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  • In this discussion, we will focus on new options for augmentation of psych therapeutic interventions with medication therapy in the setting of refractory depression. The learning objectives for this program are to review the epidemiology definition and clinical treatments available for treatment-resistant depression, to assess the benefits and limitations of resistant therapeutic strategies and therapies for depression, and finally, to discuss new data regarding the augmentation of current antidepressant therapies
  • I am a consultant for two israeli companies Brainsway and Minoguard.
  • As I mentioned, we are currently conducting a pivotal trial of Deep TMS to treat Major Depression. If successful, we expect the trial results to support our PMA application with the US FDA . In summary, the trial is enrolling 250 patients . Trial duration is 22 weeks and the primary endpoint is the Hamilton Depression Rating Scale – 21; superiority vs. sham at sixth week . Secondary endpoints includes response rates, remission rates and quality of life
  • So far no convincing answer has emerged to the question of whether transcranial magnetic stimulation (TMS) in his current version can make a clinically useful contribution to the treatment of depression. Three meta-analyses and one multicenter study confirmed a significant antidepressant effect of two weeks high frequency rTMS treatment compared to placebo rTMS). However, effect sizes have been modest to moderate and the clinical significance of its therapeutic effects is questionable. Among others two main reasons for the modest clinical effectiveness of rTMS in previous trials could be : 1) Concerns over safety have limited human studies to relatively low frequencies of stimulation (usually ≤20 Hz) (Wassermann 1998), whereas animal studies often use much higher frequencies in order to induce long-lasting alterations in localized brain connectivity 2) The depth of direct stimulation by standard rTMS coils (usually figure-8) is limited to regions at the cortex surface and may not be effective enough in therapeutically modulating regional brain activity altered in deeper lateral and medial regions of the PFC in depression. The second generation of device and method of stimulation targeted to solve this two major problems. (alternatively: To date, preclinical and clinical evidence have been accumulated supporting the antidepressant action of rTMS of the prefrontal cortex (PFC) in treatment-resistant depression (Gershon et al 2003). About 25 small placebo-controlled clinical studies have been published, mainly investigating rTMS as add-on treatment in therapy-resistant depression. Three meta-analyses confirmed a significant antidepressant effect of two weeks high frequency rTMS treatment compared to placebo rTMS (Burt et al 2002; Martin et al 2003). However, effect sizes have been modest to moderate and the clinical significance of its therapeutic effects is questionable. Very recently, data of two large multicenter trials have been presented (O´Reardon et al 2006; Herwig et al 2006). In the U.S. multicenter trial a significant antidepressant effect superior to placebo has been reported in medication-free and treatment-resistant patients. However, the response and remission rates for active vs placebo rTMS were 24% vs 15% and 17.5% vs 8%, respectively (O´Reardon et al 2006), i.e. much lower than reported for electroconvulsive therapy (ECT): 40 to 72 % (Burt et al 2002). The second multicenter trial unfortunately failed to show a significant difference between active and sham rTMS adjunctive to antidepressant medication (Herwig et al 2006). Among others two main reasons for the modest clinical effectiveness of rTMS in previous trials can be discussed: 1) Concerns over safety have limited human studies to relatively low frequencies of stimulation (usually ≤20 Hz) (Wassermann 1998), whereas animal studies often use much higher frequencies such as the theta burst paradigms (3–5 pulses at 100 Hz repeated at 5 Hz) in order to induce long-lasting alterations in localized brain connectivity such as long-term potentiation (LTP) or depression (LTD) (Larson and Lynch 1986; Huemmeke et al 2002), 2) The depth of direct stimulation by standard rTMS coils (usually figure-8) is limited to regions at the cortex surface (Nadeem et al 2003; Zangen et al 2005) and compared to ECT standard rTMS may not be effective enough in therapeutically modulating regional brain activity altered in deeper lateral and medial regions of the PFC in depression (Drevets 2001; Mayberg et al 2005).
