1. 1 The (Re)Emerging Role of Therapeutic Neuromodulation Philip G. Janicak, M.D. Professor of Psychiatry Rush University Medical Center 2012 Current Psychiatry American Academy of Clinical Psychiatrists Symposium March 29, 2012

2. Disclosures–Philip G. Janicak, M.D. Grant/Research Support: Cervel Neurotech; Neuronetics; Otsuka; Sunovion Consultant/Advisory Board: Bristol-Meyers Squibb; Neuronetics Speakers’ Bureau: Bristol-Meyers Squibb/Otsuka; Neuronetics 2

3. 3 Major Goals To review the concept of neuromodulation as an evolving therapeutic strategy To consider the application of therapeutic neuromodulation for psychiatric disorders with a focus on major depression To review the definition, indications, administration, efficacy, safety and tolerability for approved therapies

4. 4 Major Depression: A Significant Unmet Need Kessler RC, Berglund P, Demler O, et al. JAMA. 2003;289(23):3095-3105. Inadequate response Intolerant to side effects } 3.2 Million Adequately Treated 4 Million Poorly Served 7.2 Million Treated 6.8 Million Untreated 14 Million Adults U.S.

5. 5 Neuromodulation Induces electrical current in nervous tissue (i.e., neurostimulation) Based on concept of functional disturbances in distributed neuronal circuits (e.g., corticolimbic mood circuit) Episodic impact on brain Usually no sustained systemic effects © Janicak

6. Neuromodulation Techniques Electroconvulsive Therapy (ECT) Focal Electrically Administered Seizure Therapy (FEAST) Magnetic Seizure Therapy (MST) Transcranial Magnetic Stimulation (TMS) Transcranial Direct Current Stimulation (tDCS) Deep Brain Stimulation (DBS) Vagus Nerve Stimulation (VNS) Epidural Cortical Stimulation (EpCS) NON-INVASIVE INVASIVE SEIZURE NO SEIZURE 6

7. 7 ECT Disadvantages Access/patient acceptance Optimal administration Adverse effects Cognitive Cost Relapse rates © Janicak

8. ECT Adminstration: Maintenance Treatment Strategies Medication only ECT only ECT plus Medication CORE Study (n=201) Li+ plus NT vs ECT 6-month trial Relapse rates 37% for ECT 32% for medication 50% relapsed or dropped out 8 Kellner, 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 Dec;63(12):1337-44.

9. 9 Vagus Nerve Stimulation (VNS): Definition Mild electrical pulses applied to the left vagus nerve in the neck area for transmission to the brain Left vagus nerve primarily afferent fibers © Janicak

10. 10 VNS Therapy: Components Dimensions Weighs less than 1 ounce and measures 2  2  0.27 inches Location Subcutaneously in left chest Function Delivers mild pulses at programmed time intervals to left vagus nerve Stores selected information Battery life Dependent upon dose settings: 3 years at a higher setting, compared to 8 years at a lower setting* *For the full range of settings in relationship to battery life, see the Physician’s Manual. Cyberonics, Inc. Physician’s Manual for the VNS Therapy™ Pulse Model 102 Generator and VNS Therapy™ Pulse Duo Model 102R Generator. Houston, Tex; 2003. -- Data on file. Cyberonics, Inc.

11. 11 Output currentMilliamps (mA)0–3.51.0 Signal frequency Hertz (Hz)1–30 20 Pulse widthMicroseconds (  sec)130–1000 500 Duty cycle ON time Seconds7–60 30 OFF timeMinutes 0.2–1805 VNS Stimulation Parameters ParameterUnits Range Median Value at 12 Months in Pivotal Study Stimulation cycle is 24 hours/day. Cyberonics, Inc. Epilepsy Patient’s Manual for Vagus Nerve Stimulation With the VNS Therapy TM System. Houston, Texas 2002, 2004. -- Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005.

12. 12 VNS: Indications Treatment-resistant epilepsy* Treatment-resistant depression* Adjunctive treatment Chronic or recurrent depression Failed four or more adequate antidepressant trials © Janicak *FDA APPROVED

13. 13 VNS Acute Study: Response Rates 10 HAMD 24 (Primary Outcome)IDS-SR 30 (Secondary Outcome) % Responding 17 15 7 0 5 10 15 20 VNS Therapy Sham-control p=0.032 p=0.251 Rush AJ, et al. Biol Psychiatry. 2005;58:347-354. Results: 12-Week Response Rates (LOCF)

