Epub ahead of print] 82. Mantovani A, Pavlicova M, Avery D, Nahas Z, McDonald WM,. Wajdik CD, Holtzheimer III PE, George MS, Sackeim HA, Lisanby SH, Long-term efficacy of transcranial magnetic stimulation in treatment-resistant depression. Depress Anxiety. 2012 Oct;29(10):883-90. 83. Widge AS, Avery DH, Zarkowski P. Baseline and Treatment-Emergent EEG Biomarkers of Antidepressant Medication Response Do Not Predict Response to Repetitive Transcranial Magnetic Stimulation. Brain Stimul. Brain Stimul. 2013 Nov;6(6):929- 31. 84. Borckardt JJ, Nahas ZH, Teal J, Lisanby SH, McDonald WM, Avery D, Durkalski V, Pavlicova M, Long JM, Sackeim HA, George MS. The Painfulness of Active, but not Sham, Transcranial Magnetic Stimulation Decreases Rapidly Over Time: Results From the Double-Blind Phase of the OPT-TMS Trial. Brain Stimul. 2013 Nov;6(6):925-8. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 12 85. Wajdik C, Claypoole KC, Fawaz W, Holtzheimer III PE, Neumaier J, Dunner DL, Haynor DR, Roy-Byrne P, Avery DH, No Change in Neuropsychological Functioning After Receiving Repetitive Transcranial Magnetic Stimulation (TMS) Treatment for Major Depression. J ECT Accepted for publication. CHAPTERS: 1. Avery, D.H. and Mills, M.: "Electroconvulsive therapy and antidepressants in the treatment of depression: in Mood Disorders: The World's Major Public Health Problem, pp. 138-153. F. Ayd (ed.) Ayd Medical Communications, Baltimore, 1978. 2. Mills, M. and Avery, D.H.: "The legal regulation of electroconvulsive therapy" ibid, pp. 154-183. 3. Avery, D.H., Wilson, L.G., Dunner, D.L.: "Diagnostic subtypes of depression as predictors of therapeutic response." in Treatment of Depression - Old Controversies and New Approaches, pp. 193-205, Clayton, P.J., Barrett, J.E. Raven Press, New York, 1983. 4. Avery, D.H.: "Ethical issues in research in clinical psychopharmacology." Psychopharmacology Review Series Vol. 2, pp. 436-443, Excerpta Medica. Amsterdam, 1983. 5. Avery, D.H., Wildschiodtz, G., and Rafaelsen, O.J.: "Sleep EEG and body temperature in depression." in Biol. Psychiatry 7:963-965 (ed. Charles Shagass et al). Proceedings of IVth World Congress of Biological Psychiatry, 1985. Elsevier, New York, 1986. 6. Avery, D.H.: "REM sleep and temperature regulation in affective disorder." Chronobiology and Neuropsychiatric Disorders, (ed. Halaris A.) pp. 75-101, Elsevier, New York, 1987. 7. Avery, D.H.: "Electroconvulsive therapy." Current Psychiatric Therapy, (ed. Dunner, D.L.) W. B. Saunders Co. Philadelphia, pp. 524-528, 1993. 8. Avery, D.H., Dahl, K.: "Bright light therapy and circadian neuroendocrine function in seasonal affective disorder." In Hormonally Induced Changes in Mind and Brain (ed. J. Schulkin), Academic Press, New York, pp. 357-390, 1993. 9. Maiuro, R.D. and Avery, D.H. “Psychopharmacological treatment of aggressive behavior: Implications for domestically violent men.” in Domestic Partner Abuse (Editors, Hamberger, L.K, and Renzetti, C.) Springer Publishing Company, New York, 1996. 10. Avery, D. H. “Seasonal affective disorder” in Current Psychiatric Therapy II (Ed. Dunner, D.L.) W. B. Saunders Co. Philadelphia, pp. 243-47, 1997. 11. Avery, D. H. and Norden, M.J. "Dawn simulation and bright light therapy in subsyndromal seasonal affective disorder." In Beyond Seasonal Affective Disorder: Light Therapy for SAD and Non-SAD Conditions American Psychiatric Press, Inc. Washington, DC, 1998, pp. 143-157. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 13 ARTICLES IN NON-REFEREED JOURNALS: 1. Avery, D.: "The case for "shock" therapy." Psychology Today, p. 104, 1977. 2. Avery, D.H.: "Dexamethasone suppression test as a marker for depression." Resident and Staff Physician 29(8) 63-69, 1983. 3. Avery, D.H.: "Alcoholism and depression: cause and effect." Clinical Advances in the Treatment of Depression 1(1):1-2, 1987. 4. Avery, D.H.: "Bright light therapy for winter depression." Clinical Advances in the Treatment of Depression 2(6): 8-9, 1988. 5. Avery, D.H.: Book Review of Sleep and Biological Rhythms - Basic Mechanisms and Applications to Psychiatry, Light Treatment and Biological Rhythms, 3(3):30-31, 1991. 6. Avery, D.H. "FDA Sends Letters to Some Lighting Companies" Bulletin of the Society for .Light Treatment and Biological Rhythms 5(1):2-4. 1992 7. Avery, D.H. "Treatment of Seasonal Affective Disorder" Women's Psychiatric Health 2(2):13-16, 1993. 8. Avery, D.H. "Update: Federal-Industrial Relations: US Food and Drug Administration Activity" Bulletin of the Society for Light Treatment and Biological Rhythms 6(2):18-19, 1993. 9. Avery, D.H. “Dawn Simulators: Research Update” NOSAD Newsletter Volume I Number 3, 1996. 10. Avery, D.H. Hellekson C., Lewy A.J. "Light Therapy and Winter Depression" Psychiatric Update. (Audiotape) Editor-in-Chief Paul Packman, Medical Information Systems, Inc. Vol. 20, Number 7, July, 2000. 11. Holtzheimer P.E., Avery D., Schlaepfer T.E. Antidepressant effects of repetitive transcranial magnetic stimulation. British Journal of Psychiatry 184: 541-2, 2004. (Letter) 12. Avery, DH. Psychiatry and Religion: One Psychiatrist’s Perspective. Plainviews: A Publication of the Healthcare Chaplaincy. 10/1/2008. Volume 5, No. 17, 2008. (http://plainviews.healthcarechaplaincy.org/archive/AR/c/v5n17/lv.html) 13. O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. Reply regarding "efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial". Biol Psychiatry. 2010 Jan 15;67(2):e15-7. (Letter) Abstracts (First-Author) Regional Meetings: "Morning versus Evening Light in the Treatment of Winter Depression" West Coast College of Biological Psychiatry, San Diego, March 28, 1987. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 16 "Sleep and Circadian Temperature Rhythms in Winter Depression" 11th Annual international Conference of the IEEE Engineering in Medicine and Biology Society, November 9, 1989. "The Temperature Rhythm is Phase-Delayed in Winter Depression" Meeting of the Society of Biological Psychiatry New York, May 11, 1990. "Is Dawn Simulation Effective in Treating Winter Depression?" Meeting of the Society for Light Treatment and Biological Rhythms, New York May 13, 1990. "Rectal Temperature and TSH During a Constant Routine in Winter Depression" Association of Professional Sleep Societies, Minneapolis, June 1990 "Is the Temperature Setpoint Elevated in Depression?" Meeting of the Society of Biological Psychiatry, May 11, 1991. "Dawn Simulation Treatment for Winter Depression: A Controlled Study." Society for Light Treatment and Biological Rhythms, Toronto, Jun 13, 1991. "Does an Elevated Temperature Setpoint Explain the REM and SWS Abnormalities of Depression?" Meeting of the Association