  • Since the intensity of the electric field decreasing as a function of tissue depth, current magnetic stimulation techniques enable only superficial stimulation of the brain. and the current TMS coils could reach only 1-2 cm from the surface of the cortex. Stimulating deeper brain regions require a high intensity stimulation that cannot be reached by the magnetic stimulators available today, such as standard figure-8 TMS coils. Moreover, the intensity needed to effectively stimulate deeper brain regions, using currently available TMS coils, would lead to undesirable side-effects. Based on the notion that d epression traced to overactive emotion-regulating brain circuit that located deep in the brain we assume that we need adevice that could pebetrate all brain area.
  • Using the phantom brain measurements , we compare the maps of electric field….
  • This slide shows preliminary results from an fMRI study which we are currently conducting with deep-TMS. These images, obtained from data of 4 subjects, show the results of a contrast between functional connectivity (FC) with an MPFC area after sham TMS vs. after deep-TMS administered pre-frontally. (The MPFC cluster for the performance of the FC was selected individually for each subject by contrasting rest vs. an auditory task, both of which occurred before the TMS .) The results so far indicate that FC with the MPFC was significantly lower after deep-TMS in the DMPFC, PCC, and hippocampus (bil., more left) than after sham-TMS .
  • This is the H-Coil TMS device that we plan to study.
  • On the basis of our encouraging finding in the safety study we decide to conduct an open prospective trial that examine the use of the H coil in the treatment of patients suffer from refractory depression.
  • The change from baseline in HDRS-21 score was modeled as a function of study group, week and the group*week interaction term, baseline HDRS, ATHF level and center were entered as covariates.The slopes of change over time were compared between the study groups. 
  • As I mentioned, we are currently conducting a pivotal trial of Deep TMS to treat Major Depression. If successful, we expect the trial results to support our PMA application with the US FDA . In summary, the trial is enrolling 250 patients . Trial duration is 22 weeks and the primary endpoint is the Hamilton Depression Rating Scale – 21; superiority vs. sham at sixth week . Secondary endpoints includes response rates, remission rates and quality of life
  • Several subject assessment scales will be used during the course of the study. Efficacy will be assessed using the Hamilton Depression Rating Score (HDRS), Hamilton Anxiety Rating Scale (HARS), Inventory of Depressive Symptomatic Self Report (IDS-SR), Clinical Global Impression-Severity score (CGI-S), Clinical Global Impression-Improvement Score (CGI-I), Patient Global Impression Improvement scale (PGI-I), Quality of Life questionnaires (Q-LES-Q and SF-36) and Personal and Social Functioning (GAF). HDRS and HARS are both well known and widely accepted. Given the growing importance of outcome measures in caring for patients and their feelings, the IDS-SR, a validated self rated depression instrument, and the SF-36, a validated self rated health status instrument, will be used to assess subjects across several domains, e.g., mental health or emotional role, Q-LES-Q a self-report measure designed to obtain a sensitive degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. GAF will used to measure functionality.
  • Thanks for your listening and I want to thank….