14. 14 VNS Long-Term Study: Response Rates Rush AJ, et al. Biol Psychiatry. 2005;58:355-363. 0 5 10 15 20 25 30 35 IDS-SR HRSD 24 % Response 14 18 19 22 20 15 17 23 30 27 17 20 27 32 28 MADRS Evaluable Observed and LOCF Response defined as  50% reduction in IDS-SR 30, HRSD 24, MADRS compared with pre-stimulation baseline 3 Months (n=203-205) 6 Months (n=192-197) 9 Months (n=184-186) 12 Months (n=180-181) LOCF Beyond 3 Months (n=201-202)

15. 15 0 10 20 30 40 Percentage of Patients ResponseRemission IDS-SR 30 Pivotal study (n=180) Comparative study (n=112) p=0.029 p=0.006 HAMD 24 ResponseRemission 22 15 30 17 Pivotal study (n=181) Comparative study (n=104) 12 4 13 7 p=0.003 p=0.031 Evaluable observed analysis. George MS, et al. Biol Psychiatry. 2005;58:364-373. HAMD 24 and IDS-SR 30 Categorical Outcomes at 12 Months (Observed Cases) VNS Comparative Study: Response and Remission Rates

16. 16 VNS Acute Study: Adverse Events Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005. AEs were analyzed according to severity rating Mild AE: transient and easily tolerated Moderate AE: discomfort and interrupted usual activities Severe AE: considerable interference with usual activities Pivotal Study Sham-Control Group (3 Months) Pivotal Study VNS Group (3 Months) Mild Moderate Severe

17. 17 VNS Long-Term Study: Adverse Events 3 months (N=232) 6 months (N=225) 9 months (N=218) 12 months (N=209) 24 months (N=184) Rush AJ, et al. Biol Psychiatry. 2005;58:355-363. Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005. AEs  10%

18. 18 Transcranial Magnetic Stimulation (TMS): Definition Pulsed magnetic fields of ~1.5 Tesla in strength Magnetic fields pass unimpeded approximately 2–3 cm into cortex Induces a focal electrical current in cortical tissue Produces local and distal functional changes in targeted neural circuitry

19. TMS: Components  Electrical source  Large capacitors  Magnetic stimulator  Cable with minimal resistance  Stimulating coil  Computer program  produces a pattern of magnetic pulses over a brief timeframe 19 © Janicak

20. 20 TMS: Stimulation Parameters Motor threshold (80–120%) Frequency (<1 Hertz; 1–20 Hertz) Single versus repetitive (rTMS) Slow versus rapid rTMS Stimulation train Intertrain intervals © Janicak

21. TMS: Indications Unipolar major depression* Bipolar disorder Anxiety-related disorders Generalized anxiety Obsessive-compulsive disorder Posttraumatic stress disorder Panic disorder Schizophrenia and schizoaffective disorder Substance dependence Other disorders (e.g., migraine headaches) 21 © Janicak *FDA APPROVED

22. TMS: Study Design O’Reardon JP, Solvason B, Janicak PG, et al. Biol Psychiatry. 2007;62:1208–1216.; Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry. 2008;69(2):222–232.; Avery DH, Isenberg KE, Sampson SM, et al. J Clin Psychiatry. 2008;69(3):441-451; Lisanby SH, Husain MM, Rosenquist PB, et al. Neuropsychopharmacology. 2009,34:522–534.; Janicak PG, Nahas Z, Lisanby SH, et al. Brain Stimul. 2010;3(4):187-199. Maintenance of Effect Study 2,4,5 ‘103’ Open-Label Crossover Study 2,3,4 ‘102’ Randomized, Controlled Study 1,2,4 ‘101’ Not Improved Improved 22

23. 23 BaselineWeek 2Week 4Week 6 Change From Baseline P=.191 P=.057 P=.058 BaselineWeek 2Week 4Week 6 Change From Baseline P=.051 P=.012 P=.015 TMS: Efficacy in Overall Population MADRS Total Score (Baseline to Endpoint Change) HAMD-24 Total Score (Baseline to Endpoint Change) Active TMS (n=155) Sham TMS (n=146) * P<.05. LOCF, LS mean. O’Reardon JP, Solvason B, Janicak PG, et al. Biol Psychiatry. 2007;62:1208–1216. * *

24. 24 TMS: Response and Remission Rates O’Reardon JP, Solvason B, Janicak PG, et al. Biol Psychiatry. 2007;62:1208–1216. Active TMSSham TMS

25. 25 P=.007 P=.0006 P=.0041 TMS: Efficacy in Indicated Population MADRS Total Score (Baseline to Endpoint Change) 1 HAMD-24 Total Score (Baseline to Endpoint Change) 2 ** P<.01. LOCF analysis of evaluable study population. 1. Lisanby SH et al. Neuropsychopharmacology. 2009;34(2):522-534; 2. Data on file. Neuronetics, Inc: Malvern, PA; 2008. Active TMS (n=88) Sham TMS (n=76) ** BaselineWeek 2Week 4Week 6 0 -2 -4 -6 -8 Change From Baseline ** P=.0018 P=.0006 P=.0063 BaselineWeek 2Week 4Week 6 0 -2 -4 -6 -8 Change From Baseline

