Y P O Berenson-Allen Center for Noninvasive Brain Stimulation - PDF document

Y P O Berenson-Allen Center for Noninvasive Brain Stimulation Beth Israel Deaconess Medical Center C October, 2019 T Linda L. Carpenter, MD Professor, Brown University Department of Psychiatry Chief, Butler Hospital Mood Disorders Program O Providence, Rhode Island N O D E Disclosure of Financial Relationships S • NeoSync – Research Support A • Neuronetics – Research Support E • Affect Neuro- Research Support, L Consulting P • Janssen - Research Support, Consulting Off-label use of TMS devices will be discussed 1

Unresolved Symptoms Following Y Adequate Trial (Dose and Duration) of Antidepressant Medication P 67% STAR*D Study (N=2,876) O Mild symptoms Moderate Severe symptoms Very severe symptoms Remission ~28% symptoms ~12% ~4% ~33% ~23% C Percent T O N Depressive Symptoms (QID-SR Score) After Up to 12 Weeks Antidepressant Treatment STAR*D = Sequenced Treatment Alternatives to Relieve Depression Trivedi MH et al. (2006), Am J Psychiatry 163(1):28-40 O D YLD=Years Lost Due to Disability E S A E L P Depression is the #1 GLOBAL CAUSE OF DISABILITY 4 2

Y P O 1896: D’Arsonval - C demonstrates electromagnetic 1985: Jalinous, Freeston, Barker stimulation - First TMS Device T O 1985: 1982: Polson – Sheffield UK Barker & Peripheral Nerve Stimulation 1910: Sylvanus Thompson- Cain - N retina stimulation publish magneto-phosphenes TMS to cortex O D E S A E L P Tony Barker, unpublished data, February 2019 3

Y What is TMS? • Pulsed electricity through a coil of wires P • MRI-strength magnetic O fields penetrate scalp skull and meninges C • Faraday’s Law – current induced in perpendicular plane T • Neurons – Depolarize + O Fire Action Potential • Effect circuits beneath coil N and in remote brain regions O D E S A How it Works: E TMS Energy Transfer L A single TMS pulse P induces current in neurons which project from superficial to deeper cortex 4

Randomized Controlled Clinical Trials Y FDA Clearance for TMS Devices to treat Major Depressive Disorder P O “Figure-8” Shaped “H-Coil” Coil (Hersed) C O’Reardon J et al 2007, George M et al, 2010 Levkovitz Y et al 2015 October 2008 October 2013 T O N O D E S Neuronetics MagVenture NeuroSoft Mag & More A E L Magstim Nexstim P Brainsway H-Coil 5

MDD Brain Target for TMS Therapy: Y Why Target Dorsolateral Prefrontal Cortex? P O C T O N O D Baseline subgenual cingulate connectivity E predicts rTMS treatment response S A E L P rTMS normalized depression- related subgenual hyperconnectivity to DMN Liston C et al, 2014 6

Y P O Single Pulse CALIBRATE: C TMS Motor Cortex MEP APB Monitor TREAT: muscle Ground Prefrontal Cortex T Efferent Peripheral O Motor Nerve Vertebral Abductor Pollicis Brevis column N (thumb) Muscle or First Dorsal Interosseous (first finger) O D Methods for TMS Coil Targeting (DLPFC) E S EEG 10/20 Neuronavigation to Anatomic Target Site for F3 A E L ABP “5 Cm P 5 cm Rule” Where is DLPFC? Border between the anterior 1/3 and middle 2/3 of the middle frontal gyrus (F2) and between the superior and inferior frontal sulci (Brodmann areas 46 and 9). 7

Y Outcomes: RCTs Leading to FDA Clearance of TMS Devices for MDD P O MADRS C (p=.057) T - Week 6 MADRS HAMD17 O - 24% v. 13% Response (p=.006) - Subset w/ 1 med failure: 50% Resp, 33% Remit - Replicated by OPT TMS N - ALL FIGURE 8 DEVICES O’Reardon J et al 2007 O D E S TMS Response and Remission A Rates in E Neuronetics’ Controlled L Acute Study P O’Reardon J et al, 2007 8

Extended TMS Acute Course for Nonresponders (n=71) Y Open Cross Over Trial (n=85, former sham) P O C T O N Avery DH et al, 2008 O D FDA Approval based on Subset (n=164) from E Overall Study Sample (n=301) S A E L P Demitrack, MA & Thase, ME, 2009 9