  • File1

    1. 1. Hilik Levkovitz MD,MHA Professor Director Day Hospital & Cognitive and Emotional Lab. School of Medicine, Tel Aviv University, Israel. Deep Transcranial Magnetic Stimulation (TMS) for Tourette Syndrom
    2. 2. Dr. Levkovitz is a consultant and get a regular consultant fee from Brainsway Ltd. Disclosure
    3. 3. Previous rTMS Studies in Tourette Syndrome • 12 subjects, 1Hz, 80% of MT, 3 gorupd : left premotor, left motor, left sham. No improvement (Munchau et al. 2002, Orth et al. 2004) • 8 subjects, 1 or 15 Hz, 110% of MT, 3 groups: left premotor, left motor, left sham. 6 days. Improvement in OC but not tic symptoms (Jeong-Ho et al. 2004) • 5 subjects, 1 Hz, 100% of MT, SMA, 14 days. Significant improvement in Tics (Mantovani et al. 2006)
    4. 4. Barker, 1984Barker, 1984 Magstim Rapid Stimulator Cooling System CS03 Head Support Helmet comprising the H1/H2 Coil First Generation Second Generation First Generation TMS Device is Limited in Contribution to the Treatment of Neuropsychiatry Disorder Multicenter studies, O’Reardon, 2007, George, 2010
    5. 5. Example: Superficial TMS Limited in Direct Stimulated of Deep Brain Regions Superficial TMS is limited to superficial cortex (1-1.5 cm stimulation depth( Emotion-regulating brain circuit is located deep within the brain
    6. 6. H1L Coil (120% MT)H1 Coil (120% MT) E [V/m] H2 Coil (120% MT) RED ANDRED AND ORANGEORANGE COLORSCOLORS REPRESENTREPRESENT BRAINBRAIN ACTIVATIONACTIVATION Phantom Brain Measurements Electric field distribution of the H coils and figure of 8 at 120% MT Figure of 8 Coil (120% MT) While figure of 8 stimulate 1- 1.5 cm the H coils reach to 5-6 cm beneath the cortex Roth et al. J. Clin. Neurophysiology 2007 Acute feasibility and safety study in Depression LR LR LR LR LeftBilateralPartial Left Standard coil
    7. 7. H1 deep TMS (1Hz) disrupts mPFC functional connectivity during rest b P<0.001 Sham TMS subjectsFigure-8 subjectsDeep TMS subjects X=-5 PF a Deep TMS subjects Figure-8 subjects Sham TMS subjects X=-9 Front Hum Neuroscience. 2011
    8. 8. • Deeper penetration leads to activate brain circuit located deep within the brain • Different coils target to different brain area H-coil Transcranial Magnetic Stimulation (TMS(
    9. 9. Overview of Clinical Trials in DepressionOverview of Clinical Trials in Depression Safety in normal volunteers (n=35 ) Clin Neurophysiol. 2007 Acute feasibility and safety study in MDD (n=63) Brain Stimul. 2009 Long-term feasibility and safety study in MDD (n=30) World J Biol Psychiatry 2012 Randomized, controlled, multi-centre study (efficacy) (n=230)
    10. 10. 21 sites (15 from North America , 2 from Europe and 4 from Israel) participate in the study and this was one of the biggest studies in the field of TMS. International sites include:
    11. 11. Primary end point: Change in depression
    12. 12. Change in depression & history of failed on antidepressant medications Subjects who failed >2 medications in the current episode, showed a significant improve on deep TMS treatment relative to sham.
    13. 13. Prospective, Multicenter, Double-Blind, Randomized, Sham Controlled Trial • 12 TS patients • Y-GTSS > 20 at screening. • Did not response to at least 2 full trials of anti-tic pharmacotherapy • Trial duration 4 weeks • 1 Hz, 110% of the measured MT, total of 1200 pulses per session • Change from baseline in YGTSS at week 4 • Change from baseline in YBOX at week 4 • Change from baseline in QIDS at week 4 • Change from baseline in CGI at week 4 PatientsPatients TreatmentTreatment Primary Endpoint SecondarySecondary EndpointsEndpoints Feasibility Study in Tourette Syndrome
    14. 14.  Yale-Brown Obsessive Compulsive Disorder Scale (YBOCS)  Yale Global Tic Severity rating Scale (YGTSS)  Clinical Global Impression (CGI)  Social Adaptation Self-evaluation Scale (SASS)  Hamilton Anxiety Rating Scale (HARS-14)  Level of depression (HDRS-21)  Subjective improvement (IDS-SR) Efficacy rating scales used in the study
    15. 15. Primary end-point: Change in tics at the end of week 4
    16. 16. Secondary end-point: Change in Obsessive- Compulsive symptoms at the end of week 4
    17. 17. Primary end-point: change in tics at the end of week 4 For sub-group of patients suffered from Tourette & OCD :  Tics improved significantly (p=0.047)  OC symptoms a trend for improvement on YBOCS (p= 0.065)
    18. 18. Thanks !Thanks !

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