26. TMS: Maintenance of Effect Study 99 patients entered 24-week durability phase on antidepressant maintenance monotherapy 10 (12.9%) patients relapsed 38 (38.4%) met criteria for symptom worsening 32/38 (84%) reachieved symptomatic benefit with TMS reintroduction Safety and tolerability were similar to TMS monotherapy Janicak PG, Nahas Z, Lisanby SH, et al. Brain Stimulation 2010. (in press). 26

27. NIMH OPT-TMS: Study Design Medication-free, TRD subjects (n=190) Active versus sham TMS, same stimulation parameters to left DLPFC as industry trial; improved sham control; MRI-guided targeting Flexible duration, an initial 3-weeks (15 sessions) with the option for additional 3-weeks if improving Primary outcome was remission at exit George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516. 27

28. NIMH OPT-TMS: Study Results TMS Sham P<0.015 Odds ratio = 4.2; P<0.02NNT=12 TMS Sham Remission 0% 5% 10% 15% 28 George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516.

29. 29 TMS vs ECT No seizure necessary No anesthesia No cognitive disruption No drug interaction issues Subjects remain independent © Janicak

30. 30 TMS vs ECT Literature Summary 5 of 9 trials reported antidepressant equivalence 1 trial reported UND/BL ECT to be superior to TMS 1 trial reported BL ECT to be superior to TMS 1 trial found UND/BL ECT plus medication superior to TMS monotherapy in MDD with psychosis but comparable in efficacy to TMS for MDD without psychosis 1 trial found improvement with both but ECT>TMS for mood and suicidality Janicak PG, Dowd SM, Rosa M, et al. Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation for treatment of psychiatric disorders (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97–109.

31. 31 TMS: Common Adverse Events Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry. 2008;69(2):222–232. Prestudy 1 2 3 4 5 6 7 8 9 Week 50 45 40 35 30 25 20 15 10 5 0 No. of Events 70 60 50 40 30 20 10 0 Prestudy 1 2 3 4 5 6 7 8 9 Week No. of Events Time Course of Incidence of Headache in RCT Time Course of Incidence of Application-Site Pain in RCT Active TMS (n=155) Sham TMS (n=146)

32. 32 TMS: Serious Adverse Events Active TMS (N=165) N (%) Sham (N=158) N (%) Serious Adverse Events Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry 2008;69(2):222-232.

33. TMS: Safety I No seizures; deaths or suicides Minimal systemic effects No adverse effect on cognition Most common adverse events were headache and scalp discomfort during treatment <5% of patients discontinued due to adverse events No seizures; deaths or suicides Minimal systemic effects No adverse effect on cognition Most common adverse events reported were headache and scalp discomfort 5.5% (n=5) of patients on active TMS discontinued due to adverse effects TMS StudyNIMH Study Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry 2008;69(2):222-232.; George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516. 33

34. 34 TMS: Safety II Precautions Pregnancy Children and adolescents Heart disease Medication pumps Medication that may lower the seizure threshold Warnings Implanted device activated or controlled by physiologic signals, even if the device is located outside the 30 cm distance. Wearable or implantable cardioverter defibrillators Contraindications Conductive, ferromagnetic, or other magnetic sensitive metals that are implanted or are non-removable within 30 cm of the treatment coil (excludes dental hardware) © Janicak

35. 35 Deep Brain Stimulation (DBS): Definition Delivery of electrical stimulation Produced by an internal pulse generator Administered to specific CNS locations Chronically implanted electrodes Minimal tissue injury © Janicak

36. 36 DBS: Components/Parameters A brain lead (1.27 mm in diameter) is stereotactically implanted onto specific brain targets The stimulator leads are connected by a wire to pulse generators, usually placed in the chest Parameters such as frequency (2 to 185 Hz), intensity (0 to 10.5 volts), and pulse width (60 to 450 μs) are programmable Stimulators can also be programmed to vary in several respects (e.g., continuous versus intermittent stimulation) © Janicak

37. 37 Parkinson’s disease Tremors Dystonia Refractory obsessive-compulsive disorder (OCD) Treatment-resistant depression (TRD)* DBS: Indications © Janicak *NOT FDA APPROVED

38. 38 DBS: Efficacy in TRD Chronic stimulation to modulate overactivity of the subgenual cingulate gyrus and impact downstream targets Chronic stimulation to modulate overactivity of the subgenual cingulate gyrus and impact downstream targets Maximum benefit delayed and progressive, plateaued at 6 months and was sustained for up to 12 months Maximum benefit delayed and progressive, plateaued at 6 months and was sustained for up to 12 months PET demonstrated alterations in blood flow PET demonstrated alterations in blood flow No adverse cognitive effects No adverse cognitive effects Mayberg, et al, Neuron. 2005.; Lozano, et al. Biological Psychiatry. 2008.

