Focally Electrically Administered Seizure Therapy (FEAST) and other developments in stimulatory techniques.

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1 Focally Electrically Administered Seizure Therapy (FEAST) and other developments in stimulatory techniques. Mark S. George, MD Distinguished Professor of Psychiatry, Radiology and Neurology Layton McCurdy Endowed Chair Director, Brain Stimulation Laboratory Medical University of South Carolina Staff Physician Ralph H. Johnson VA Medical Center Charleston, SC USA Royal College of Psychiatrists ECT Team Meeting London UK November, 2016 (via skype)

2 Acknowledgments - Foundations - NARSAD, Stanley, Dana, Hope, Tiny Blue Dot NIMH, NINDS, NIDA, NIAAA, NASA, DARPA, DOD, VA Industry grants (last 20 yrs) Brainsway, Cadwell, Cortex, Cyberonics, Dantec, Darpharma, Electrocore, Glaxo Smith Kline, Jazz, MagStim, MECTA, Medtronic, Neostim, Neosync, Neuronetics, Neotonus, St. Jude Medical. Disclosures - No equity in any device or pharma company Speakers fees from industry (none in past 3 years) Past Paid Consultant - GSK, Cyberonics, NeuroPace, Jazz Unpaid Consultant Brainsway, Neuronetics, Neostim, Neosync Paid Consultant Tal Medical Editor-in-Chief, Brain Stimulation, Elsevier

3 The forgotten half of the truth Electricity is the Currency of the Brain All of synaptic pharmacology simply serves to transmit electrical signals to the next neuron The Brain is an Electrochemical Organ

4 Neuroscience Revolution Much of the brain and behavior conforms to circuitbased models, much like those worked out initially in movement disorders. Non-invasive brain stimulation can interact with these pathological circuits as therapy These new non-invasive techniques have unique side effect, onset of action, and durability profiles, suggesting they are different than traditional therapies (medications, talking, rehab)

5 US FDA Approved Main Transcranial Brain Stimulation Techniques ECT - Electroconvulsive Therapy rtms - repeated Transcranial Magnetic Stimulation Depression DBS - Deep Brain Stimulation PD, dystonia, OCD, epilepsy RST - Responsive Stimulation Therapy, epilepsy Epidural Cortical Stimulation VNS - Vagus Nerve Stimulation depression, epilepsy, morbid obesity Not FDA Approved MST - Magnetic Seizure Therapy tdcs - transcranial Direct Current Stimulation TENS - transcutaneous Electrical Nerve Stimulation EPI-fMRI - echoplanar fmri (LFMS) Transcranial alternating current (tacs) Thync Transcranial pulsed ultrasound

6 Themes Substantial Changes in Thinking Since the 1 st Gottingen Conference Overview of new techniques Focus on ECT, TMS in depression What we know What we are investigating Where it is heading

7 Advances in ECT Use differences in electrode placement, pulse width, type of current to improve efficacy, reduce side effects Right Unilateral Ultrabrief Pulse ECT Advance came from studying TMS pulses, chronaxie Now standard of care, similar efficacy, fewer cognitive side effects. SACKEIM, H. A., PRUDIC, J., NOBLER, M. S., FITZSIMONS, L., LISANBY, S. H., PAYNE, N., BERMAN, R. M., BRAKEMEIER, E. L., PERERA, T. & DEVANAND, D. P Effects of Pulse Width and Electrode Placement on the Efficacy and Cognitive Effects of Electroconvulsive Therapy. Brain stimulation, 1,

8 Treatment efficacy appears to correlate with PreFrontal alterations. Rationale for FEAST Amnestic side effects appear to correlate with Fronto-Temporal alterations.

9 Rationale for FEAST More focal forms of ECT appear to have similar efficacy to less focal forms. However have fewer amnestic Side effects.

10 Focal Electrically Administered Seizure Therapy (FEAST)

11 Experimented with: -Current delivery. -Electrode size. -Electrode placement. N=17 age 53±16 Amnestic Outcome: 5.5±6.4 Mins to 4/5 Clinical Outcome: -5/16 Remission -8/16 Response -Mainly a Feasibility and Methods Development Study

12 The depressed brain: major areas of dysfunction Limbic System Frontal Cortex Medial prefrontal Anterior cingulate Dorsolateral prefrontal Orbital frontal Hippocampus Cortico-limbic dysfunction : a hypothetical view Amygdala Hypothalamicpituitary-adrenal (HPA) axis Nucleus accumbens Higgins and George. Chapter 18, Neuroscience for Clinical Psychiatry, 2007

