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  • My name is Dr, Levkovitz and first of all I want to thanks the Organizer of this symposia Dr. Zacheim and and Dr. Padberg for inviting me to give this talk. The topic of my talk is the application of deep transcranial magnetic stimulation in major depression and I will present data from the safety study in healthy volunteers and open study in depressed patients.
  • 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 goals of this study were: First: to examine antidepressive response of two designs of the H-Coil TMS Device in the treatment of a sample of young depressed patients patients ( less than 65) Second: to examine the safety and tolerability of deep TMS in depressed patients.
  • Using the phantom brain measurements , we compare the maps of electric field … .
  • Diagnosed by two senior psychiatrist as suffering from major depression episode according to DSM IV using the Structured Clinical Interview for DSM-4 (SCID). Rating on HADRS>22. Age: 18-65 years. Treated for the current depressive episode , at least 5 weeks per antidepressant with two different antidepressant in accepted dose, without improvement, according to there medical chart and ATFH (antidepressant treatment history form) instruction guidelines. Gave informed consent for participation in the study . A family member agree that that the patient will participate in the study. When family member is not available an advice will take for the head of the local IRB. Negative answers on safety screening questionnaire for transcranial magnetic stimulation . Alternative: All patients met DSM- 4 criteria for a major depressive episode. All patients were rated al least moderately ill on the Clinical Global Impression Scale and had a pretreatment score on the HDRS of greater than 22 ( man score of ??)
  • 63 outpatients with non-psychotic, major depressive disorder who were in a current major depression ( Hamilton 17 item score of >20) were treated 5 days a week for 4 weeks. Subject were randimaly assigned to receive treatment with H1 or H2 or H1L 110 coil and 120% of MT. There was a 3 phases for the study . 1. Patients were tapered-off their psychotrophic medication proior the beginning their course of TMS. 2. All subjects will receive daily prefrontal rTMS (20 Hz, 8 s on 22 s off, over 20 min period) each day morning, for 4 consecutive weeks (24,000 stimuli). 3. One week and 3 weeksof follow-up. Yoram: Note that 2 patients left at the taper-down period. Also- the previous n included the healthy controls.
  • The primary objective was the antidepressant response at the end of the treatment, define as a decline in 24 items Hamilton depression rating scale from the baseline rating by 50%. Clinical antidepressant remission at the end of the treatment, defined as 24 items Hamilton Depression Rating Scale less than 12. The secondary objectives define as symptomatic improvement at the 4-week end point as measured using Hamilton Anxiety Rating Scale ( HARS), Beck Depression Inventory (BDI), Clinical Global Impression (CGI). And cognitive changes using the CANTAB neuropsychological test battery (a computerized battery of neuropsychological functions).
  • The average number of years since the first diagnosis of depression in this group was /???. The average length of time in the current index episode of depression was also quit hugh as a group ( ??? Months). ??? Subjects has previously been treated with ECT and had not been responded
  • We clearly found a significant imoprovement in HDRS comparing the end of the treatment and baseline level except for the H1L 110% COIL . This improvement was reflected by patients subjective report using the Beck depression inventory scale. Analyses of HAMD factors (visits 1, 10 & 21) : Depression: There was a significant visit effect [ F (2,106)=97.97, p<.001]; planned contrast tests indicated a linear change in subjects' scores [later assessments associated with lower scores; F (1,53)=199.7, p<.001]. There was no significant treatment main-effect or treatment x day interaction [ F (3,53)=2.1, n.s.; F (6,106)=0.8, n.s.; respectively]. Maier: There was a significant visit effect [ F (2,106)=88.1, p<.001]; planned contrast tests indicated a linear change in subjects' scores [later assessments associated with lower scores; F (1,53)=179.3, p<.001]. There was no significant treatment main-effect or treatment x day interaction [ F (3,53)=2.0, n.s.; F (6,106)=2.1, n.s.; respectively]. Gibbons factor: There was a significant visit effect [ F (2,106)=107.3, p<.001]; planned contrast tests indicated a linear change in subjects' scores [later assessments associated with lower scores; F (1,53)=195.1, p<.001]. There was no significant treatment main-effect or treatment x day interaction [ F (3,53)=2.7, n.s.; F (6,106)=1.7, n.s.; respectively]. Anxiety/Somatization: There was a significant treatment main-effect [ F (3,53)=2.8, p<.05]; post-hoc analyses indicated no significant differences between the groups. There was also a significant visit main-effect [ F (1.6,89.9)=51.2, p<.001]; planned contrast tests indicated a linear change in subjects' scores [later assessments associated with lower scores; F (1,53)=54.4, p<.001]. There was no significant treatment x day interaction [ F (5.0,89.9)=1.8, n.s.]. Retardation: There was a significant visit effect [ F (2,106)=94.5, p<.001]; planned contrast tests indicated a linear change in subjects' scores [later assessments associated with lower scores; F (1,53)=199.9, p<.001]. There was no significant treatment main-effect or treatment x day interaction [ F (3,53)=1.5, n.s.; F (6,106)=1.5, n.s.; respectively]. Sleep: There was a significant visit effect [ F (1.7,94.2)=13.3, p<.001]; planned contrast tests indicated a no linear change in subjects' scores. There was no significant treatment main-effect or treatment x day interaction [ F (3,53)=1.0, n.s.; F (5.3,94.2)=1.0, n.s.; respectively].