39. 39 Percent of Subjects Meeting Criteria for Response or Remission by Time Patients meeting response or remission criteria after DBS. The proportion of patients responding or reaching remission increased over time to plateau from 6 to 12 months. Mayberg, et al, Neuron. 2005.; Lozano, et al. Biological Psychiatry. 2008.

40. Percentages of Patients With Treatment-Resistant Depression (N=20) Who Responded or Remitted 40 Response was defined as a reduction of ≥50% from baseline in Hamilton Depression Rating Scale (HAM-D) score; remission was defined as a HAM-D score ≥7. Kennedy, Giacobbe, Rizvi, et al. Am J Psychiatry 2011;168:502-510.

41. 41 Surgical procedure (e.g., seizure, bleeding, infection) Device (e.g., lead breakage, malfunctioning) Stimulation (e.g., paresthesias, muscle contractions, mood changes) DBS: Adverse Effects © Janicak

42. 42 Potential Role of Therapeutic Neuromodulation for Psychiatric Disorders I Organic psychosis (e.g., refractory Parkinson’s syndrome) Catatonia unresponsive to medication NMS unresponsive to medication Bright light therapy Switch/Augmentation Strategies (seasonal pattern) (insufficient response) Prior response to ECT only High risk Patient preference Psychotic depression Manic delirium TMS/ w/ and w/o medication ECT (insufficient response) ANTIDEPRESSANT (if psychotic, consider AP as well) LITHIUM/VPA/SGA SCHIZOPHRENIC EPISODE ANTIPSYCHOTIC MANIC EPISODE MAJOR DEPRESSIVE EPISODE © Janicak 10/7/2015

43. 43 Nonemergent Prior good response to unilateral, nondominant ECT High risk (e.g., acutely suicidal) Prior poor response to unilateral, nondominant ECT Unilateral, nondominant ECT (2.5-6.0 x seizure threshold) (insufficient response) Bilateral ECT (excessive cognitive adverse effects) (chronic, relapsing) Maintenance medication (e.g., lithium plus NT) Maintenance ECT (± medication) Maintenance TMS/VNS (± medication) Possibly DBS Adapted from: Janicak PG, 2006 ECT Potential Role of Therapeutic Neuromodulation for Psychiatric Disorders II © Janicak 10/7/201543

44. 44 Major Goals To review the concept of neuromodulation as an evolving therapeutic strategy To consider the application of therapeutic neuromodulation for psychiatric disorders with a focus on major depression To review the definition, indications, administration, efficacy, safety and tolerability for approved therapies

45. Janicak PG, Dowd SM, Rado JT, Welch MJ. The (re)emerging role of therapeutic neuromodulation. Curr Psychiatry 2010;9(11)66-74. Janicak PG, Dowd SM, Rado JT, Welch MJ. The (re)emerging role of therapeutic neuromodulation. Curr Psychiatry 2010;9(11)66-74. Janicak PG, Nahas Z, Solvason SH, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6- month, multisite, open-label study. Brain Stimul 2010;3(4):187-199. Janicak PG, Nahas Z, Solvason SH, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6- month, multisite, open-label study. Brain Stimul 2010;3(4):187-199. Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depressive: preliminary results of a randomized trial. Biol Psychiatry. 2002;51:659–667. Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depressive: preliminary results of a randomized trial. Biol Psychiatry. 2002;51:659–667. Janicak PG, Dowd SM, Rosa M, et al. Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation for treatment of psychiatric disorders (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97–109. Janicak PG, Dowd SM, Rosa M, et al. Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation for treatment of psychiatric disorders (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97–109. 45 References I

46. 46 References II Janicak PG, O’Reardon J, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69(2):222–232. Janicak PG, O’Reardon J, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69(2):222–232. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: Clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology. 2009;34(2):522–534. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: Clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology. 2009;34(2):522–534. Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461– 467. Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461– 467. O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–1216. O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–1216. Pilitsis JG, Bakay AE. Deep brain stimulation for psychiatric disorders. Psychopharm Review. 2007;42(9):67–74. Pilitsis JG, Bakay AE. Deep brain stimulation for psychiatric disorders. Psychopharm Review. 2007;42(9):67–74.