Is TMS Useful for the Treatment of Depression

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Is TMS Useful for the Treatment of Depression?
Pro - Mark S. George, MD Distinguished Professor
of Psychiatry, Neurology and Radiology Director,
Center for Advanced Imaging Research Director,
Brain Stimulation Laboratory Medical University
of South Carolina Charleston, SC, USA
2001 World Congress of Biological
Psychiatry Berlin
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Initial Comments

• Remember, this is a debate
• Views in heat of debate are not my more reasoned
  approach outside of debate
• Unbiased - no equity stake in any device, no
  patents
• Six Important Points!!
• Then we can all just stop

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Important Point 1I Declare Victory!!

• We are not debating
• The dogma that a seizure is necessary for a
  physical treatment to change mood (firmly
  entrenched in 1994 - debate in Conv Therapy with
  H Sackeim)
• A Seizure is necessary but not sufficient for ECT
• A Seizure is not needed for mood effects of
• Vagus Nerve Stimulation (epilepsy data, open data
  in depression)
• Deep Brain Stimulation (mood worsening case
  reports)
• TMS

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Important Point 1I Declare Victory!!

• We are not debating
• Whether TMS has neurobiological or antidepressant
  effects
• TMS has Profound Neurobiological Effects that can
  last beyond the moment of stimulation
• TMS has antidepressant effects
• Sufficient evidence has accrued that it is safe
  to conclude that rTMS (l DLPFC) exerts
  antidepressant effects, over and beyond placebo
  contributions - Sackeim, 2000 Bio Psych
  (Editorial)

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Important Point 1I Declare Victory!!

• We are not debating
• Whether TMS has troublesome side effects or other
  barriers to use
• TMS is very safe - no unintended seizures in last
  three years, nothing but safe publications in the
  literature

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Important Point 1I Declare Victory!!

• We are debating
• Is TMS Useful for the Treatment of Depression?
• At an International Congress
• Scientific thinking and understanding in this
  area has undergone a profound shift in the last 7
  years and has caught up with the forward thinkers
  who envisioned that TMS might treat depression
• Zyss, Hoflich, Kolbinger, Grisaru, George

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I Declare Victory

• And will just sit down and let the con convince
  us why TMS is not yet useful for treating
  depression

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A Few Other Important Points

• 2 TMS is a powerful way to modulate brain
  circuits
• 3 We are beginning to understand TMS use
  parameters and translational neurobiology
• 4 -TMS Can Effect the Brain in Ways That
  Modulate Depression Symptoms and Circuits
• 5 Many RCT Studies Demonstrate TMS
  Antidepressant Efficacy
• Forced to Conclude - TMS is Effective for
  Depression, will prove useful in due time

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TMS is Electrodeless Electrical Stimulation
1) Electrical Energy in Coil Induces 2) Magnetic
Field (right hand Rule, Maxwells Equations) 3)
Passes unimpeded through the Skull 4) Induces an
electrical current in The brain
From TMS Review in Science, June 18, 2001
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Important Point 2TMS is a powerful way to
modulate brain circuits

• High frequency arrests function in the moment -
  speech arrest
• High frequency trains can excite cortex
• Low frequency inhibits function
• Challenge tool
• Large percentage of talks at Cognitive
  Neuroscience 2001 meeting
• Paired Pulse studies can examine cortical
  inhibition and excitation
• Combinations with functional imaging
• 30 abstracts at Human Brain Mapping 2001

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Important Point 3We are beginning to understand
TMS use parameters and translational neurobiology

• Intensity - prefrontal
• Frequency
• Circuitry

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The Distance from Coil to Cortex Matters
Kozel, Nahas et al J Neuropsychiatry (2000)
McConnell et al, Biological Psychiatry (2001)
As the distance increases to reach cortex, the
amount of electricity needed to move the thumb
increases
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Diagram of How to Perform TMS within an fMRI
Scanner
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Higher Intensity TMS Affects Local and Connected
Prefrontal Cortex
7 healthy adults, prefrontal TMS (1 Hz, variable
intensity, 21 seconds) Interleaved with 1.5 T
fMRI, plt0.001, TMS minus rest
Nahas et al, 2001, Biological Psychiatry, (In
Press)
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4 -TMS Can Effect the Brain in Ways That
Modulate Depression Symptoms and Circuits

