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Stimulation and/or Surgical Approaches to Psychiatric
Illness
Darin D. Dougherty, MD MMSc Director, Division of Neurotherapeutics
Department of Psychiatry Massachusetts General Hospital Associate Professor of Psychiatry
Harvard Medical School
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Disclosures
• Research Support: Cyberonics, Medtronic, Eli Lilly, Roche
• Honoraria: Insys, Johnson & Johnson
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Current Depression Model
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Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal
sadness. Am J Psychiatry. 1999 May;156(5):675-82.
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Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000 Oct 15;48(8):830-43.
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Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000 Oct 15;48(8):830-43.
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Current OCD Model
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Psychiatric Neurotherapeutics
• Definition = surgical & device-based treatments
• Electroconvulsive therapy (ECT) • Vagus Nerve Stimulation (VNS) • Transcranial Magnetic Stimulation (TMS) • Psychiatric Neurosurgery
– Lesion (ablative) procedures – Deep Brain Stimulation (DBS)
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Electroconvulsive Therapy (ECT)
• Used since 1930s; “gold standard” for TRD • Numerous meta-analyses* have found ECT
more effective than sham or medication and bilateral ECT more effective than unilateral
• Often require maintenance ECT, may be associated with cognitive side effects
*e.g., UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: A systematic review and meta-analysis. Lancet 2003;361:799-808.
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VNS Therapy for Treatment-Resistant Depression
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Vagus Sensory Afferents Go to Midbrain, Limbic, and Prefrontal Structures
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0
10
20
30
40
% o
f Pat
ient
s
Response Remission
IDS-SR30
Pivotal study (n=180) Comparative study (n=112)
p=0.029
p=0.006
HAMD24
Response Remission
22
15
30
17
Pivotal study (n=181) Comparative study (n=104)
12
4
13
7
p=0.003
p=0.031
Evaluable observed analysis.
George MS, et al. Biol Psychiatry. 2005;58:364-373.
Pivotal Study vs Comparative Study: Secondary Analysis
HAMD24 and IDS-SR30 Categorical Outcomes at 12 Months (Observed Cases)
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Decreases with VNS (all scans across time)
Z>2.45
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rTMS
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General Principles
• Uses magnetic field introduced on scalp surface to generate electrical stimulation of focal areas of brain cortex
• Unlike ECT, does not involve general anesthesia of seizures
• Approved by US FDA for use in treatment of depression
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Clinical Efficacy for MDD
• Initially, many small sample size sham-controlled studies with variability in stimulation parameters, stimulation site, trial duration, etc
• Nonetheless, meta-analyses and recent large multisite trials (Neuronetics1 n=301 & NIH2 n=190) support positive outcomes for rTMS
1. O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007 Dec 1;62(11):1208-16. 2. George, MS,SH Lisanby,D Avery,WM McDonald,V Durkalski,M Pavlicova,B Anderson,Z Nahas,P Bulow,P Zarkowski,PE Holtzheimer, 3rd,T SchwartzHA Sackeim, Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry, 2010. 67(5):507-16.
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Epidural Cortical Stimulation for Treating Major Depression
PROSPECT Feasibility Study
Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, rainey C, Kondziolka D, Howland R, Eskandar E, Evans KC, Dougherty DD. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 2011. Nov;69(5):1015-29.
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Study Design
• Multi-center US trial • 12 subjects • Single-blinded, sham-
controlled • Assess device and
procedure safety • Assess efficacy via
depression scales (HDRS, MADRS) and quality of life measures (GAF, Q-LES-Q)
Cortical Stimulation Lead
Implantable Pulse Generator
Programming System
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Surgical Target
• Left Hemisphere • Posterior array 2 cm
anterior to precentral sulcus • Inferior array above inferior
frontal sulcus • Target area is middle third
of middle frontal gyrus • Brodmann area 9/46 • Target used in rTMS trials
Anterior to Precentral Sulcus Inferior to the Sulcus Frontalis Superior
Superior to the Sulcus Frontalis Inferior
Middle Frontal Gyrus
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Surgical Target
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Inclusion/Exclusion Criteria
Inclusion • Non-psychotic, unipolar major depressive disorder (MDD)
–Current major depressive episode (MDE) lasting for at least 2 years –Or at least 4 lifetime MDEs with the current episode lasting for at least 1 year
• Minimum score of 20 on the 28 item Hamilton Depression Rating Scale (HDRS28)
• Score of 60 or lower out of 100 points in the Global Assessment of Function (GAF) scale
• Failed response to at least four different antidepressant treatments
Exclusion • Other Axis I or Axis II diagnosis • Previous brain surgery, other serious medical condition or other implanted