Highly Significant Outcomes in Subset (n=164) Y who failed ONE Adequate Antidepressant Trial P O C T O N ** P <.01.; LOCF analysis of evaluable study population. Demitrack, MA & Thase, ME, 2009 O D TMS Response and Remission E Rates in FDA-Indicated Population S HAMD-24 Response Rates HAMD-24 Remission Rates (>50% Improvement from Baseline) (HAMD-24 Total Score <11) A 60 60 54 E 50 50 40 37 40 L Rate (%) Rate (%) 33 30 30 23 P 19 20 20 10 10 7 0 0 Week 2 Week 4 Week 6 Week 2 Week 4 Week 6 Demitrack, MA & Thase, ME, 2009 10

TMS Side Effects in Y Neuronetics TMS Trial P O C T O N O’Reardon J et al, 2007 21 O D NIH Optimization of TMS for E Depression Study (OPT-TMS) S 4 University Hospital TMS Clinics A Novel Sham (more effective blind) E Same device and stim parameters as Neuronetics clinical trial but no Industry sponsorship L P MRI-guided coil placement Large Sample N=190 (ITT) 11

OPT-TMS “Active Sham” Condition Y • Mimicked the somatosensory experience of TMS P • Masked the TMS administrators and patients to TMS acoustic signals • Serial Assessment of Potential unblinding O C T O N George MS et al, 2010 O D OPT- TMS E Primary S Efficacy A Outcome (Remission) E L Replicated Neuronetics’ P Trial Results b Adjusted odds ratio - adjusted for site, age duration of current depressive episode, and George MS et al, 2010 medication resistance 12

OPT- TMS Continuous Outcomes Y P O C T O Confirmed efficacy as reported by Neuronetics’ Sponsored Trial N George MS et al, 2010 O D Naturalistic Outcomes Study E 58% Responders, 37% Remitters S A E L • Clinical results matched those reported in controlled research trials. P • Confirmed that TMS therapy is safe and well tolerated in a nonresearch population. • 54% of the patients had ATR>1 but, resistance level NOT a predictor of response Carpenter LL et al, 2012 13

Y Long-Term Durability of TMS? P O C T O N 27 O D For Comparison with Relapse Following TMS: Relapse E During Follow- Up in STAR*D S The greater the level of treatment resistance A (prior to remission), the more quickly a patients E with TRD will relapse L P Level 1 (non-resistant) Level 2 (1 prior Tx failure) Level 3 (2 prior Tx failures) Level 4 (3 prior Tx failures) Rush et al, 2006 14

Durability of Y Response (n=99 followed 24 weeks) P Time to Relapse (recurrence of full DSM-IV criteria for MDD for 2 weeks OR no improvement • 10% Relapsed O despite 6 week course of TMS reintroduction) (Kaplan-Meier survival estimate=12.9%) • 38% had “symptom C worsening” •TMS re-introduction “rescue” T •2 session/week x 2 weeks, then daily O Time to Reintroduction of TMS • 84.2% who got “booster” (CGI Severity change of 1 point over two TMS re-achieved response successive weeks) N Janicak PG et al, 2010 O D E Naturalistic Long-Term Outcomes 63% Acute TMS S Responders Remained A Responders Throughout Follow up E 36% Required L Additional TMS Treatments P Mean Number of Additional Treatments=16 Dunner D et al, 2014 15

Maintenance TMS – Prospective RCT Y 6-site study P Med-Free Responders to Acute Course of TMS O N=49 randomized: “SCHEDULED” (1 C TMS/month) OR ”OBSERVED” (assess/month) T BOTH get ‘RESCUE TMS’ when indicated O Is RESPONSE TO TMS N maintained longer with once/month maintenance Philip N et al, 2015 TMS? O D TMS Coil Size/Shape E o Impacts Spread Shape and Depth of S o o Electric Field Tradeoff: Stimulation Field o o Depth vs. Focality A Depth E L P Deng Z et al, 2012 16

Outcomes: RCT Leading to FDA Y Clearance of Brainsway Device P - Week 5 HAMD O - 38% v. 21% Response - 33% v. 15% C Remission - Unique Coil Design - L>R DLPFC (ITT) Change in HDRS- T 21 from BL to Week5 p=.06 O Significantly Higher Remission N In Less Resistant Depression Levkovitz Y, et al 2015 O D H-Coil Continuation Phase Treatment E (2 sessions/week) S 33 Nonresponders to Active A TMS during Acute Phase Of Blinded RCT E (20 sessions/4 weeks) Continued Blinded TMS L 2/week for 12 more weeks P 61% Achieved RESPONSE Status with the additional sessions Yip AG, et al 2017 17