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TMS - Depression Tx for 21st Century.ppt

  1. Louis B. Cady, MD – CEO & Founder – Cady Wellness Institute Adjunct Clinical Lecturer – Indiana University School of Medicine Department of Psychiatry Child, Adolescent, Adult & Forensic Psychiatry – Evansville, Indiana Grand Rounds – Saint Mary’s Hospital April 2, 2014 TMS: The 21st Century Treatment for Depression
  2. Continuing Medical Education Commercial Disclosure Requirement for Louis B. Cady, M.D. I, Louis B. Cady, MD, have the following commercial relationships to disclose: •Speaker honoraria received from: • Immunolaboratories, Great Plains Diagnostic Labs, LABRIX •Speaker’s bureaus (active) for: • Forest Pharmaceuticals, Sunovion •Historical data – speaker’s bureau for Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi!~aventis, Sepracor, Shire, McNeil, Takeda, Janssen, Searle, Shire, Takeda, Wyeth-Ayerst This CME presentation is not being underwritten by any pharmaceutical or medical device company, and Dr. Cady is not receiving a fee or honorarium for presenting it.
  3. “Slumber not in the tents of your fathers. The world is advancing. Advance with it.” - Giuseppe Mazzine
  4. – How it works – Safety and tolerability – Where it fits in the “Treatment Algorithm” for Major Depression Topics we will cover in this talk – Diagnosis – Unmet medical needs Major Depression TMS
  5. Major Depression Unmet Medical Needs
  6. Depression & Anxiety & a malpractice suit in 1 Easy Lesson DEPRESSION SIG: E- CAPS! • Sleep • Sadness • Interest loss • Guilt • *Energy • Concentration • Appetite • Psychomotor Sx • Suicidal thinking Gen. ANXIETY D.O. •Somatic Sx (“energy”,etc.) •WORRY •Irritability •Concentration •Keyed up •Insomnia (“sleep”) •Restlessness SWICKIR is Quicker: Worry + 3 = GAD (Baughman) 5of 9 with 1 of 2 x 2 weeks *ACCURATE MEDICAL diagnosis “mood disorder due to a general medical condition” AND r/o bipolar disorder BEWARE BEWARE – “too much” energy
  7. Lifetime Prevalence of Common Psychiatric Disorders Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000. *In menstruating women. Lifetime prevalence (%) 0 2 4 6 8 10 12 14 7.8% PTSD 5.1% Generalized anxiety d.o 3.5% Panic disorder 2.5% OCD 16 18 Alcohol dependence 14.1% Major depressive disorder 17.1% 13.3% Social anxiety disorder 5%* PMDD
  8. Conceptual Evolution of Depression/Anxiety Comorbidity 67.8% of patients diagnosed with depression also fulfill the criteria for an anxiety disorder. Boerner and Möller, 1999. of all psychological disorders of all psychological disorders 67.8% 10.4% 10.5%
  9. Depression—Impact on the Healthcare System • Compared with those without depression, depressed individuals: – Utilize all types of healthcare services more often – Incur 1½ to 2 times greater healthcare costs – increased length of hospital stay – significant worsening of physical, social, and role functioning Simon 1995; Luber 2000; Verbosky 1993; Wells 1989.