device • Active suicidal ideations • Recent history of substance abuse
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Included Subjects
Gender 6 female, 6 male Age (years) 48±6 (39-56) Years since onset of MDD 27±10 (11-42) Failed treatments 9.8±1.7 (7-13)
ECT treatments 10 of 12 subjects 16.5±23.2 (0-84)
Duration of current MDE (yrs) 6.9±8.1 (1.3-30)
Baseline HDRS 34.3±5.3 (27.8-46.4)
Baseline MADRS 32.2±4.0 (26.4-40.6)
Baseline GAF 42.0±5.3 (35-50)
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Effect of Therapy on Depression Scores
Trend: Cortical stimulation improves depression scores at 8 weeks relative to sham
Baseline
Week 8
HDRS Active
34.4±6.5
27.2±8.4 (-
21±20%)
Sham
34.0±3.0
32.6±3.8 (-3±17%)
MADRS
Active
32.0±5.1
24.8±7.4 (-
22±21%)
Sham
32.2±2.1
29.4±4.2 (-8±14%)
P-values: HDRS, p=0.14; MADRS p=0.23
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Active Stimulation at 8 and 16 Weeks
Trend: Subjects continue to improve with active cortical stimulation from 8 to 16 Weeks
* 16-wk time point for sham stimulation patients, 8-wk time point for active stimulation patients
** 24-wk time point for sham stimulation patients, 16-wk time point for active stimulation patients
Baseline
8 Weeks
16 Weeks
HDRS 34.3±5.0
27.0±8.9 (-
21±23%)
25.7±11.0 (-
26±29%)
MADRS
32.1±3.8
25.0±9.0 (-
22±27%)
21.8±10.9 (-
32±35%)
GAF 42.3±5.8
52.3±13.3
(25±32%)
60.1±13.0
(46±34%)
All p-values > 0.5
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Electrode Location Influences Outcome
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Baseline Metabolic Activity Predicts Patient Response
• Baseline FDG-PET acquired prior to implantation
• Magnitude of decreased metabolism at left DLPFC correlates with magnitude of improvement with active stimulation (p<.001)1
• Potential exists for improving the subject selection process
Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, rainey C, Kondziolka D, Howland R, Eskandar E, Evans KC, Dougherty DD. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 2011. Nov;69(5):1015-29.
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Ablative Limbic System Surgery
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Prior Treatment Criteria
• Ensure: – Multiple serial adequate trials of antidepressants – Adequate trial of multiple serial augmentation
strategies – Adequate trials of alternative monotherapies – Adequate trial of psychotherapy (especially CBT) – Adequate trial of ECT
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Anterior Cingulotomy
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Anterior Cingulotomy
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Effectiveness of Cingulotomy for MDD
• 33 patients undergoing anterior cingulotomy
• At mean f/u of 30 months, 12 (36%) were responders and 12 (39%) were partial responders
• Therefore, approximately 75% received some benefit
• Minimal adverse events Shields DC, Asaad W, Eskandar EN, Jain FA, Cosgrove GR, Flaherty AW, Cassem EH, Price BH, Rauch SL, Dougherty DD. Prospective assessment of stereotactic ablative surgery for intractable major depression. Biol Psychiatry. 2008 Sep 15;64(6):449-54. Epub 2008 May 16.
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Baseline subgenual PFC metabolism predicts subsequent response To anterior cingulotomy for major depression
Dougherty DD, Weiss AP, Cosgrove GR, Alpert NM, Cassem EH, Nierenberg AA, Price BH, Mayberg HS, Fischman AJ, Rauch SL. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for major depression. J Neurosurg 2003; 99:1010-1017.
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Effectiveness of Cingulotomy for OCD
• Total n =64; mean f/u = 63.8 months • Full response (35%+ YBOCS improvement) = 47% • Partial response (25-34% YBOCS improvement) = 22% • Minimal adverse events Sheth SA, Neal J, Frances Tangherlini F, Mian MK, Andre Gentil A, Cosgrove GR, Eskandar EN, Dougherty DD.
Cingulotomy for treatment-refractory obsessive-compulsive disorder: a prospective long-term follow-up of 64 patients. J Neurosurg. 2012 Dec 14. [Epub ahead of print]
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Rauch SL, Dougherty DD, Cosgrove GR, Cassem EH, Alpert NM, Price BH, Nierenberg AA, Mayberg HS, Baer L, Jenike MA, Fischman AJ. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder. Biol Psychiatry 2001; 50:659-667.
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Deep Brain Stimulation
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S1
S4 S3
S2 Coronal T1 or T2 (when T1 not available) MRI scans of the four patients (S1-S4), demonstrating electrode placement.
Patient #1: 33F
Patient #2: 24F
Patient #3: 52F
Patient #4: 55M
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Motor
Orbital
Premotor Dorsolateral
Medial
Courtesy of SN Haber
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DBS Patient Demographics*
Mean (years) Minimum (years)
Maximum (years)
Age at Implantation 37.1 22.0 59.0
Age at OCD Onset 15.1 7.0 34.0
Symptom Duration 22.0 8.0 41.0
Gender M = 53.8% F = 46.2%
History of Depression Yes = 88.5% No = 11.5%
* Reclaim DBS Therapy for OCD - Lead Kit for Deep Brain Stimulation Implant Manual; part number MA10549A002.
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Y-BOCS Scale
Follow-up Period (months)
Perc
ent C
hang
e Y-
BO
CS
Scor
e
All Subjects Responders Only
1 3 6 12 24 36 N=25 N=26 N=24 N=21 N=17 N=12 N=26
Baseline
0
-10
-20
-30
-40
-50
-60
*
* * * * *
* Within-subject change statistically significant (p ≤ .001, two-sided test).