• Immediately change local and connected brain
  activity
• Cingulate changes (George 98, Paus, Ebmeier)
• Insula and anterior temporal increases (Fox, Li)
• Alter neurohormones
• Elevate TSH (George, 1994, Szuba 2000, Cohrs
  2000),
• Convert DST response (Pridmore et al 1999)

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Prefrontal TMS Effects Limbic Blood Flow
TMS Coil Location
Pooled effects of 1 Hz prefrontal TMS In 5
healthy adults, 120 MT, BOLD fMRI, Plt0.001,
cluster plt0.05 For display
Nahas et al, Biological Psychiatry, In Press, 2001
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Changes in Regional Brain Perfusion (SPECT) in 8
Adults During Left Prefrontal rTMS Compared to
Baseline (20 Hz, 2 secs, 80 MT, 20 mins)
George, et al, Human Psychopharmacology, 1998
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Cingulates rCBF increased in TMS responders
rCBF SPECT before and after 10 treatments of left
prefrontal rTMS SPM, contrast of after TMS minus
baseline, plt0.01 for display
Findings c/w other antidepressant
treatments Sleep deprivation, Prozac (Mayberg)
Teneback et al, Human Psychopharmacology, 1999
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Prefrontal TMS Affects Mood Circuits in Depressed
Adults
R
Insula Hippocampus
Cerebellum Cingulate
TMS Coil location
Pooled results of 1 Hz 100 MT TMS for 20 seconds
minus rest, 1.5 T BOLD fMRI, 3 adults with
depression, zgt3.09 for display Li, Nahas et al,
Work in Progress, MUSC
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Important Point 5A Large Body of Studies
Demonstrate TMS Antidepressant Efficacy

• Multiple different researchers and countries
• Not driven by one industrial sponsor
• Generally small sample sizes and varying TMS use
  parameters
• Supported by animal studies which have also shown
  TMS antidepressant effects (Swim test)

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Initial TMS Antidepressant Studies
Study N FrequencyLength Repeats
Intertrain Time of Total Intensity
Drop Interval Peak Effect
HAMD Open, Vertex Stimulation, Low
Frequency Hoflich et al, 1993 2 .3 Hz
1 250 constant 10 days 250/day 2500
105-130 Grisaru et al, 1994 10 .016
Hz1 60 constant / 60 60 2 Tesla Kolbinger
et al, 1995 15 .25 Hz 1 250 constant 5
days 250/day 1250 90, 110
15 Inconclusive, promising Open, Left
Prefrontal Stimulation, High Frequency George
et al, 1995 6 20 Hz 2 secs 20 58 secs 5
days 800/day 4000 80 26
NeuroReport Promising, but only marginally
significant, 2/6 responders at 2 weeks Blind,
Prefrontal Stimulation, Cross-0ver George et al,
1997 12 20 Hz 2 secs 20 58 secs 10
days 800/day 8000 80 17
American Journal of Psychiatry Statistically
Significant Effect, 20 Drop in Hamilton at 2
weeks Pascual-leone, 1996 17 10 Hz 10 secs
20 50 secs 5 days 2000/day 1000 90
45 Lancet Robust Response, 11/17
Responders After One Week
Real Damage to Field, From which we are only now
recovering
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George et al, 2000 Bio Psych
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George et al, 2000
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Does TMS Have Antidepressant Effects Greater than
Sham?
Performed Meta-analysis of published studies,
RCT, TMS versus sham, as of 1/01 Selection
Criteria - Prefrontal TMS -Clearly defined
patients with depression, -Treated for at least
10 sessions, - Used Hamilton as end-point. -
Published 5 Studies qualified - Berman, Loo,
George 97, George 2000, Klein
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Summary of 5 Published RCTTMS Antidepressant
Trialsn86 active, 83 placebo, 2 Weeks,
Prefrontal
Percent Improvement in Hamilton Depression Score
Plt0.05, Students unpaired t-test
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We need to treat For more than 2 weeks
Data, Bill Lyndon, Under Review
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TMS compared to other treatmentsHow does the
clinical effect compare to other treatments?