  10. STAR*D Study demonstrates that current treatments have limited effectiveness Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
  11. TMS* Therapy Outcomes vs. Pharmacotherapy (STAR*D) % of Patients Relapsing During Long Term Follow Up Relapse Rate among those patients in remission at entry into long term follow up rTMS *Using Neurostar TMS device
  12. Likelihood of discontinuing treatment increases with each new medication attempt Systemic Drug Side Effects  Weight Gain  Constipation  Diarrhea  Nausea  Drowsiness  Insomnia  Decreased Libido  Nervous Anxiety  Increased Appetite  Decreased Appetite  Fatigue  Headache/ Migraine  Abnormal Ejaculation  Impotence  Sweating  Tremor  Treatment Discontinuation Side Effects  Weakness  Dry Mouth  Dizziness Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file)
  13. Question 1 • Based on the STAR*D Trial, it appears that there is a “law of diminishing returns” for every antidepressant after the first one employed. – TRUE – FALSE
  14. Best Practices Treatment Guideline for Depression Based on 2010 APA guidelines and NeuroStar TMS Therapy® indication for use. Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010) Unmet Medical Needs
  15. TMS is Included in Practice Guidelines Following Failure of Initial Treatment Schlaepfer, et al. World J Biol Psychiatry (2009); Kennedy, et al J Aff Disorders (2009); American Psychiatric Association (2010) Canadian Network for Mood and Anxiety Treatments (2009) Guideline Sources American Psychiatric Association (2010) “…Acute phase treatment may include pharmacotherapy, depression- focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy…” World Federation of Societies for Biological Psychiatry (2009)
  16. A quick look back in history The Interpretation of Dreams – 1885 - 1890 Ugo Cerletti 1935 Prozac - 1987
  17. Shrinking Shocking or Drugging [Supposedly] the only three things you could do to a patient’s brain…] The Therapeutic Trifecta of Psychiatry:
  18. ECT – origins • Origin in 1700’s – Middlesex Hospital – machine with weak electrical current used for range of illnesses. – John Birch, English neurosurgeon, used it to shock the brains of depressed patients – Benjamin Franklin, after shocked, recommended electric shock for tx of mental illness • Ugo Cerletti – 1935 – noted (incorrectly) that epilepsy and schizophrenia didn’t occur in same patient • Problems with ECT – memory loss, anesthesia risk • Cost of $6400 for eight treatments • 80% improvement • 33,000 hospitalized Americans – ECT in 1980, last year for NIMH figures –
  19. "The Shock Shop, Mr. McMurphy, might be said to do the work of the sleeping pill, the electric chair and the torture rack. It's a clever little procedure, simple, quick, nearly painless it happens so fast, but no one ever wants another one. Ever.”
  20. But even before these guys… • Electromagnetic induction – 1831 (Faraday & Joseph Henry) • 1st demonstrated by Faraday August 29, 1831
  21. Faraday’s law • “The induced electromotive force (EMF) in any closed circuit is equal to the time rate of change of the magnetic flux through the circuit.” • Discovered by Michael Faraday and Joseph Henry in 1831 – Faraday first to publish. 
  22. Faraday’s Law of Induction TMS Magnetic field Induced neuronal current
  23. From electricity to magnetism • Bartholow, R (1874) – Stimulation of human brain (exposed cortex) of patient with cranial defect. • d’Arsonval – “Phosphenes and vertigo” induced inside powerful magnetic coil • Silvanus P. Thomson, Ph.D. – new type of magnetic stimulation (1910) Thompson, SP. “A Physiological Effect of an Alternating Magnetic Field.” Proceedings of the Royal Society of London B82:396-399, 1910
  24. First patent application for magnetic therapy: • 1902 Adrian Pollacsek and Berthold Beer – Vienna, Austria for a “therapeutical apparatus” • Electromagnetic coil, placed over the skull was noted to “pass vibrations into the skull” and “treat depression and neuroses.”
  25. First modern TMS: • Barker AT, et al. “Non- invasive magnetic stimulation of the human motor cortex. The Lancet 1:1106-1107, 1985. • 1st device – designed by Barker – Univ. of Sheffield, England. – 100 microsecond, 2 T pulse
  26. Coil types and rationale From Matt Edwardson, MD – Research Fellow and Acting Instructor, Dept. of Neurology, Univ. of WA 10/16/2011
  27. TMS Targeted Effects on Local and Distant Regional Blood Flow Nahas Z et al. Brain Effects of TMS Delivered Over Prefrontal Cortex in Depressed Adults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.
  28. Nahas Z et al. Brain Effects of TMS Delivered Over Prefrontal Cortex in Depressed Adults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.