Percent of Improvement with DBS Follow-up Study Results
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GAF Scale
Aver
age
GAF
Sco
re
Follow-up Period (months) * Within-subject change statistically significant (p ≤ .001, two-sided test).
Improvement in Score with DBS Follow-up Study Results
* * * * * *
1 3 6 12 24 36 N=20 N=21 N=20 N=18 N=16 N=12 N=21
Baseline 30
40
50
60
70
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VC/VS DBS for OCD
• Approved by FDA under the HDE mechanism in 2009
• Reimbursed by third party payers
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Methods
• 15 subjects from MGH, Brown University, and Cleveland Clinic with treatment resistant depression
• Similar inclusion/exclusion as cortical stimulation and anterior cingulotomy
• Mean baseline MADRS was 34.8 (7.3) • Device implantation followed by stimulation two
weeks later • Primary outcome measure was MADRS
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Malone DA Jr*, Dougherty DD*, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen SA, Machado AG, Kubu CS, Tyrka AR, Price LH, Stypulkowski PH, Giftakis JE, Rise MT, Malloy PF, Salloway SP, Greenberg BD. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009 Feb 15;65(4):267-75. Epub 2008 Oct 8.
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Results
• 8/15 subjects experienced at least a 50% reduction of MADRS scores at 3 months follow-up
• 5/15 subjects experienced remission (MADRS score of 10 or less) at 3 months follow-up
• Adverse events included two instances of worsening depression (device inadvertently turned off) and one instance of hypomania (resolved with reduction of stimulation parameters)
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However…
• Large, multisite randomized controlled trial for potential FDA approval…
NEGATIVE!! • Results being prepared for publication
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DBS: Subgenual Cingulate (Cg25) Region
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• Response in 4 of 6 patients Mayberg HS, et al. Neuron. 2005;45:651-660.
Table 2. Hamilton Depression Rating Scale, HAMD17, Scores over Time for Each Subject
Time Hamilton Scorea
Pt 1b Pt 2c Pt 3b Pt 4c Pt 5b Pt 6b
Pre-op baseline 29 22 29 24 26 25
1 week post-op (acute stimulation) 5 10 12 18 17 12
2 week post-op (DBS off) 9 13 23 18 22 n/a
1 month 10 14 17 20 22 12
2 months 13 11 12 18 10 12
3 months 2 15 14 25 7 14
4 months 4 9 12 24 6 12
5 months 5 18 7 23 8 n/a
6 months 5 15 9 23 6 12 aClinical response: decrease HDRS score >50%. Clinical remission: absolute HDRS score <8. bClinical responders. cClinical nonresponders
This information concerns a use that has not been approved by the US Food and Drug Administration.
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18% Remission and 41% Response @ 24 weeks 36% Remission and 36% Response after 1 year 58% Remission and 92% Response after 2 years Holtzheimer et al, Arch Gen Psychiatry.\Published online January 2, 2012.
DBS of Subcallosal Cingulate
10 MDD, 7 Bipolar Single-blind sham 4-weeks lead-in 24 weeks active discontinuation (N=3)
This information concerns a use that has not been approved by the US Food and Drug Administration.
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However…
• Large, multisite randomized controlled trial for potential FDA approval…
Halted following interim futility analysis!!
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Nucleus Accumbens Target
• 10 patients with TRD • At 12 month f/u, 5 pts achieved at least
50% reduction of HDRS
Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, Axmacher N, Lemke M, Cooper-Mahkorn D, Cohen MX, Brockmann H, Lenartz D, Sturm V, Schlaepfer TE. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010 Jan 15;67(2):110-6.
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Future Directions
• Surgical interventions to potentiate neurotransmitter release
Dougherty DD, Sortwell CE, Sagen J. Pharmacologic specificity of antidepressive activity by monoaminergic neural transplants. Psychopharmacology (Berl). 1995 Mar;118(1):10-8.
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Future Directions
• Surgical introduction of neurotrophic factors
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Future Directions
• Optogenetics
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Future Directions: Closed Loop DBS
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Collaborators
Massachusetts General Hospital
Psychiatric Neurosurgery Committee Emad Eskandar, Darin Dougherty, Cris Cusin, Karleyton Evans, Alice Flaherty, Bruce Price, Scott Rauch (emeritus)
Center for Morphometric Analysis Nikos Makris, David Kennedy, Verne Caviness
PET Laboratory Tom Brady, Alan Fischman, Nat Alpert
Butler Hospital Site Ben Greenberg, Steve Rasmussen, et al
Cleveland Clinic Site Don Malone, Ali Rezai et al
University of Florida Site Wayne Goodman et al Medical College Wisconsin Brian Koppell et al
Psychopharmacology Friday, September 28 – Sunday, September 30, 2012
The Westin Copley Place
39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015
The Westin Copley Place MGHCME.ORG
Massachusetts General Hospital Department of Psychiatry
Presents
39th Annual Psychopharmacology
Conference
THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE
BOSTON, MA