• ECT - most effective treatment, 50 years of
  experience to refine technique
• Grunhaus 1 - Biological Psychiatry 2000
• Open study, Near Equivalence
• Grunhaus 2 - Under Review
• Double Blind, Near equivalence to RUL ECT
• Janicek Under review
• small sample - Near equivalence with n14

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TMS Compared to ECT
Grunhaus et al, 2000, Biological Psychiatry
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Conclusions - rTMS Depression Studies

• 1) Speed of Onset
• - Except for Pascual-Leone (Lancet) and Figiel
  open study, most have found only modest
  improvement at 2 weeks (start at treatment 4,5)
• - More like antidepressant than acute mood probe
• Need to treat for at least 3 weeks before
  stopping
• 2) Effect Size - varies, higher with larger
  stimulation intensity, as powerful as
  antidepressant medications,
• treatment resistance of population important,
  equal to ECT?
• 3) Location
• - Hint that prefrontal better than other
  regions, but only directly tested in Lancet
  study.
• - Laterality unclear as well (Klein right side
  study)

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Conclusions - rTMS Depression Studies

• 4) Patient Subgroups
• - Hint in Epstein study of poor response gt age
  65.
• - Hint in Grunhaus study of poor response in
  psychotic depression (in direct contrast to
  Pascual-leone Lancet Study)
• - Several studies show efficacy in bipolar
  depression
• Can Cause Hypomania, mania
• 5) Intensity - gtMT better than ltMT ? - need
  direct measure of cortex to be stimulated
• Frequency - Effects found in range from 0.5 - 20
  Hz
• Dose - Unclear - from 400 - 10,000 pulses

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Important Point 6TMS is likely to be a useful
treatment for depression

• Usefulness is not efficacy - requires tool in
  the hands of clinicians - is it useful?
• Limited data in hands of non-researchers
• TMS has demonstrated efficacy, in range of other
  antidepressants

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Important Point 6TMS is likely to be a useful
treatment for depression

• Non-invasiveness, ease of administration of TMS
  would make it not first line, but early in a
  treatment algorithm for depression -
• 1st medication, 2nd medication, TMS, ..
• A debate in 5 years will have data on true
  usefulness

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Whats Left to Debate?
Dr. Phil Mitchell
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Does TMS work for depression?

• Philip B. Mitchell
• University of New South Wales,
• Sydney, Australia

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REGIONS OF INCREASED ACTIVITY DURING 15 Hz rTMS
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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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TMS - sham-controlled studies

• Ten studies have compared rTMS to sham
  treatment
• Involved 240 subjects
• Three used cross-over design seven used
  parallel-group design
• Six studied efficacy in treatment-resistant
  depressed subjects four in non-resistant samples

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TMS - sham-controlled studies II

• Percent reduction in HAMD scores (all studies)
• TMS range 6 to 49 median 26
• Sham range -13 to 24 median 0 to 7
• Note responses of -13, -4 and 0 to sham
  treatment in the three cross-over studies

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TMS - sham-controlled studies III

• Percent responders (gt 50 decrease in HAMD
  scores) in four studies
• TMS 0, 10, 45, 49 (note that latter two
  responses were in non-resistant samples)
• Sham 0, 0, 0, 25 (note that latter two
  responses were in non-resistant samples)

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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TMS v. active comparator

• Grunhaus et al, 2000
• Open randomised comparison v. ECT (rater not
  blind)
• 40 depressed subjects (19 psychotic)
• Responders
• Total group ECT 80 gt TMS 45
• Psychotic ECT 100 gt TMS 22
• Non-psychotic ECT 60 TMS 64

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Response rates to ECT (Janicak, 1985)

• ECT v. sham
• ECT 67 responders
• Sham 34 responders
• ECT v. TCAs
• ECT 87 responders
• TCAs 67 responders
• (Note TMS v. sham 0 to 49 v. 0 to 25)

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Response to antidepressants (US DHHS review,
1993)