  29. An unusual side effect of imaging (2004)… • CONCLUSIONS: “These preliminary data suggest that the EP-MRSI scan induces electric field that are associated with reported mood improvement in subjects with bipolar disorder.”
  30. Neuron TMS Directly Depolarizes Cortical Neurons Pulsed magnetic fields from TMS: • induce a local electric current in the cortex which depolarizes neurons • eliciting action potentials • causing the release of chemical neurotransmitters Neurons are “electrochemical cells” and respond to either electrical or chemical stimulation
  31. TMS Releases Neurotransmitters in the Brain Depolarization of neurons in the DLPFC causes local neurotransmitter release Depolarization of pyramidal neurons in the DLPFC also causes neurotransmitter release in deeper brain neurons Activation of deeper brain neurons then exerts secondary effects on remaining portions of targeted mood circuits Dorsolateral prefrontal cortex Anterior cingulate cortex Kito (2008) J Neuropsychiatry Clin Neurosci These effects are associated with improvements in depressive symptoms
  32. • TMS uses Faraday’s principle of magnetic induction to: – Induce a current flow and depolarization in “local” neurons close to the TMS Coil, and – It also induces, by additional synaptic pathways, release of neurotransmitters diffusely in the brain from deep brain nuclei • Choose one: – TRUE – FALSE Question 2
  33. ECT vs. TMS ECT TMS Anesthesia, LOC Yes No Induction of seizure Yes No Systemic effects Anesthetic drugs, increase HR none Treatment schedule 3X/ week (8 -15 tx) Daily, M-F, six weeks (30 tx) Rapidity of onset 2 – 3 treatments 2 – 3 weeks Mechanism of action SEIZURE. Massive NT release; rise in sz threshold Reactivation of neural circuits. Precise, LOCAL release of NT’s. Side effects Memory loss, confusion Essentially none (mild HA 1st week) Psychosocial impact can’t work Drive to and from tx’s, work improved After-effects Mild (usually transient) memory loss None. Pro-cognitive Insurance coverage Almost always Rare. Improving
  34. Identify which of these statements are true: a)ECT induces seizures; TMS does not. b) There is systemic exposure to drugs with ECT; there is none for TMS. c)ECT causes memory loss/confusion; TMS does not d)ECT is well reimbursed by insurance; TMS is not yet well reimbursed. ANSWERS: 1)All are true 2)Not all of these statements are true. Question 3
  35. • Outpatient 37-minute daily procedure (3000 pulses) • 4-6 week treatment course • “Antidepressant medication monotherapy” may be used for maintenance – we use multiple both during and after. • At CWI – multiple medications thyroid balancing, NT balancing, and psychotherapy (during treatment) • “Hot-rodding” the TMS machine – ( ) TMS in Clinical Practice at CWI
  36. O’Reardon, JP, et al. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multi-Site Randomized Controlled Trial. Biol Psychiatry 62:1208-1216.
  37. Who Was Studied? • Primary diagnosis: DSM-IV Major Depressive Disorder – Unipolar type, non-psychotic – Moderate to severe symptoms at baseline – Approximately one-third of patients had a co-morbid anxiety disorder (OCD excluded) • Antidepressant Treatment History: – Average number of antidepressant medication trials in current episode = 4 (range: 1 to 23 attempts) • Majority of treatment attempts were unable to achieve adequate dose and duration of treatment due to intolerance – all patients had failed to achieve satisfactory benefit from one antidepressant medication at an adequate dose and duration in current episode Demitrack and Thase (2009) Psychopharm Bulletin 42
  38. • In the original registration study for TMS: – There were multiple failed medications trials in these patients (average of four) – 1 out of 2 patients responded – 1 out of 3 patients remitted – The effect size of the treatment was roughly 0.5 • Choose one: – All of the previous statements are TRUE – Not all of the previous statements are true Question 4
  39. Optimization of TMS (‘OPT-TMS’) Study • NIMH-funded, independent of industry • N=190 patients, 4 premier academic sites • Primary outcome measure: % Remission - Active 15% vs Sham 4% (P = 0.015); Odds Ratio of achieving remission: 4.2 (95%CI, 1.3-13.2) Major Findings: • MADRS total score decreased:16.6% (Active) vs 6.9% (Sham) p=0.01 (Effect size: 0.51) • 30% of patients achieved remission in open-label extension phase • Excellent safety and adherence Conclusion: “Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.” Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, PhD; Berry Anderson, PhD, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD
  40. Recent TMS Literature Review • Roughly 30 controlled clinical research studies to date • Most recent meta-analysis (Slotema, et al, 2010): – Included analysis of 34 studies involving 1,383 patients – Estimated standardized effect size = 0.55 (P < 0.001) Conclusion: “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression…and has a mild side effect profile….” 1.Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)J Clin Psych 71(7):873-84. 2.Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine, 39:65-75.