of Professional Sleep Societies. Toronto, June 16, 1991. "Dawn Simulation Treatment of Winter Depression: A Second Controlled Study." Meeting of the Society for Light Therapy and Biological Rhythms, Bethesda, April 30, 1992. "Dawn Simulation Treatment of Winter Depression" Association of Professional Sleep Societies, Phoenix, June 2, 1992. "Dawn Simulation Treatment of Winter Depression: A Second Controlled Study" Meeting of the Society of Biological Psychiatry, San Francisco, May 21, 1993. “Is PSI E-M Increased in Winter Depression?” Society for Light Treatment and Biological Rhythms, San Diego, June 19, 1993. "Is the Low Temperature Trough Duration Increased During a Constant Routine in Winter Depression?" Meeting of the Association of Professional Sleep Societies, Los Angeles, June 23, 1993. Sleep Research 22: 392, 1993. “Is PSI E-M Increased in Winter Depression?” Meeting of Society of Biological Psychiatry. Philadelphia, May 20, 1994. Biological Psychiatry 1994;35:668. "Difficulty Awakening as a Symptom of Winter Depression" Meeting of the Society of Light Treatment and Biological Rhythms, Bethesda, MD, June 23, 1994. "A Seasonal and Circadian Study of Suicide over a 10-year period in the Seattle Area" Meeting of the Society of Biological Psychiatry. Miami, May 18, 1995. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 17 "Temperature Rhythms and Sleep in a 48-Hour Cyclothymic Patient" Meeting of the Society for Light Therapy and Biological Rhythms, Bethesda, MD, June 3, 1996. "The Morningness-Eveningness Questionnaire in SAD in the Summer, Winter, and After Light Treatment." Meeting of the Society of Light Treatment and Biological Rhythms, Vancouver, British Columbia, June 7, 1997. "Nocturnal Sweating in Depression" Meeting of the Society of Light Treatment and Biological Rhythms, Amelia Island, Florida, May 8, 1998. "Dawn Simulation and Bright Light Treatment of SAD" Meeting of the Society of Light Treatment and Biological Rhythms, Chicago, May 8, 2000. "Dawn Simulation and Bright Light Treatment of SAD" Meeting of the Society of Biological Psychiatry, New Orleans, May 5, 2001 "Transcranial Magnetic Stimulation in the Treatment of Depression" NCDEU Meeting, Phoenix, AZ, May 29, 2001 “Repetitive transcranial magnetic stimulation (rTMS) is clinically effective in treatment-resistant major depression.” Society of Biological Psychiatry, New York, May 1, 2004. “The Efficacy of Transcranial Magnetic Stimulation in Major Depression” NCDEU Meeting, Phoenix, AZ, June 2, 2004 International: Suicide, Attempted Suicide, and Relapse Rates in Depression Following ECT and Antidepressant Therapy" VI World Congress of Psychiatry, Honolulu, August, 1977. "An Association between REM Latency and Nocturnal Temperature in Depression. Fourth International Congress of Sleep Research, Bologna, Italy, 1983. "Nocturnal Temperature Discomfort and Night Sweats in Primary Depression and Insomnia" 24th Annual Sleep Research Society Meeting, Toronto, Canada, June, 1984. "Sleep EEG and Body Temperature in Depression" 4th World Congress of Biological Psychiatry, Philadelphia September 11, 1985. "Temperature Rhythm Phase-Typing of Seasonal Affective disorder and Response to AM and PM Bright Light" 5th International Congress of Sleep Research, Copenhagen, Denmark, June, 1987. "Resynchronization of the Temperature Rhythm in a Catatonic Patient Treated with ECT" 5th International Congress of Sleep Research, Copenhagen, Denmark, June, 1987. Sleep Research 16:285, 1987. "Bright Light Treatment of SAD: AM versus PM Light" as part of the World Psychiatric Association Regional Symposium "New Developments in SAD and Phototherapy", Washington DC, October 15, 1988. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 18 "Dawn Simulation Treatment of Winter Depression" XIXth Collegium Internationale Neuro- Psychopharmacologium Congress, Washington, D.C. June 28, 1994. “Is PSI E-M Increased in Winter Depression?” Meeting of the International Society of Psychoneuroendocrinology, Seattle, August 15, 1994. "Dawn Simulation in the Treatment of Abstinent Alcoholics" Meeting of the Society for Light Treatment and Biological Rhythms, Frankfurt, Germany, June 10, 1995. "rTMS Treatment of Depression: Preliminary Data" Conference on Transcranial Magnetic Stimulation (TMS), Interlaken, Switzerland, August 12, 1997. "ISTS database for studies of transcranial magnetic stimulation in the treatment of depression." International Symposium on Transcranial Magnetic Stimulation. Goettingen, Germany, October 2, 1998. Electroencephalography and Clinical Neurophysiology 107 (3):93P, 1998. "TMS in the Treatment of Medication-Free Major Depression" International Society of Transcranial Stimulation Meeting, Chicago, May 10, 2000. " Repetitive Transcranial Magnetic Stimulation (rTMS) is Clinically Effective in Medication-Resistant Major Depression” XXIV Collegium Internationale Neuro-Psychopharmacologium Congress, Paris, June 24, 2004 “The Basics of Transcranial Magnetic Stimulation” World Federation of Societies of Biological Psychiatry Meeting, Vienna, Austria July 2, 2005. “Transcranial Magnetic Stimulation in the Treatment of Medication-Resistant Depression and Chronic Widespread Pain.” Hebei Medical University, Shijiazhuang, China, October 11, 2008. “Seasonal and Circadian Aspects of Mood Disorders and the Use of Light Therapy” Hebei Medical University, Shijiazhuang, China, October 11, 2008. “Transcranial Magnetic Stimulation in Treatment-Resistant Depression” Danish University Antidepressant Group. Fredensborg, Denmark, November 7, 2008. “TMS in the Treatment of Chronic Pain” EEG and Clinical Neuroscience Meeting, Keynote Lecture, Istanbul, Turkey, September 16, 2010. “TMS in Treatment of Medication Resistant Major Depressive Disorder” EEG and Clinical Neuroscience Meeting, Istanbul, Turkey, September 16, 2010. “Is Combining Non-invasive Brain Stimulation (TMS) with Non-invasive Brain Imaging (fMRI) – interleaved TMS/fMRI – the Ultimate in Multimodal Imaging or a Mere Distraction?” EEG and Clinical Neuroscience Meeting, Istanbul, Turkey, September 16, 2010. “Transcranial Magnetic Stimulation and Pulsed Electromagnetic Field Therapy in Treatment-Resistant Depression” Danish University Antidepressant Group. Nyborg, Denmark, November 7, 2010. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 21 "Circadian Rhythm Abnormalities in Depression, University of British Columbia, February 12, 1988. "Bright Light Treatment of Winter Depression", University of British Columbia, February 12, 1988. “Dawn Simulation Treatment of Seasonal Affective Disorder” Meeting of the Association of Professional Sleep Societies, Los Angeles June 23, 1993. "Light Boxes, Light Visors, Dawn Simulators, and SSRIs: Which is the Best Approach to Treat Winter SAD?" Meeting of the Society for Light Treatment and Biological Rhythms, June 24, 1994. "Recent Advances in the Treatment of Seasonal Affective Disorder" Commonwealth Club, San Francisco, October 14, 1994. "Recent Advances in the Treatment of Seasonal Affective Disorder" Psychochemistry Institute, University of Depression" University of Iowa, September 23, 1996. "Recent Advances in the Treatment of Seasonal Affective Disorder" Grand Rounds, University of Iowa, September 24, 1996. Co-Leader of Workshop, "Transcranial Magnetic Stimulation (TMS): Technique and Demonstration" Meeting of the Society of Biological Psychiatry, San Diego, May 17, 1997. "Transcranial Magnetic Stimulation Treatment of Depression" Psychochemistry Institute, University of Copenhagen, Copenhagen, Denmark, August 18, 1997. "Transcranial Magnetic Stimulation Treatment of Depression" Gentofte University, Gentofte, Denmark, April 1, 1998. "Transcranial Magnetic Stimulation Treatment of Depression" Grand Rounds, Oregon Health Sciences University, Portland, September 14, 1999. "Transcranial Magnetic Stimulation Treatment of Depression" Central Neuropsychiatric Association 1999 Scientific Program, Los Angeles, October 15, 1999. "Psychopharmacology of Aggression" Seattle Forensic Institute, Seattle October 21, 1999. "Light Treatment of SAD and Other Psychiatric Disorders" Psychiatry Update, Seattle, Nov. 18, 1999. "Recent Advances in the Treatment of Medication-Resistant Depression", Psychiatry Update, Seattle, Nov. 18, 1999. "Psychopharmacology of Aggression" Psychiatry Update, Seattle, Nov. 19, 1999. "Recent Advances in Light Therapy in the Treatment of SAD and Other Disorders" Steven's Hospital, Edmonds, WA January 18, 2000 David H. Avery, M.D. Curriculum Vitae February, 2014 Page 22 "Light therapies for winter depression and other psychiatric disorders.", Grand Rounds, Sacred Heart Medical Center, Spokane, March 14, 2000. "Management of Treatment-Resistant Depression: New Antidepressants and New Approaches in Light Therapy" Northwest Mental Health Institute, Redmond, Oregon, June 9, 2000 "Management of Treatment-Resistant Depression: New Antidepressants and New Approaches in Light Therapy" Snoqualmie, WA June 11, 2000. "Light Therapy in the Treatment of Winter Depression" Washington State Psychiatric Association, Wenatchee, WA, September 23, 2000. "Transcranial Magnetic Stimulation in the Treatment of Depression" Washington State Psychiatric Association, Wenatchee, WA, September 23, 2000. "Effects of Light on Mood and Human Behavior" Northwest Section of the Dark-Sky Association, University of Washington, Seattle, Dec. 2, 2000. "Light, Melatonin, and Sleep" Grand Rounds, Overlake Hospital, March 13, 2001. "ECT and Transcranial Magnetic Stimulation in Treatment Resistant Depression" Nonpharmacological Approaches to Treatment Resistant Depression, April 28, 2001. "Transcranial Magnetic Stimulation in the Treatment of Depression" NCDEU Meeting, Phoenix, May 29, 2001. “Transcranial Magnetic Stimulation in the Treatment of Depression” University of Louisville, Louisville, Kentucky, March 23, 2002. “Recent Advances in the Treatment of Seasonal Affective Disorder.” Alaska Native Hospital, Anchorage, Alaska, April 18, 2002. “Recent Advances in the Treatment of Seasonal Affective Disorder.” Providence Hospital, Anchorage, Alaska, April 19, 2002. “Recent Advances in the Treatment of Seasonal Affective Disorder.” Alaska Regional Hospital, Anchorage, Alaska, April 19, 2002. “Recent Advances in the Treatment of Seasonal Affective Disorder.” University of Washington CME Course, Seattle, WA., December 13, 2002. “Psychopharmacologic Management of Agitation” CME presentation at Providence St. Peters Hospital, Olympia, WA , January 16, 2003. “Psychopharmacologic Management of Agitation” CME presentation at Western State Hospital, Steilacoom, WA , February 6, 2003. David H. Avery, M.D. Curriculum Vitae February, 2014 Page 23 “Recent Advances in Transcranial Magnetic Stimulation in the Treatment of Depression” Grand Rounds, University of Illinois at Chicago, March 12, 2003. “Transcranial Magnetic Stimulation in the Treatment of Major Depression.” West Coast College of Biological Psychiatry, Seattle, WA, April 5, 2003. “Assessment and Treatment of Sleep Disorders” Nursing CME Program, Shoreline, WA June 13, 2003. “Transcranial Magnetic Stimulation in the Treatment of Major Depression” Tanta University, Tanta, Egypt, February 19, 2004. “Light and Circadian Rhythm Abnormalities in Major Depression.” Tanta University, Tanta, Egypt, February 19, 2004. “Transcranial Magnetic Stimulation in the Treatment of Major Depression.” West Coast College of Biological Psychiatry, Los Angeles, CA, March 13, 2004. “Transcranial Magnetic Stimulation in the Treatment of Major Depression: A Review of the Meta- analyses.” National Institute of Drug Abuse Workshop, Transcranial Magnetic Stimulation in the Treatment of Drug Abuse and other Brain Disorders, Bethesda, MD, March 16, 2004. “Transcranial Magnetic Stimulation in the Treatment of Major Depression: A Review of the Meta- analyses.” New Clinical Drug Evaluation Unit (NCDEU) Meeting, Phoenix, AZ, June 3, 2004. “Transcranial Magnetic Stimulation in the Treatment of Depression” Oringe Hospital, Vordingborg, Denmark, June, 2004 “Transcranial Magnetic Stimulation Course” with Sarah H. Lisanby, M.D., EEG and Clinical Neuroscience Society (ECNS) Meeting, Irvine, CA, October 1, 2004. “The Basic Principles of TMS” 8th World Congress of Biological Psychiatry. Vienna, July, 2005. “Treatments for Medication-Resistant Depression”: Transcranial Magnetic Stimulation and Vagus Nerve Stimulation.” Oregon Health Sciences University, Portland, OR, February 28th, 2006. “Recent Advances in the Treatment of Insomnia” Washington State Pharmacy Association, September 19, 2006. “Transcranial Magnetic Stimulation in the Treatment of Depression” Grand Rounds, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, September 25, 2006. “The Use of Repetitive Transcranial Magnetic Stimulation (rTMS) and Vagus Nerve Stimulation (VNS) in Treating Depression” UCLA’s Twelfth Annual Review of Psychiatry and Psychopharmacology Update- Evidence Based Treatments” University of California, Los Angeles, Los Angeles, CA October 27, 2007. Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 2 Treatment Resistant Depression (TRD) Setting the Stage Some definitions: • No response < 25% improvement • Partial response 26‐49% • Response >50% improvement • Remission: rating back to the normal range of the  depression scale being used 3 Background 4 • How common is TRD? – STAR*D  Trial • Progressive levels of treatment for patients not remitting, (Back to normal  score of scale) • After 4 “courses” of AD therapy 67% of patients achieved remission • 37%  did not respond • Definition of TRD • No agreed upon definition • Growing consensus for TRD definition = failure of >2 adequate trials of  different antidepressants   (“Adequate” lengths range from 4 ‐ 8 weeks at max tolerable dose.) • There is no standard definition for a “clinically meaningful response”. Treatment Resistant Depression (TRD) Setting the Stage http://www.nimh.nih.gov/health/trials/practical/stard/backgroundstudy.shtml Background Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 3 5 Gaynes BN, Lux L, Lloyd S, Hansen RA, et. Al. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. Comparative Effectiveness Review. Agency for Healthcare Research and Quality. September 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Background 6 Gaynes BN, Lux L, Lloyd S, Hansen RA, et. Al. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. Comparative Effectiveness Review.Agency for Healthcare Research and Quality. September 2011.www.effectivehealthcare.ahrq.gov/reports/final.cfm. Background Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 4 Treatment Modalities • ECT (Electroconvusive therapy) • rTMS (repetive Transcranial Magnetic Stimulation) • tDCS (transcranial Direct Current Stimulation) • DBS (Deep Brain Stimulation) 7 Treatment Resistant Depression Treatment Types 8 ECT rTMS tDCS DBS Treatment Resistant Depression Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 7 Treatment Resistant Depression: State Agency Utilization Electroconvulsive Therapy, All Agency  Summary, 2009‐2012 2009 2010 2011 2012 4 Yr Overall  Total** ECT Patients (any diagnosis*) 71 89 78 61 213 ECT Procedures (treatment days) 568 655 665 533 2421 Average Count per Patient 8.0 7.4 8.5 8.7 11.4 Max Count per Patient 48 48 62 49 205 ECT Total Paid $354,296  $355,896  $455,032  $389,658  $1.6M  Average Paid per Patient $4,990  $3,999  $5,834  $6,388  $7,300  Average Paid per Procedure $624  $543  $684  $731  $642  PEB/UMP and L&I – 100% episodic and depression diagnoses Medicaid – 85% episodic & depression diagnoses. Other diagnoses: schizophrenia, psychosis Electroconvulsive Therapy (ECT) PEB/UMP  ECT Top Diagnosis Codes n=72 Patients % of All  ECT  Patients RECUR DEPR PSYCH‐SEVERE                                                                                 38 52.8% RECURR DEPR PSYCHOS‐UNSP                                                                             31 43.1% EPISODIC MOOD DISORD NOS                                                                             12 16.7% BIPOL I SINGLE MANIC NOS                                                                                  11 15.3% DEPRESSIVE DISORDER NEC                                                                                  11 15.3% DEPRESS PSYCHOSIS‐UNSPEC                                                                               10 13.9% BIPOL I CURR DEP W/O PSY                                                                                  8 11.1% BIPOLAR DISORDER NEC                                                                                        8 11.1% BIPOL I CUR DEPRES NOS                                                                                      7 9.7% DEPRESS PSYCHOSIS‐SEVERE                                                                                7 9.7% REC DEPR PSYCH‐PSYCHOTIC                                                                                7 9.7% Treatment Resistant Depression: State Agency Utilization Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 8 Medicaid ECT Top Diagnosis Codes n=134 Unique  Patients % of All ECT  Patients Recur depr psych‐severe 97 72.4% Schizoaffective dis NOS 77 57.5% Bipol I single manic NOS 64 47.8% Bipol I cur depres NOS 53 39.6% Recurr depr psychos‐unsp 44 32.8% Bipol I curr dep w/o psy 40 29.9% Rec depr psych‐psychotic 34 25.4% Episodic mood disord NOS 25 18.7% Depressive disorder NEC 21 15.7% Bipolar disorder NEC 13 9.7% Follow‐up exam NOS 13 9.7% Simpl schizophren‐unspec 13 9.7% Treatment Resistant Depression: State Agency Utilization PEB/UMP & Medicaid Procedure Counts,  2009‐2012 2009 2010 2011 2012 4 Yr Overall  Total PEB/UMP Average Annual Members 210,501 213,487 212,596 212,684 PEB Members w/Depression (Avg 9.2%) 19,475 19,922 19,581 19,425 PEB/UMP ECT Patients  (all with depression diagnoses) 26 32 30 30 72 Average Treatment Count per Patient 15.5 13.7 16.4 12.7 23.8 Max Treatment Count per Patient 48 48 62 49 205 PEB/UMP ECT Total Paid $298,744  $288,606  $384,272  $312,751  $1.3M  Medicaid Fee for Service Population 463,966 474,676 473,356 477,727 Medicaid Pts w/Depression (Avg 11.1%) 54,869 54,787 51,422 49,507 ‐4.30% Medicaid ECT Patients  (85% depression diagnoses) 43 55 45 28 134 Average Treatment Count per Patient 3.2 3.3 2.8 3.5 4.1 Max Treatment Count per Patient 8 9 10 10 22 Medicaid ECT Total Paid $26,017  $30,959  $14,574  $14,726  $86,275  ECT Usage State Agency Utilization Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 9 Electroconvulsive Therapy, PEB/UMP and  Medicaid Average Payments, 2009‐2012 2009 2010 2011 2012 4 Yr Overall  Total PEB/UMP ECT Patients  (all with depression diagnoses) 26 32 30 30 72 Average Treatment Count per Patient 15.5 13.7 16.4 12.7 23.8 PEB/UMP ECT Total Paid $298,744 $288,606 $384,272 $312,751  $1.3M  Average Paid per Patient $11,490  $9,019  $12,809  $10,425  $17,839  Average Paid per Patient, PEB Primary $16,756  $10,891  $16,508  $15,548  $23,067  Medicaid ECT Patients  (85% depression diagnoses) 43 55 45 28 134 Average Count per Patient 3.2 3.3 2.8 3.5 4.1 Medicaid ECT Total Paid  $26,017  $30,959  $14,574  $14,726  $86,275  Average Paid per Patient $605  $563  $324  $526  $644  Average Paid per Patient, Non‐Medicare4 $652  $686  $496  $925  $787  ECT Payments Treatment Resistant Depression: State Agency Utilization Electroconvulsive Therapy, PEB/UMP and  Medicaid Average Costs, 2009‐2012 2009 2010 2011 2012 4 Yr  Overall  Total PEB/UMP ECT Patients  (all with depression diagnoses) 26 32 30 30 72 Average Treatment Count per Patient 15.5 13.7 16.4 12.7 23.8 PEB/UMP ECT Total Paid $298,744 $288,606 $384,272 $312,751  $1.3M  Average Paid per Procedure $739  $657  $779  $823  $748  Average Paid per Procedure, PEB Primary $1,160  $1,122  $1,138  $1,503  $1,214  Medicaid ECT Patients  (85% depression diagnoses) 43 55 45 28 134 Average Count per Patient 3.2 3.3 2.8 3.5 4.1 Medicaid ECT Total Paid $26,017  $30,959  $14,574  $14,726  $86,275  Average Paid per Procedure $191  $170  $114  $149  $158  Average Paid per Procedure, Non‐Medicre $215  $227  $231  $278  $230  Treatment Resistant Depression: State Agency Utilization ECT Payments Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 12 Evidence Summary: rTMS Safety:  Compared to sham, low quality evidence of more local side effects Compared to ECT, low quality evidence suggests no difference in  cognitive effects, insufficient evidence to assess withdrawal rates due  to lack of efficacy Efficacy:  Compared to sham: moderate quality evidence demonstrates  reduction in severity, improved response and remission rates, low  quality evidence, suggests the effects are short lived 2‐3 weeks Compared to ECT*: low quality studies demonstrate mixed results on  which is more effective, inconsistent impacts on QoL and function.   