A Clinical Evaluation for the Management of Patients With Major Depressive Disorder, Single or Recurrent Episode, With Deep Brain Stimulation
Phase: NA
Conditions: Depressive Disorder, Major, Unipolar Depression
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the 
express written consent of Abbott. 
87173 CIP Posting Cover Page Ver C 
Template 
Page 1 of 1 
 
NCT Number: NCT00617162 
BROADEN 
A Clinical Evaluation for the Management of Patients with Major Depressive Disorder, Single or 
Recurrent Episode, with Deep Brain Stimulation 
Study Document No: C-07-01 
Version A 
Date: 8-May-2023 
 
 
Sponsor  
 
 
Abbott Neuromodulation 
        
 
 
 
6901 Preston Road 
      
  
 
 
Plano, Texas 75024 
        
 
 
 
United States 
 
 
 

 
 
 
Clinical Protocol 
 
 
 
Protocol Number: 
C-07-01, Revised with Amendment I-IX, 10/05/2011 
 
Protocol Title: 
A clinical evaluation for the management of patients with 
Major Depressive Disorder, single or recurrent episode, with 
deep brain stimulation. 
 
Investigator: 
______________, MD  
 
University/Hospital 
 
Address 
 
Address 
 
City, State   Zip Code 
 
Sponsor: 
Advanced Neuromodulation Systems, Inc. (ANS) 
6901 Preston Road 
Plano, Texas 75024  
 
 
Approval Signatures: 
 
 
 
 
Investigator               ___________________ Date   ___________________ 
 
 
 
 
 
Director, Clinical       ___________________ Date   ___________________ 
Research     
 
 
 
Study Monitor            ___________________ Date   ___________________

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 2 
Table of Contents 
 Page No 
 
Clinical Protocol
 
 ................................................................................................... 1
1 
Introduction
 
 .................................................................................................... 6
2 
Objective
 
 ...................................................................................................... 10
2.1 Primary Objectives
 
 .................................................................................. 10
2.2 Secondary Objectives
 
 ............................................................................. 10
2.3 Primary Variable
 
 ..................................................................................... 10
2.4 Secondary Variables
 
 ............................................................................... 10
2.5 Other Variables
 
 ....................................................................................... 11
3 
Study Design
 
 ................................................................................................ 11
3.1 Design
 
 ..................................................................................................... 11
3.2 Baseline Evaluations
 
 ............................................................................... 17
3.3 Justification for Study Design
 
 .................................................................. 17
3.4 IPG Implantation
 
 ..................................................................................... 19
3.5 Patient Evaluation
 
 ................................................................................... 19
4 
Test Articles
 
 ................................................................................................. 20
4.1 System Components
 
 ............................................................................... 20
4.2 Regulatory Status
 
 ................................................................................... 20
5 
Patient/Subject Selection
 
 ............................................................................ 21
5.1 Inclusion Criteria
 
 ..................................................................................... 21
5.2 Exclusion Criteria
 
 .................................................................................... 22
6 
Subject Assignment to Treatment and Blinding
 
 ....................................... 23
7 
Methods and Procedures
 
 ............................................................................ 24
7.1 Informed Consent
 
 ................................................................................... 24
7.2 Screening/Baseline
 
 ................................................................................. 24
7.3 DBS System Implantation
 
 ....................................................................... 33
7.4 Concomitant Treatments
 
 ......................................................................... 34
7.5 Postoperative Visits
 
 ................................................................................ 36
7.6 Long-Term Follow-Up
 
 ............................................................................. 41
8 
Adverse Events (AEs)
 
 ................................................................................. 42
8.1 AE Definitions
 
 ......................................................................................... 42
8.2 AE Recording
 
 .......................................................................................... 42
8.3 Reporting AEs
 
 ......................................................................................... 42
8.4 Anticipated Adverse Events and Complications
 
 ...................................... 43
8.5 AE Classification
 
 ..................................................................................... 44
9 
Data Analysis and Statistical Plan
 
 ............................................................. 45
9.1 Statistical Plan
 
 ........................................................................................ 45
9.2 Sample Size
 
 ............................................................................................ 45
9.3 Datasets
 
 .................................................................................................. 45
9.4 Primary Effectiveness Analysis
 
 ............................................................... 45
9.5 Secondary Effectiveness Analyses
 
 ......................................................... 46
9.6 Other Analyses
 
 ....................................................................................... 47
9.7 Safety Analyses
 
 ...................................................................................... 47
9.8 Stopping Rule for Futility
 