13 Rational For, and Development of FEAST Study Design of Our Completed Trial Results of Our Completed Trial Limitations of Our Completed Trial Current and Future Directions Sahlem et al, J ECT 2016

14 Inclusion Criteria 1:Major Depressive Episode (MDD or BPAD) 2: HRSD 24-Item 21 3: ECT Indicated Exclusion Criteria 1: Primary Psychosis 2: Substance Use Disorder Past 6 Months 3: Neurological Illness 4: Unstable Medical Condition

15 Baseline 1: Enrollment: SCID, ATHF, etc. 2: Baseline HRSD 24, Baseline Cognitive Battery, etc. Primary outcomes: Clinical Efficacy: -HRSD 24 Remission Amnestic Effects: Re-orientation Time *Initially Pts Were unmediated (N=16), then either NTP, or VLF allowed (N=4) Acute Treatment Phase 24 hours following final treatment FEAST 6X ST treatments 3X/week until remission or plateau in response. Option to switch to RUL or FEAST 9X ST if not improved 40% following tx 6 1: HRSD 24 prior to each odd # treatment. 2: Re-orientation time collected following each treatment. Post Treatment HRSD 24, Cognitive Battery, etc.

16 Rationale For, and Development of FEAST Study Design of Our Completed Trial Results of Our Completed Trial Limitations of our Completed Trial Current and Future Directions

17 Participant/Treatment Characteristics:

18 Newest Study Average Time to Reorientation: (Eyes open to 4/5 correct responses Columbia Autobiographical Memory Index-Short Form: Consistency score: 4.4+/-3.0 mins 97.5%+/-4.1% Sahlem et al,. Expanded Safety and Efficacy Data for a New Method of Performing Electroconvulsive Therapy (ECT): Focal Electrically Administered Seizure Therapy (FEAST). Journal of ECT, 2016

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23 Rationale For, and Development of FEAST Study Design of Our Completed Trial Results of Our Completed Trial Limitations of Our Completed Trial Current and Future Directions

24 Limitations: Open Label Design Using Historical Data to Contextualize Results Potential for Selection Bias (We may have unintentionally selected less severe/higher functioning patients Potential for Expectation Bias (We may have unintentionally rated optimistically)

25 Rationale For, and Development of FEAST Study Design of Our Completed Trial Results of Our Completed Trial Limitations of Our Completed Trial Current and Future Directions

26 Current/Future Directions: 1: Trials with an UBP-RUL comparison arm Baseline 1: Enrollment: SCID, ATHF, etc. 2: Baseline HRSD 24, Baseline Cognitive Battery, etc. 3: Imaging 2: Studies further explorin mechanism of action Acute Treatment Phase 24 hours following final treatment FEAST 6X ST treatments 3X/week until remission or plateau in response. End HRSD 24, Cognitive Battery, etc. End Imaging UBP-RUL 6X ST treatments 3X/week until remission or plateau in response. 3: Further refinement of technique Follow-up Data out to 6-Months

27 FEAST Conclusions Arose out of cross-fertilization of brain stimulation thinking TMS to ECT, refinement of location, charge, pulse width, other parameters Pilot Studies appear promising More focal application of current (FEAST, MST) may continue to improve and refine ECT Same efficacy Fewer side effects Current Gold Standard (RUL UBP) is pretty hard to beat, a high bar

28 How TMS Works George MS. Sci Am. 2003;289:66-73.

29 Ways to use TMS As a neurophysiological research tool to ping the brain and measure response As an interruption tool to temporarily disrupt a brain region (temporary lesion) As a way to measure brain plasticity paired associative stimulation (PAS) As a potential treatment tool, usually with multiple stimuli over several days

30 Why Brain Stimulation and Depression (1993) MDE is a brain state, reset, normal function, no real residue, unlike AD, Schizo, epilepsy Brain imaging studies suggesting role of cortical governance over limbic activity Response to ECT Presence of cortico-thalamic loops, potential for therapeutic intervention (Alexander, Delong and Strick)

31 Summary of TMS Acute Unipolar Depression Trials 3 Large Prospective RCT support TMS for treating acute moderately treatment resistant depression (3-6 weeks) Remission rates from 15%-30% in the double-blind phase, and 30% or more in open-label Safe, tolerable, but inefficient Modest clinical adoption In US all major insurance, VA Most major countries cover, even the UK NHS Durability appears good 90% retention of response at 12 months

32 No Efficacy/Effectiveness Gap 307 real world US patients, on medication, Neuronetics sponsored, 58% response, 37% remission, average 28 sessions (Carpenter et al, 2012) 100 patients, U Penn practice model, 50% response, 25% remission (Connelly et al, 2012)