  • The improvement in depression was found using the Clinical Global Impression Scale . Improve in Anexity levels observed by measure the changes In HARS comparing 4 weeks of treatment with baseline levels.
  • In the second ppart of the study we try to find the H coils effect on Executive Functions in Depression
  • A number of colored boxes are shown on the screen. The subject should find a blue ‘ counter ’ in each of the boxes. The subject must touch each box in turn until one opens with a blue ‘ counter ’ inside (a search). Returning to an empty box already sampled on this search is an error. Spatial Working Memory task has been linked to frontal lobe and sub-divisions (such as the dorsolateral and ventrolateral frontal), and may be considered an additional test of frontal activity (with the SSP task) . H2 -coil subjects showed a dramatic decrease in error rates after 1Hz TMS stimulation [comparing pre to post 1Hz TMS, with error rats remaining low in following testing in 10Hz and 20Hz.Sham-coil, H1 -coil and figure-8 coil subjects showed a more varied pattern, showing some learning with a higher variance and less stability (compared to that of the H2 -coil ). These findings emphasizing the ability of the H2-coil to facilitate cognitive tasks associated with the frontal lobe, leading to a faster learning curve (compared to the other TMS coils and sham condition).
  • Spatial memory span (SSP) is a computerized version of Corsi ’ s block tapping test, giving a measure of the subject's spatial memory span. The performance of this task is correlated with ventrolateral prefrontal cortex functions and is one of the two tasks assessing frontal lobe functions, the second being the SWM task. Our results indicated that H2 ­ -coil subjects made significantly less trails until reaching the optimal span length of 9 blocks (there was no significant difference between H 2-coil and H1 -coil subjects). The findings indicate that H2-coil subjects had a steeper learning curve, compared to the other coils. White squares are shown, some of which briefly change colour in a variable sequence. The subject must then touch the boxes which changed colour in the same order that they were displayed by the computer. The number of boxes increases from 2 at the start of the test to 9 at the end.
  • The H coils found to be well tolerated by the patients with no major side effect like head ache. We use the Visual Analog Scale to measure headacheand did not find increase in headache during end of the deep TMS treatment. Patients did not required analgesics to control the headache.
  • Important limitation in this study is the : absence of shame control group. So with the open label desgin of this study a placebo effect can not ruled out in the patients who responded to deep TMS. We do not know at the moment what is the best maintenance protocol for patients how responsed to TMS.
  • Thanks for your listening and I want to thank … .
  • Transcript

    • 1. Deep Transcranial MagneticDeep Transcranial Magnetic Stimulation for Acute &Stimulation for Acute & Maintenance Treatment inMaintenance Treatment in DepressionDepression Dr.Dr. Levkovitz Y.Levkovitz Y. Cognitive and Emotional Laboratory,Cognitive and Emotional Laboratory, Shalvata Mental Health Center,Shalvata Mental Health Center, School of Medicine, Tel Aviv University, Israel.School of Medicine, Tel Aviv University, Israel.