• SSRIs
• Inpatients 54 responders v. placebo 29
• Outpatients 47 responders v. placebo 27
• TCAs
• Inpatients 50 responders v. placebo 25
• Outpatients 52 responders v. placebo 30
• (Note TMS v. sham 0 to 49 v. 0 to 25)

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Response in treatment resistance (Nelson 1997
Howland, 1997)

• Lithium augmentation
• 30 show marked response
• Switch from SSRIs to TCAs
• 50 to 75 response rate
• (Note TMS v. sham 0 to 49 v. 0 to 25)

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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Duration of response to rTMS

• Effect compared to sham persists for two weeks
  after rTMS (Pascual-Leone et al, 1996
  Garcia-Toro et al, 2001)
• Sham-controlled ECT studies inconsistent (some
  showed persistent benefit at one month others
  did not)

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Criteria for regulatory approval of a new
treatment

• Safety
• Efficacy
• clinically and statistically significant
• v. placebo
• v. appropriate active comparators
• acute and long-term
• Dosage

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rTMS for depression - Conclusions I

• Safety well established
• Efficacy
• Not as effective as ECT (but no blind
  comparisons)
• Possibly not as effective as lithium augmentation
  or other strategies for resistant depression (but
  no controlled comparative trials)

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rTMS for depression - Conclusions II

• Possibly of similar efficacy to antidepressants
  in non-resistant samples, but no evidence of
  meaningful persistence of effect or of
  prophylactic benefit (but no controlled
  comparative studies)
• Dosage uncertainty about optimal site or
  preferred stimulation parameters

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rTMS for depression - Conclusions III

• Conclusion
• An exciting scientific and heuristic tool, but
  there is a lack of evidence of substantive
  clinical efficacy in depression
• Currently not registrable
• Need for the research community to develop a more
  effective form of TMS

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Rebuttal Slides

• There are poor uses of sham or blinding
• Not all RCT show effects greater than sham
• We do not know how long TMS effects last
• TMS does not work in elderly subjects

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Point - There are no good mechanistic theories
about how TMS works

• 1) We do not understand how ECT works, or for
  that matter, medications
• 2) There are good ideas about mechanisms being
  tested

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How does TMS treat depression?

• Hormonal - hits HPA circuit, resets thryoid, CRH,
  cortisol
• Cortical Governing - rebalances relationship
  between cortex and limbic
• Anticonvulsant - mimics brains antiseizure
  surveillance mechanism with local transmitter
  changes (GABA)

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Rebuttal Remarks, Mark S. George, MD
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TMS as a maintenance tool
Allegation - There are no studies of TMS as
Maintenance

• Counter - 1) No medications or non-invasive
  therapies have ever been required to show
  maintenance effects prior to adoption for acute.
  Why single out TMS?
• 2) There are studies emerging hinting at the
  potential for TMS as maintenance
• Bill McDonald - 2001 APA New Research
• Pascual-Leone et al
• Li, Nahas et al (MUSC), 2001 Bio Psych

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Li et al, MUSC Bio Psych 2001 Abs
6 adult depressed patients following acute TMS
response Weekly TMS sessions, Ham-D, Redo Acute
if HamDgt20 All made it to 4 months, with only 3
needing re-acute
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A Single Case of Maintenance TMS53 yo woman with
BPAD depression, previous maintenance with ECT
(gt60 rx)
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Maintenance Conclusions

• Acknowledge small amount of data at present
• TMS shows promise as maintenance tool
• Ultimate usefulness needs to be determined with
  widespread clinical use

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AllegationThere are no good TMS sham methods

• Acknowledge -1) have been variations, with some
  active -- make the results even stronger - dose
  effect studies
• 2) There are now effective means of creating a
  sham coil and truly blind conditions and these
  are being used in clinical trials
• 3) Failure to show diff with placebo is common in
  new treatment development

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Failed TMS trials

• Prozac, prior to market approval, had two large
  negative studies (samples in hundreds)
• ECT, when subjected to RCT conditions in England,
  had two negative studies (of 8 done)
• Conclusion - failed trials are common, especially
  with underpowered studies, TMS no different

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Development of True Placebo TMS Administration
- Mu Metal Coil - Reversed Flow Coil
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