Optimal treatment regimens or differences among subpopulations  were not identified. Cost: Low quality economic studies ‐mixed results, (rTMS better than drugs,  ECT at times), unable to draw any conclusions 23 Evidence Summary: tDCS Safety:  Increased itching in 1 SR, no serious events, unclear effect on  treatment induced mania, withdrawal rates similar to sham rates Efficacy: tDCS vs. sham: Low quality studies with mixed results, 2 MA & 1 small  RCT suggest improved MADRS scores  tDCS +sertraline vs. sham and placebo: low quality studies suggest  improved depression scores  Insufficient evidence for durability, utility in maintenance, effects on  QoL or the best way to use technology.  There is insufficient evidence  to evaluate differences across subpopulations. Cost: No information reported 24 Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 13 Evidence Summary: DBS Safety:  Serious device related events are possible, side effects reported  include bleeding, infection, lead fracture and erosion, no apparent  changes in cognitive function, overall insufficient evidence to state  harms with certainty  Efficacy:  Insufficient evidence from small, poor to very poor quality studies  with indeterminate effects on depression relief, durability of benefit  or changes in QoL/function  Unable to draw conclusions about treatment parameters or  subpopulations Cost:  No information available 25 ECT: Cover with conditions Severe persistent depression w or w/o psychotic features after  failure of at least 2 adequate antidepressant trials w or w/o  augmentation rTMS: Cover with conditions  Severe persistent depression w or w/o psychotic features after  failure of at least 2 adequate antidepressant trials with or w/o  augmentation. While the available evidence does not supports  its superiority over ECT, its safety profile is high and for severe  refractory depression it provides an alternative treatment  method. tDCS, DBS: Do not cover 26 State Agency Recommendations: Charissa Fotinos, Deputy Chief Medical Officer Health Care Authority March 21, 2014 WA ‐ Health Technology Clinical Committee 14 Questions? More Information:  http://www.hca.wa.gov/hta/Pages/trd.aspx Contact: shtap@hca.wa.gov 27 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 3 Severe MDD refractory to multiple therapies: 4M Americans No established definition of TRD ◦ 2 systematic reviews (Berlim and Turecki, 2007; Gaynes et al., 2011 [AHRQ]): Growing “consensus” that TRD = failure of ≥2 adequate trials of different ADs ◦ No explicit evidence-based rationale stated in literature ◦ STAR*D trial suggests sharp drop after 2 failed ADs “Adequate” AD trial = maximum tolerable dose for sufficient duration: ◦ American Psychiatric Association: 4-8 wks ◦ Studies selected for this report: Typically, 6 wks ◦ Antidepressant Treatment History Form (ATHF): 4 wks Actual time to remission in STAR*D ◦ 6.3 wks at Step 1 ◦ 5.4 wks at Step 2 © 2014 Winifred S. Hayes, Inc. 5 AHRQ evidence review (Gaynes et al., 2011) ◦ After ≥2 failed ADs, change in pharmacotherapy superior to no change Indirect evidence, overlapping CIs 2 SRs: AHRQ (2011); Trivedi et al. (2011) ◦ Psychotherapy is effective ◦ Psychotherapy vs pharmacotherapy: Unclear Disadvantages of multiple AD attempts ◦ Diminishing effectiveness ◦ Increased risk of adverse events and drug interactions © 2014 Winifred S. Hayes, Inc. 6 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 4 © 2014 Winifred S. Hayes, Inc. 7 ECT rTMS tDCS DBS MST ECS VNS CES CES, cranial electrotherapy stimulation; ECS, epidural cortical stimulation; MST, magnetic seizure therapy; VNS, vagus nerve stimulation Response: Typically, ≥50% reduction in depression score Remission: Score < specified cutoff ◦ E.g., ≤8 on HAM-D17, ≤10 on HAM-D21, or ≤8 on MADRS Depression scales empirically validated ◦ Definitions of response/remission – convention No standard definition of clinically relevant improvement ◦ Response definition (50% improvement) implies definition of clinical importance ◦ 25% improvement = partial response ≈ MCID MCID, minimal clinically important difference © 2014 Winifred S. Hayes, Inc. 8 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 5 Global Assessment of Functioning (GAF) ◦ Recommended by DSM-IV ◦ 0-100, ≤50 signifies severe symptoms and/or psychosocial dysfunction SF-36 Health Survey World Health Organization Disability Assessment Schedule (WHODAS) ◦ An “emerging measure” featured in DSM-V ◦ Not used in studies selected for this report No standard definition of clinically relevant difference/improvement © 2014 Winifred S. Hayes, Inc. 9 Depression scales ◦ Content, e.g., HAM-D Depression symptoms (e.g., mood, guilt, insomnia) Suicide Work/activities Retardation, agitation Somatic symptoms/problems Anxiety, hypochondriasis, depersonalization, paranoia, OCD ◦ Validity Comparison w/ “global” measures of depression Comparison w/ other depression scales Depression scores vs QOL/function © 2014 Winifred S. Hayes, Inc. 10 HAM-D / MADRS QOL •Concordance (low HAM-D vs high QOL), 90% (Pridmore, 2000) •Correlation (Hung et al., 2009) •Frequency high/low scores (Zimmerman et al., 2012) •No mapping of HAM-D to QOL score Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 8 Search for SRs and guidelines ◦ All KQs: Core online sources and PubMed, July 2008 to July 2013 ◦ KQs #1b, #2, #3: Search expanded to include 2003-2008 ◦ Relevant specialty societies Initial search for primary clinical studies (August 1-4, 2013) ◦ Starting with end of search time frame in selected SRs ◦ Additional search for studies of pts w/ bipolar depression, no date limit ◦ PubMed, Embase, and PsycInfo ◦ Excluded Studies list of 2011 AHRQ report Search for cost studies (August 2, 2013) ◦ National Health Service Economic Evaluation Database (NHS-EED) ◦ PubMed ◦ Past 10 years Final update search: November 12, 2013 © 2014 Winifred S. Hayes, Inc. 15 Inclusion criteria varied by technology ◦ ECT and rTMS Randomized