33 Prefrontal TMS Clinical Use, Depression

34 Themes Substantial Changes in Thinking Since the 1 st Gottingen Conference Overview of new techniques Focus on ECT, TMS in depression What we know What we are investigating Where it is heading

35 Accelerated TMS 14 Treatment Resistant Depressed Patients, on medications Open-Label TMS, 15 sessions over 2 days, 15,000 total pulses 10 Hz, 5 sec, 25 rest, 100% MT Safe, well-tolerated

36 TMS Anti-suicide Study Can you bake the cake faster? Is Off time needed? High dose, 3 day adjunctive TMS study on inpatients admitted for suicidal ideation Randomized, sham-controlled N=45, two sites RAJVAMC, Walter Reed Two years 18,000 stimuli/day, 54,000 total George et al, Brain Stimulation, 2014

37 Active TMS significantly reduced suicidal ideation Beck Suicide Scale Visual Analog Scale I am currently bothered by thoughts of suicide

38 Seok et al, The efficacy and safety of accelerated rtms in MDD. RCT, 10 patients daily prefrontal rtms for 3 weeks (15 sessions) 10 patients, 15 sessions in 3 days At 3 weeks, no difference between the two groups, similar efficacy and side effects More rapid response in the accelerated group Abstract, Brain Stimulation, 2015, presented in Singapore

39 Dosing pattern conclusions - soft There is nothing sacred about one treatment session per weekday. It appears likely that there is a total dose (stimuli) effect, and that novel delivery patterns are possible May fit better with the logistics of patients and clinics The minimum off time, and max per day, have not been fully established.

40 But Depression Often Recurs Harold Sackeim, PhD

41 Relapse Prevention Study 6 Clinical enrolling sites in US Neuronetics Sponsored Active open 6 weeks treatment, medication free 67 enrolled, 49 later randomized after acute response 73% acute response rate ½ were treated one session per month, the other ½ just monitored All retreated if they begin to relapse

42 Once Monthly rtms, medication free, delayed relapse time Shortened number of sessions needed for re-remission Philips et al, Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: ( /j.brs )

43 Relapse Prevention Summary It is possible to maintain TRD patients off antidepressants using periodic TMS Once a TMS responder, always a TMS responder high rates of re-response (78% reresponse) The one/month schedule may have been underdosed

44 Other active areas of TMS/Depression Investigation Patterned pulses (theta burst) more efficient. Some open label studies showing near equivalence, much fewer pulses and chair time EEG synchronization? Engaging the brain in cognitive therapy during TMS Are we still underdosing (number of pulses)?

45 When to give up and try the next therapy? Early TMS trials were 2,3,4, then 6 weeks in duration. Gradual improvement in remission rates with longer duration ( %) What to do with a TRD patient at the end of 6 weeks and no response? Try a different form of TMS? Non randomized, then post hoc ergo proctor hoc What about just more of the same?

46 61% of Unmedicated Treatment Resistant Depression Patients Who Did Not Respond to Acute TMS Treatment (6 weeks) Responded After Four Weeks of Twice Weekly Blinded Deep TMS in the Brainsway Pivotal Trial Yip, Roth, Zangen, Carpenter, George Under Review

47 Implications if true With herculean amounts of prefrontal TMS on a daily or twice weekly basis (10 weeks), we may be able to get remission rates approaching ECT (60-70% in TRD patients), with fewer side effects, and longer durability. But at what cost? Chair time, personnel, travel time for patient We thus need to understand what we are doing neurobiologically with each trip to the gym, and make TMS more efficient, less expensive

48 Summary We have exciting new refinements of an older technique ECT (RUL UBP, FEAST, MST) Vastly underutilized There is a quiet revolution underway with the other forms of brain stimulation TMS is emerging as a clinically important tool The various brain stimulation methods are not competitive, but rather synergistic and can be used creatively in treatment algorithms A rising tide floats all boats.

49 ECT course the day before See you there!!

50 Consilience Jumping together of knowledge across diverse backgrounds, viewpoints, reinforcing new conclusions Grateful that organizers of 1 st Gottingen conference invited psychiatrists (me especially), and shared their knowledge, expertise and tools It has taken the combined brainpower of many in this room to launch this new revolution in psychiatry This is an exciting time for brain stimulation in psychiatry New, low hanging fruit, of therapies are within grasping range pain, addictions, anxiety disorders, stroke rehab

51 Acknowledgements MUSC Team: Harold Sackeim Mark George Baron Short James Fox Jon Snipes Suzanne Kerns Will Devries Carol Burns Al Lopez UAB Team: Ziad Nahas MECTA Team:

52 Thanks, Questions