    • 2. Overview of Clinical Trials • Safety (n=9 ).Safety (n=9 ). • Open pilot (Open pilot (feasibility, n=9) ., n=9) . • Controlled, multi-center (efficacy)Controlled, multi-center (efficacy)
    • 3. Open Pilot inOpen Pilot in Acute &Acute & Maintenance Treatment inMaintenance Treatment in DepressionDepression Purpose:Purpose: Evaluate the feasibilityEvaluate the feasibility and safety of the H-Coil inand safety of the H-Coil in AcuteAcute & Maintenance Treatment in& Maintenance Treatment in DepressionDepression
    • 4. H1 Coil (120% MT) E [V/m] RED ANDRED AND ORANGEORANGE COLORSCOLORS REPRESENTREPRESENT BRAINBRAIN ACTIVATIONACTIVATION Phantom Brain MeasurementsPhantom 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
    • 5. Inclusion CriteriaInclusion Criteria:: 18-65 years.18-65 years. Diagnosed as suffering from aDiagnosed as suffering from a depressive episode according to DSM IVdepressive episode according to DSM IV using the (SCID).using the (SCID). Rating onRating on HADRS->20HADRS->20.. Treated for the current depressiveTreated for the current depressive episode, at least 5 weeks perepisode, at least 5 weeks per antidepressant with two antidepressantantidepressant with two antidepressant (ATHF>3).(ATHF>3). Negative answers on safety screeningNegative answers on safety screening questionnaire for TMS.questionnaire for TMS. Acute & Maintenance Treatment in Depression. Safety and feasibility study
    • 6. N=9 Clinical Assessments were carried out once a week. Cognitive Assessments were carried out at screening day And after the last treatment. Prospective, Feasibility and Safety StudyProspective, Feasibility and Safety Study in Acute & Maintenance Treatment inAcute & Maintenance Treatment in DepressionDepression Prefrontal rTMS (42 trains of 2 seconds, 20 Hz, with 20 seconds inter-train intervals, 120% of motor threshold) each morning for 4 consecutive weeks (5 days a week), followed by 8 weeks (2 days a week) and 10 weeks (1 day a week). Day -0 Screening Maintenance Phase: 4weeks of dTMS 5 days a week. H1-120% Acute & Maintenance Treatment in Depression. Safety and feasibility study. 8weeks of dTMS 2days a week. 10weeks of dTMS 1day a week. Acute Phase:
    • 7. Primary Objective :Primary Objective : 11..Safety of theSafety of the H1H1 coil acute and maintenance treatment ascoil acute and maintenance treatment as defined by maintained subject baseline, pre treatment,defined by maintained subject baseline, pre treatment, physical and neurological statusphysical and neurological status.. 22..Clinical antidepressantClinical antidepressant responseresponse at the end of the acuteat the end of the acute treatment, and during the maintenance phase, defined astreatment, and during the maintenance phase, defined as a decline in Hamilton depression rating scale from thea decline in Hamilton depression rating scale from the baseline rating by 50%baseline rating by 50%.. Secondary Objectives:Secondary Objectives: 11..Clinical antidepressantClinical antidepressant remissionremission at the end of theat the end of the treatment, defined as exit Hamilton Depression Ratingtreatment, defined as exit Hamilton Depression Rating Scale <8Scale <8.. 22..Symptomatic improvement at the end point as measuredSymptomatic improvement at the end point as measured with Hamilton Anxiety Rating Scale (HARS), Beckwith Hamilton Anxiety Rating Scale (HARS), Beck Depression Inventory (BDI), and Clinical GlobalDepression Inventory (BDI), and Clinical Global Impression (CGIImpression (CGI).). Acute & Maintenance Treatment in Depression. Safety and feasibility study
    • 8. Demographic and BaselineDemographic and Baseline CharacteristicsCharacteristics Characteristic Mean (SD) Age, yAge, y 45.12 (12.21)45.12 (12.21) Sex M/F, NoSex M/F, No.. 3/63/6 Baseline HDRSBaseline HDRS 25.67 (3.46)25.67 (3.46) Baseline BDIBaseline BDI 32.44 (9.96)32.44 (9.96) Baseline HARSBaseline HARS 14.3314.33))6.606.60(( Baseline CGIBaseline CGI 4.78 (0.44)4.78 (0.44) Acute & Maintenance Treatment in Depression. Safety and feasibility study