controlled/comparator trial Observational study, n≥100 (adverse event data) Observational study with comparative data for KQ #3 ◦ tDCS and DBS Any clinical study Exclusion criteria ◦ SRs and cost/economic studies published before August 2003 ◦ No abstract ◦ <10 pts ◦ For RCTs of rTMS vs sham published after AHRQ report: <43 randomized pts ◦ Enrollment not based on TRD and no information suggesting most patients had experienced ≥1 AD failure (some exceptions – KQs #1b, #2, #3) Quality assessment ◦ Hayes methodology (similar to GRADE) © 2014 Winifred S. Hayes, Inc. 16 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 9 © 2014 Winifred S. Hayes, Inc. 17 ECT rTMS tDCS DB S KQ #1a - Effectiveness 4 RCTs (3 sham, 1 ECT vs pharmacotx) 1 SR/MA (AHRQ; pooled estimates, 24 RCTs [sham]) 3 RCTs (sham), post-AHRQ 1 ad hoc analysis 5 RCTs, rTMS vs ECT 2 RCTs, rTMS+ECT vs ECT 2 SRs/MAs (7 RCTs [sham] and 4 case series) 1 RCT (2 publications) 1 SR (Hayes 2012; no pooled estimates; 5 uncontrolled studies, 9 publications) KQ #1b – Effectiveness by treatment parameter 1 SR/MA 7 RCTs (comparator) Data from 6 KQ #1a RCTs 4 RCTs (comparator) Data from the KQ #1a SRs and RCT --- KQ #2 - Safety Data from the KQ #1a and KQ #2b RCTs 2 SRs/MAs Data from the KQ #1a and KQ #1b SR and RCTs 3 SRs/MAs Data from the KQ #1a SRs and RCT 1 SR w/ safety-only data Data from KQ #1a SR 3 SRs, safety-only data KQ #3 – Differential effectiveness by patient characteristics 2 SRs/MAs 1 post hoc analysis of 2 randomized comparator trials Data from KQ #1a SR and RCTs Data from KQ #1a SRs and RCT Data from KQ #1a study KQ #4 – Cost implications --- 2 EEs, rTMS vs ECT 1 EE, rTMS vs pharmacology --- --- Key source of evidence for ECT and rTMS, KQ #1a (effectiveness) Nonpharmacologic treatments for TRD Excluded ◦ Uncontrolled studies ◦ Publication prior to 1980 ◦ Pts not selected on the basis of TRD or the lack of clinical context suggesting high probability of TRD Stated conclusions based on studies where ◦ All pts failed ≥2 AD trials © 2014 Winifred S. Hayes, Inc. 18 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 10 Moderate-severe unipolar MDD ≥ 2 prior AD failures (where reported) ◦ Sometimes specified ≥2 classes Failures in current or previous episode? ◦ Mixed, rarely reported “Adequate” prior AD trial ◦ ≥6 wks at maximum tolerable dose, where defined ◦ Usually not defined © 2014 Winifred S. Hayes, Inc. 19 Findings: ECT © 2014 Winifred S. Hayes, Inc. 20 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 13 Cognitive decline (low quality) ◦ Transient decline over course of tx in some pts (SR: Gardner and O’Connor, 2008, good; SR: Verwijk et al., 2012, fair; pretest/posttest studies) ◦ Autobiographical memory loss may persist for several months (Verwijk et al., 2012) ◦ Changing tx parameters may reduce effects (very sparse evidence) ◦ Depression also diminishes cognitive performance Otherwise, generally safe (low quality) ◦ No large case series ◦ 2 serious events in 3 RCTs: 1 vascular event (retina), 1 tx- emergent mania Withdrawal due to lack of benefit (insufficient) ◦ 4.3% (ECT) vs 1.4% (sham) (1 RCT, 70 pts) © 2014 Winifred S. Hayes, Inc. 25 Quantity/Quality, Studies Quality, Body of Evidence Direction of Findings Magnitude of Benefit Unipolar vs bipolar MDD Dierckx et al., 2012 (fair SR/MA; 6 cohort studies of unknown quality) 1106 pts Insufficient Inconsistency across studies Heterogeneity in pooled estimate Unknown applicability to the population of interest No difference OR of remission, 1.08 (95% CI, 0.75 to 1.57). Confirmed TRD vs lack of well-documented AD failure Heijnen et al., 2010 (fair SR/MA; 7 cohort studies w/o tx controls) 958 pts Low Poor study quality Inconsistency across studies Heterogeneity in pooled estimate (May not be generalizable to current practice of bilateral ECT or high-dose unilateral ECT) Less effective in confirmed TRD OR of remission, 0.52 (95% CI, 0.39 to 0.69) © 2014 Winifred S. Hayes, Inc. 26 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 14 Quantity/Qualit y, Studies Quality, Body of Evidence Directio n of Finding s Magnitude of Benefit Subgroups: Psychosis retardation, agitation Post hoc analysis of 2 related RCTs Low Small quantity data Lack of corroboration by analyses of other trials Differential effectiveness of ECT according to electrode placement and dose – same in subgroups as overall. Age, race/ethnicity, gender, disease severity, disease duration, symptom type, or comorbidities Insufficient No data --- --- © 2014 Winifred S. Hayes, Inc. 27 See Findings for rTMS, KQ #4 © 2014 Winifred S. Hayes, Inc. 28 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 15 Outcome (# Studies) Direction of Findings (Quality of Evidence) KQ #1a:* Depression relief, vs sham (2 RCTs) or psychotx (1 RCT) 3 fair RCTs (134 pts) (low) Unknown relevance of posttx difference. KQ #1b: Bifrontal (vs unilateral or bilateral [bitemporal]) 1 SR/MA (8 RCTs) (low) KQ #1b: Bilateral (vs unilateral) 1 SR/MA (22 RCTs) (moderate) KQ #1b: High dose (vs low dose) 1 SR/MA (6 RCTs) (moderate) KQ #1b: 3x/wk (vs once/wk) 1 SR/MA (6 RCTs) (low) © 2014 Winifred S. Hayes, Inc. 29 *Insufficient evidence for: •ECT vs usual tx, tDCS, or DBS •Durability of sham-controlled effect •Effect on QOL/function Outcome (# Studies) Direction of Findings (Quality of Evidence) KQ #2: Safety, vs sham (low) Generally safe; cognitive decline possible, usually transient KQ #3: Subgroups (psychosis, retardation, agitation): Differential effectiveness of ECT according to electrode placement and dose Post hoc analysis of 2 RCTs (low) KQ #4: See Findings for rTMS © 2014 Winifred S. Hayes, Inc. *Uncertain generalizability to current typical tx parameters. * Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 18 Quantity/Qu ality, Studies Quality, Body of Evidence Direction of Findings Magnitude of Benefit QOL/ function 5 RCTs (at least fair) 275 pts Low Small quantity of data Inconsistency Conflicting findings, rTMS vs sham Comparable, rTMS vs ECT or rTMS+ECT vs ECT Improvements, where observed, were very small, i.e., negligible to 2.2 points on 100-point scales rTMS as maintenance tx Insufficient No data --- --- © 2014 Winifred S. Hayes, Inc. 35 © 2014 Winifred S. Hayes, Inc. 36 Source Change in Score Within Tx Arms Response* Within Tx Arms Remission* Within Tx Arms STAR*D, Step 2 (1 AD failure) (Rush et al., 2006) 1475 pts --- --- 30.6% STAR*D, Step 3 (2 AD failures) 622 pts; 2006 --- --- 14.3% AHRQ (≥2 AD failures) (Gaynes et al., 2011) Pharmacotx arms of 12 RCTs (# pts NR); 1999- 2010 Switch: ‒11.2 Augmentation: ‒11.2 Maintenance: ‒7.6 (Scale 0-60. CI overlap.) Switch: 39.8% Augmentation:38.1% Maintenance: 27.3% (CI overlap.) Switch: 22.3% Augmentation: 27.2% Maintenance: 16.8% (CI overlap.) rTMS arms of 25 selected RCTs Published 1990s to 2013 15% to 63.2% 12% to 57% AHRQ/Gaynes et al., 2011: WMD of 5.92 (24 RCTs, rTMS vs sham) using scales of 0 to 52-75 (HAM-D) or 0 to 60 (MADRS). *Response, 50% relative improvement. Remission, score at conventional cutoff for scale used. Duration of AD trials: ≤14 wks in STAR*D; 4-8 wks, if reported, in other studies. Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 19 Quantity/Qual ity, Studies Quality, Body of Evidence Directi on of Findin gs Magnitude of Benefit Bilateral vs unilateral high frequency 4 RCTs (sham control in 3 studies; at least fair according to AHRQ or direct assessment) 373 patients Insufficient Small quantity of data Inconsistency Mixed Response rates (bilateral vs unilateral): • 20% vs 35% (NS) • 31% vs 48% (P=0.08) • No difference • 38.5% vs 4.5% vs 10% (sham) (global P=0.006) © 2014 Winifred S. Hayes, Inc. 37 Compared with sham tx: ◦ No increase in cognitive deterioration (6 fair/good RCTs) ◦ No increase in withdrawal due to adverse events (16 fair/good RCTs) ◦ No increase in seizure (1 case in >38 RCTs) ◦ Lower overall rate of withdrawal (NS difference) (2 fair SR/MAs; Berlim et al., 2013 a and b) ◦ Greater incidence local side effects (mainly discomfort or pain in slap) (7 fair/good RCTs) ◦ Greater incidence (0.73% to 0.84%) treatment-emergent mania (especially bipolar) (1 fair SR/MA) ◦ No data, withdrawal due to lack of benefit © 2014 Winifred S. Hayes, Inc. 38 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 20 Compared with ECT ◦ No overall difference in cognitive effects (3 RCTs) ◦ Insufficient evidence regarding withdrawal due to adverse events, overall withdrawals, or specific side effects High- vs low-frequency rTMS; bilateral sequential vs unilateral rTMS ◦ No difference (4 RCTs) Overall conclusions ◦ rTMS appears to be safe (moderate quality) (> 38 RCTs) ◦ Possibly no difference compared with sham in withdrawal due to lack of benefit (low quality) Indirect evidence based on no difference in overall withdrawal © 2014 Winifred S. Hayes, Inc. 39 No association of effect (low quality) with ◦ Duration of episode (3 RCTs, 321 pts) ◦ Gender (2 RCTs, 122 pts) ◦ Unipolar vs bipolar depression (very indirect evidence, stratified analysis, AHRQ/Gaynes et al., 2011 MA) ◦ Degree of medication resistance No difference in 1 RCT Somewhat smaller pooled estimates for ≥1 AD failure than for ≥2 AD failures, AHRQ/Gaynes et al. MA; overlapping CIs suggest NS difference Conflicting evidence from small trials, or no evidence (insufficient): age, race/ethnicity, disease severity, symptom type, comorbidities, or history of prior ECT © 2014 Winifred S. Hayes, Inc. 40 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 23 Outcome (# Studies) Direction of Findings (Quality of Evidence) KQ #2: Overall safety, vs sham or ECT (≥16 RCTs w/ explicit safety data; >38 RCTs overall; fair/good quality) (moderate) Scalp discomfort/pain common but transient. No other risks. KQ #2: Withdrawal due to lack of benefit, vs sham (indirect evidence from 2 SRs/MAs) (low) KQ #3: Duration of episode/depression relief, vs sham (3 RCTs) (low) KQ #3: Gender/depression relief, vs sham (2 RCTs) (low) KQ #3: Unipolar vs bipolar/depression relief, vs sham (very indirect evidence, stratified analysis, AHRQ MA) (low) KQ #3: Degree of medication resistance/depression relief, vs sham (1 RCT; indirect evidence, stratified analysis, AHRQ MA) (low) © 2014 Winifred S. Hayes, Inc. 45 Comparison (Study Author; Country) Results/Conclusion Comments rTMS vs pharmacotherapy (Simpson et al., 2009; U.S.) rTMS was cost saving Reporting omissions diminish confidence in conclusions ECT acute and maintenance vs rTMS acute and maintenance (Kozel et al., 2004; U.S.) $460,031/QALY ECT more expensive Multiple data sources w/ extrapolation 1-way sensitivity analysis (no simultaneous variance of rTMS and ECT effectiveness) rTMS-then-ECT-for- nonresponders vs ECT alone (Kozel et al., 2004; U.S.) rTMS-then-ECT-for- nonresponders dominated rTMS vs ECT (Knapp et al., 2004; UK) Unlikely rTMS would be considered cost- effective rTMS more expensive Cost and QALY data from same trial No inclusion of work loss; no transportation costs for ECT © 2014 Winifred S. Hayes, Inc. 46 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 24 Findings: tDCS © 2014 Winifred S. Hayes, Inc. 47 © 2014 Winifred S. Hayes, Inc. 48 Quantity/ Quality, Studies Quality, Body of Evidence Direction of Findings Magnitude of Benefit Depression relief, vs sham 2 MAs (1 good [Berlim et al., 2013c], 1 fair [Kalu et al., 2012]), including 7 RCTs) 1 additional RCT (good) 320 pts total Low Small quantity of data Inconsis- tency Im- precision Favored tDCS (NS, pooled response and remission) Pooled tDCS-vs-sham effect size based on % change from baseline: 0.74 (CI, 0.21 to 1.27; P=0.006); 6 RCTs (Kalu et al., 2012) Pooled response (rTMS, sham, pooled OR): 23.2%, 12.4%, 1.97 (95% CI, 0.85 to 4.56; P=0.11); 6 RCTs (Berlim et al., 2013c) . NNT 10* Pooled Remission (tDCS, sham, pooled OR): 12.2%, 5.4%, 2.13 (9.5% CI, 0.64 to 7.06; P=0.22); 6 RCTs (Berlim et al., 2013c). NNT 10* Difference, mean MADRS (tDCS vs sham): –5.6 (CI, –1.30 to –10.01; P=0.01) (1 RCT) Difference, mean MADRS (tDCS+sertraline vs sham+sertraline): –8.5 (CI, –2.96 to –14.03; P<0.001) (1 RCT) Remission (OR, tDCS vs sham): 4.3 (CI, 1.2 to 15.6; P=0.02) (1 RCT) Remission (OR, tDCS vs sham : 8.6 (CI, 2.5 to 29.1; P<0.001) (1 RCT) *Calculated on the basis of rate data supplied by the authors. Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 25 © 2014 Winifred S. Hayes, Inc. 49 Quantity/ Quality, Studies Quality, Body of Evidence Direction of Findings Magnitude of Benefit Durability of benefit 2 RCTs (not rated), 2 case series (very poor) Insufficient Very small quantity of controlled data Posttx effect NS in 1RCT Sustained or additional benefit up to 1 mo Positive results maintained at 1 mo (1 RCT, 2 case series) Difference increased in favor of tDCS (1 RCT) Maintenance tx w/ continuing tDCS 2 RCTs (1 good, 1 not rated) 30+ pts Insufficient Very small quantity of data Sustained or additional benefit Response persisted mean 11.7 wks (1 RCT); reduction in symptom scores increased (1 RCT) QOL/function Insufficient No data --- --- © 2014 Winifred S. Hayes, Inc. 50 Source Change in Score Within Tx Arms Response* Within Tx Arms Remission* Within Tx Arms STAR*D, Step 2 (1 AD failure) (Rush et al., 2006) 1475 pts --- --- 30.6% STAR*D, Step 3 (2 AD failures) 622 pts; 2006 --- --- 14.3% AHRQ (≥2 AD failures) (Gaynes et al., 2011) Pharmacotx arms of 12 RCTs (# pts NR); 1999- 2010 Switch: ‒11.2 Augmentation: ‒11.2 Maintenance: ‒7.6 (Scale 0-60. CI overlap.) Switch: 39.8% Augmentation:38.1% Maintenance: 27.3% (CI overlap.) Switch: 22.3% Augmentation: 27.2% Maintenance: 16.8% (CI overlap.) Berlim et al., 2013c tDCS arms of 6 RCTs, 201 pts; 2006-2012 23.2% 12.2% AHRQ/Gaynes et al., 2011: WMD of 5.92 (24 RCTs, rTMS vs sham) using scales of 0 to 52-75 (HAM-D) or 0 to 60 (MADRS). *Response, 50% relative improvement. Remission, score at conventional cutoff for scale used. Duration of AD trials : ≤ 14 wks in STAR*D; 4-8 wks, if reported, in other studies. Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 28 Findings: DBS © 2014 Winifred S. Hayes, Inc. 55 © 2014 Winifred S. Hayes, Inc. 56 Quantity/Quality, Studies Quality, Body of Evidence Direction of Findings Magnitude of Benefit Depression relief, vs sham 5 prospective uncontrolled studies, including 1 w/ sham lead-in phase (4 poor, 1 very poor) 86 pts Insufficient Small quantity of data Poor/very poor studies Improvement w/ respect to BL* Response rate: 40%-60% at 6 mos (4 studies); 29%-55% at 12 mos (3 studies). Remission rate: 18%-35% at 6 mos (3 studies); 18%-36% at 12 mos (2 studies) Durability of benefit 5 studies (as above) Insufficient Small quantity of data Poor/very poor studies Inconsistency Variable Improvement vs decline after 6 mos was inconsistent across studies. QOL/function 2 prospective uncontrolled studies (2 poor) 34 pts Insufficient for very small quantity of data and poor/very poor studies Improvement w/ respect to BL* Increase in GAF score: 18.4 points at 2 yrs (P=0.0009); 28.3 points at 1 yr (P<0.001) (1-100 scale) *But no difference in improvement in 1 study during 4 wks of active stimulation compared with improvement during 4 wks of sham stimulation. Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 29 © 2014 Winifred S. Hayes, Inc. 57 Insufficient evidence ◦ No differences detected in small number of poor- quality studies Serious device-related events possible; treatment-emergent rate of somatic events uncertain Narrative review ◦ Hemorrhage in 10% pts Poor-quality SR of 546 studies, ≤10,339 pts (any indication) (Appleby et al., 2007) ◦ Of 6574 reported device-related events Infection, 16%; explantation, 15%; lead fracture, 15%; erosion,14% ◦ Of 6573 reported somatic adverse events No type of event occurred in ≥ 5% pts 4 non-suicide deaths; 11 completed suicides 2 SRs of DBS (any psychiatric indication) (Bergfeld et al., 2013, fair; Duits et al., 2013, poor) ◦ Cognitive decline was minimal and/or transient 5 uncontrolled studies (86 pts) selected for this report ◦ Infection the only common event (5%-20% in 3 studies) Overall conclusion: Insufficient evidence © 2014 Winifred S. Hayes, Inc. 58 Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 30 Insufficient evidence ◦ A single uncontrolled study evaluated certain response predictors ◦ No controlled studies © 2014 Winifred S. Hayes, Inc. 59 © 2014 Winifred S. Hayes, Inc. 60 Evidence for all KQs was insufficient (very low quality or nonexistent) Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 33 Guideline Sponsor ECT rTMS tDCS DBS APA Recommended for TRD (unipolar and bipolar) May be considered for TRD No recommendation No recommendation CANMAT Recommended for TRD (unipolar and bipolar) Recommended for TRD (unipolar) No recommendation for bipolar No recommendation Investigational ICSI Recommended for TRD No recommendation No recommendation No recommendation NICE Recommended for TRD For research only No recommendation No recommendation VA/DoD Recommended for TRD No recommendation No recommendation No recommendation © 2014 Winifred S. Hayes, Inc. 65 Payer ECT rTMS tDCS DBS Aetna Covered for medication resistance; unipolar, bipolar, mixed episode depression Not covered No policy Not covered CMS No NCD No NCD No NCD No NCD Regence No policy Not covered No policy Not covered Group Health No policy Not covered No policy No policy New England CEPAC Evidence is inadequate Equivalent to or superior to ECT and to usual care No evaluation No evaluation OR HERC For MDD after failure ≥2 AD txs For MDD after failure ≥ 2 AD txs No evaluation No evaluation © 2014 Winifred S. Hayes, Inc. 66 CEPAC, Comparative Effectiveness Public Advisory Council; HERC, Health Evidence Review Commission; NCD, National Coverage Determination Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 34 Final Summary © 2014 Winifred S. Hayes, Inc. 67 KQ ECT rTMS tDCS DBS #1a: Effective vs sham?* Depression: Yes (low) Durability: I QOL/fxn: I Depression: Yes (moderate) Durability: A few weeks (low) QOL/fxn: Yes (low) Depression: Yes (low) Durability: I QOL/fxn: I I vs other nonpharm tx? See rTMS rTMS vs ECT: Mixed results rTMS+ECT = ECT (low) QOL/fxn: Negligible to small effect (low) I vs usual care or pharmacotx? I I I I #1b: Effect varies by tx parameter? Bifrontal = Uni/bitemp (low) Bilateral > Uni (moderate) High dose > Low dose (moderate) 3x/wk > 1x/wk (low) I I I #2: Safe? Overall, yes (low) Overall, yes (moderate) Safe (low) I (potentially serious AEs) #3: Effect varies by pt factor? Confirmed TRD < Unclear med history (low) No association w/ psychosis, retardation, agitation (low) Duration of episode, gender, uni- vs bipolar, degree of medication resistance: No assn (low). Baseline severity: No association (low) I #4 rTMS vs AD: May be cost saving (1 study) ECT vs rTMS: Not cost-effective, rTMS-then-ECT for nonresponder: Dominates ECT alone (1 study) rTMS vs ECT: Not cost-effective (1 study) I I © 2014 Winifred S. Hayes, Inc.* Clinical relevance uncertain Bitemp, bitemporal (bilateral); fxn, function; I, insufficient evidence; uni, unilateral Teresa L. Rogstad, Hayes, Inc. March 21, 2014 WA - Health Technology Clinical Committee 35 Trials of sufficient size and design to determine the efficacy of tDCS and DBS. More randomized comparator trials addressing specific options for the manner in which treatments are delivered. RCTs and cohort studies powered to demonstrate differential effectiveness and safety according to patient characteristics. Additional cost-effectiveness analyses. Trials comparing the technologies of interest with active treatment. A standard definition of TRD with criteria for judging the adequacy of previous AD trials, acknowledgment that AD failure can be due to intolerable side effects, and clarification of whether lifetime AD trials or only AD trials that took place in the current episode should be considered. More uniform reporting of all 3 forms of symptom outcomes: score change, response rate, and remission rate. Empirically derived definitions of clinically relevant improvement, response, and remission in patients with MDD. © 2014 Winifred S. Hayes, Inc. 69 Thank you. © 2014 Winifred S. Hayes, Inc. 70