  41. • Independent, Peer-reviewed • 15 TMS clinical trials involving nearly 500 patients – Average HAM-D decrease in depressive symptoms >5 points vs. sham control • Meets clinical significance threshold of 3 points on the HAM-D scale – Response rate with active TMS was >3x higher than sham treatment – Remission rate with active TMS was >6x higher than sham treatment • “High strength of evidence” for efficacy from well- controlled RCTs Independent U.S. Agency for Healthcare Research and Quality (AHRQ) Confirms Evidence for Efficacy of TMS Agency for Healthcare Research and Quality: Comparative Effectiveness Report on Non-Pharmacologic Treatments for Depression , October 2011
  42. • Pharmacologic “switch” to next best medication: • 22.3% (95% CI: 16.2%-28.4%) • Augmentation: • 27.2% (95% CI: 20.4%-34.0%) • TMS (Neuronetics) Outcomes Study: • 37.2% (95% CI: 31.9%-42.7%) 47 AHRQ – the “betting odds” on remission in the next step in treatment Agency for Healthcare Research and Quality: Comparative Effectiveness Report on Non-Pharmacologic Treatments for Depression , October 2011
  43. NeuroStar TMS Therapy: Acute Efficacy Outcomes in Real-World Clinical Practice
  44. • Goal – Define real world outcomes associated with NeuroStar TMS Therapy across a broad spectrum of patients and practitioners • Patient Population & Sites – 307 evaluable unipolar, non-psychotic MDD patients in acute phase – 42 sites comprised of institutions and private practice • Study Design Phases – Acute phase (clinician determined care based on clinical progress) – Long-term outcomes at 12 months (ongoing) • Patient Treatment – Clinical care initiated per current labeled guidelines 49 Treatment Utilization and Outcomes Study ( Protocol No. 19-50001-000) Neuronetics, Inc. (data on file) ; listing number NCT 01114477
  45. Patient and Treatment Characteristics (N=307) N (%) Female 205 (66.8) Age in years, mean (SD) 48.6 (14.2) Disease and Treatment History N(%) - Recurrent Major Depression - Comorbid Anxiety Disorder 285 (92.8) 46 (15.0) Psychiatric Treatment History N(%) - History of Inpatient Hospitalization - History of ECT Treatment 133 (43.3) 15 (4.9) Prior Antidepressant Medication Treatment mean(SD) - Avg # of Adequate Treatments in Current Episode 2.5 (2.3) Mean (SD) Number of TMS Sessions During Acute Treatment 28 (10.1) Neuronetics, Inc. (data on file) ; listing number NCT 01114477 50
  46. % of Patients (N=307) LOCF Analysis of intent-to-treat population Comparison of End of Acute Treatment Clinical Status: Clinician- and Patient-Assessed Outcomes Clinician Rating (CGI-Severity of Illness) Patient Rating (PHQ-9 Scale) Markedly ill or worse Moderately ill Mildly ill or better
  47. TMS Reintroduction Summary Long Term Follow Up Phase (N=257) # of Patients Treated with TMS Date Following Completion of Acute Treatment Phase Month 1 (Taper) N=93 (36.2%) patients received at least 1 TMS treatment day during long term follow up after Taper Phase (i.e., from month 2 thru month 12) Mean (SD) # of TMS treatment days among those patients receiving TMS = 16.2 days (21.1)
  48. Long Term Follow Up After Acute Treatment Janicak, et al. Brain Stimulation, 2010. • Safety confirmed during long term, open-label 6 month follow up period • During open-label follow up on antidepressant medication monotherapy, – ~37% of patients required TMS reintroduction – ~85% of patients who received TMS reintroduction benefited • Net incidence of illness relapse under these open-label follow up conditions: 11% – Six-month relapse with antidepressant treatment alone in STAR*D study was 35-50% (Level 2 and 3 range)