    • 9. Clinical Characteristics of Patients CharacteristicCharacteristic Mean (SD)Mean (SD) Age at onset (years)Age at onset (years) 27.6727.67±±8.838.83 Duration of currentDuration of current episode (monthsepisode (months)) 12.9612.96±±8.368.36 Number of past episodesNumber of past episodes 6.606.60±±4.824.82 Number of hospitalizationsNumber of hospitalizations 1.881.88±±3.013.01 Number of suicideNumber of suicide attemptsattempts 00 Acute & Maintenance Treatment in Depression. Safety and feasibility study
    • 10. Results: Significant improvement in HDRS when comparing baseline and end of the acute phase Acute & Maintenance TreatmentAcute & Maintenance Treatment in Depressionin Depression.. Open study Acute & Maintenance Treatment in DepressionAcute & Maintenance Treatment in Depression.. feasibility study Hamilton Depression Rating Scale (HDRS) in Acute PhaseHamilton De pre ssion Rating Scale (Acute Phase ) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 screening 1 4 10 15 20 Visit numbe r TotalScoreHDRS Severe depression (>24( Moderate depression (18-24( Mild depression (<18(
    • 11. Results: Acute & Maintenance TreatmentAcute & Maintenance Treatment in Depressionin Depression.. Open study Acute & Maintenance Treatment in DepressionAcute & Maintenance Treatment in Depression.. Safety and feasibility study Hamilton Depression Rating Scale (HDRS) in Maintenance Phase Hamilton Depression Rating Scale (Maintanance Phase) 0 2 4 6 8 10 12 14 16 22 24 26 28 30 32 34 36 37 Visit number TotalScoreHDRS Mild depression (<18(
    • 12. Results: Acute & Maintenance TreatmentAcute & Maintenance Treatment in Depressionin Depression.. Open study Acute & Maintenance Treatment in DepressionAcute & Maintenance Treatment in Depression.. Safety and feasibility study HamiltonAnxietyRatingScale (Acute Phase) 0 2 4 6 8 10 12 14 16 18 screening 1 4 10 15 20 Visit number TotalScoreHAM-A Hamilton anxiety Rating Scale (HAM-A) in Acute Phase Hamilton anxiety Rating Scale (HAM-A) in Maintenance Phase mild anxiety (<17( HamiltonAnxietyRatingScale (Maintenance Phase) 0 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 34 36 37 Visit number TotalScoreHAM-A mild anxiety (<17(
    • 13. Results: Acute & Maintenance TreatmentAcute & Maintenance Treatment in Depressionin Depression.. Open study Acute & Maintenance Treatment in DepressionAcute & Maintenance Treatment in Depression.. Safety and feasibility study BeckDepressionInventory(Acute Phase) 0 5 10 15 20 25 30 35 40 screening 1 4 10 15 20 Visitnumber TotalscoreBDI Severe(>29) Moderate(20-28) Mild(14-19) Beck Depression Inventory (BDI) Acute Phase Beck Depression Inventory (BDI) maintenance Phase Beck DepressionInventory(Maintenance Phase) 0 5 10 15 20 25 30 35 22 24 26 28 30 32 34 36 37 Visitnumber TotalScoreBDI Severe (>29) Moderate (20-28) Mild (14-19)
    • 14. Clinical Global Impression (CGI) in Maintenance Phase Clinical Global Impression (CGI) in Acute Phase Results: Improvement in depression was also reflected by the Clinical Global Impression Scale Bipolar depression feasibility study Clinical Globlal Impression- Severity (Acute Phase) 0.00 1.00 2.00 3.00 4.00 5.00 6.00 screening 1 4 10 15 20 Visit number TotalScoreCGIS ClinicalGloblalImpression- Severity(Maintenance Phase) 0 1 2 3 4 5 22 24 26 28 30 32 34 36 37 Visit number TotalScoreCGIS
    • 15. H coil effect on Executive Functions in BipolarH coil effect on Executive Functions in Bipolar DepressionDepression Working Memory (SWM) Planning (SOC) Inhibition
    • 16. LimitationLimitation:: • No sham control.No sham control.
    • 17. Thanks !Thanks ! Shalvata MentalShalvata Mental Health CenterHealth Center Dr. E. HarelDr. E. Harel Dr. Y. BrawY. Braw Neurobiology Dep. Weizmann InstNeurobiology Dep. Weizmann Inst.. A.A.Zanegn and Y. RothZanegn and Y. Roth

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