  49. TMS Open-Label Durability of Effect Study Outcome TMS (in remission) (N=56) Outcome ECT - Combination Pharmacotherapy 1 (N=95) ECT - Continuation ECT 1 (N=89) % Early Discontinuation 16.1% % Early Discontinuation 22.1% 16.8% % Disease Recurrence 10.7% % Disease Recurrence 31.6% 37.1% % In Remission by Study Completion 73.2% % In Remission by Study Completion 46.3% 46.1% 1 Kellner, CH, Knapp, RG, Petrides, G, et al. Continuation Electroconvulsive Therapy vs Pharmacotherapy for Relapse Prevention in Major Depression: A Multisite Study From the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 2006, 63:1337-1344. Janicak, et al., Brain Stimulation (2010)
  50. NeuroStar TMS Therapy Outcomes vs. Pharmacotherapy (STAR*D) % of Patients Relapsing During Long Term Follow Up Relapse Rate among those patients in remission at entry into long term follow up
  51. • In research settings, two large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS • Prospective, naturalistic study confirms these results in real-world practice settings • Overall, 1 in 2 patients respond and 1 in 3 patients achieve remission • Meta-analyses from multiple studies shows TMS effect size of >0.5 • High level of treatment adherence , >80% of patients completed acute treatment in both research setting and in clinical practice • Appears to be at least as effective as ECT for treatment and relapse prevention Summary of Clinical Outcomes 56
  52. Safety and Tolerability of NeuroStar TMS Therapy
  53. • No systemic side effects • No adverse effect on cognition • Most common adverse event associated with treatment was scalp pain or discomfort – < 5% of patients discontinued due to adverse events • No seizures with NeuroStar device during clinical studies (over 10,000 treatments) • Rare risk of seizure with NeuroStar TMS in post-market use (0.003% per treatment, <0.1% per acute treatment course) (>150,000 treatments in post-marketing experience to date) • Long term safety demonstrated in 6 months follow-up NeuroStar TMS Therapy: Safety Overview Janicak, et al. J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010.
  54. No Evidence of Emergent Suicidal Ideation * Shift Score indicates the percent of subjects who experienced a change in HAMD Item 3 score from 0 or 1 at baseline to 3 or 4 at later point in time. HAMD Item 3 Suicidal Ideation Shift Score (%)* 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Baseline Week 2 Week 4 Week 6 NeuroStar TMS Therapy (n=155) Sham TMS (n=146) Janicak (2008) J Clinical Psychiatry.
  55. • Appropriate patients for TMS might include the following: – Failed one antidepressant at appropriate dose and duration of treatment – Desire for no seizures, memory loss, or systemic exposure to drugs (e.g. pregnancy, breast feeding) – Appropriate if patient MUST keep working. • Choose one: – All of the previous statements are TRUE – Not all of the previous statements are true Question 5
  56. “But my patients don’t know about this and aren’t asking for it….” “It’s not the consumers’ job to know what they want.” - Steve Jobs
  57. “For me, the practice of medicine has opened the door to the greatest adventure in life. Medicine is like a hallway lined with doors, each door opening into a different room, and each room opening into another hallway, again lined with doors. Medicine is always wonderful and never will be finished.” - Charles H. Mayo, M.D.