 ......................................................................... 48
10 Withdrawal of Subjects from Study
 
 ........................................................... 49

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 3 
11 Data Safety Monitoring Board
 
 .................................................................... 49
12 Modification of Protocol
 
.............................................................................. 50
13 Discontinuation of Study
 
 ............................................................................ 50
14 Administrative Requirements and Quality Assurance
 
 ............................. 50
14.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
 
50
14.2 
Clinical Supplies
 
 ................................................................................. 51
14.3 
Reporting and Recording of Data
 
 ....................................................... 51
14.4 
Monitoring
 
 ........................................................................................... 51
14.5 
On-site Audits
 
 ..................................................................................... 51
14.6 
Record Storage and Retention
 
 ........................................................... 52
14.7 
Clinical Monitors
 
 ................................................................................. 52
15 References
 
 ................................................................................................... 54
16 Appendices
 
 .................................................................................................. 56
16.1 
Appendix A:  Product Labeling
 
 ........................................................... 56
16.2 
Appendix B:  Sample Informed Consent
 
 ............................................ 56
16.3 
Appendix C: Case Report Forms (CRFs)
 
 ........................................... 56
16.4 
Appendix D: Study Visit Schedule
 
 ...................................................... 56
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 5 
Protocol Summary 
 
Title: 
A clinical evaluation for the management of patients with Major 
Depressive Disorder, single or recurrent episode, with deep brain 
stimulation. 
 
Test Articles:  
ANS Libra®
 
 Deep Brain Stimulation System 
Objectives: 
To demonstrate the safety and efficacy of deep brain stimulation 
(DBS) to the subgenual white matter (Brodmann Area 25WM) as an 
adjunctive treatment for single or recurrent Major Depressive 
Disorder (MDD). 
 
Patient 
Population: 
Patients who have single or recurrent Major Depressive Disorder 
(MDD) complying with specific inclusion/exclusion criteria. 
 
Sample Size: 
A total of 201 patients will be randomized to treatment from up to 20 
investigational sites. 
 
Structure: 
Prospective, controlled, multi-centered, double blind, randomized, 
study with endpoint evaluation at 6 months post device implantation.  
Control group patients will not have the investigational device 
activated for the first 6 months of study. 
 
Method of 
Assignment: 
All patients who meet the inclusion/exclusion criteria will be 
randomized.   
 
Randomization: 
Randomization will be performed according to a computer 
generated scheme after device implant in a 2:1 ratio (Active 
Stimulation vs. Control Group). 
 
Statistical  
Analysis: 
The primary endpoint, at least a 40% decrease from baseline to 6 
months in Montgomery and Asberg Depression Rating Scale 
(MADRS) and no worsening in Global Assessment of Functioning, 
will be analyzed by logistic regression that includes the effects of 
treatment group, study site, and baseline MADRS, and will be 
tested at the 5% level of significance. 
 
   
Adverse Events: 
Volunteered and solicited. 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 6 
1 
 Introduction 
Depression, also known as major depressive disorder (MDD), is a serious medical 
illness that affects a person’s physical and mental state.  When a person is 
clinically depressed, his or her ability to function both mentally and physically is 
drastically affected. This impaired functional and symptomatic state may last for 
weeks, months, or even years. Typical symptoms of depression include: an 
"empty" feeling, sadness and anxiety, tiredness, lack of energy or interest in 
activities, sleep disturbances, including early morning awakening or oversleeping, 
and thoughts of death or suicide, a suicide attempt.  These problems can become 
chronic or recurrent and lead to substantial impairments in an individual’s ability to 
take care of their daily responsibilities.  MDD is one of the leading causes of 
disability in the United States and established market economies worldwide 
(Murray et al. 1996). The World Health Organization (2006) estimates that at its 
worst, depression can lead to suicide, a tragic fatality associated with 
approximately 850,000 lives every year.   
Major depressive disorder affects approximately 9.9 million American adults or 
about 5.0 percent of the U.S. population age 18 and older in a given year (Narrow 
1998).  While MDD can develop at any age, the average age of onset is the mid-
20s (American Psychiatric Association – APA, 1994).  Among this disease 
population, a large number of patients are consistently resistant to the many and 
different therapies utilized to treat depression.  This subgroup is diagnosed as 
having treatment resistant depression (TRD) and treatment alternatives are 
desperately needed for this growing population of severely depressed patients.  
Modern brain imaging technologies are revealing that in depression, neural circuits 
responsible for the regulation of moods, thinking, sleep, appetite, and behavior fail 
to function properly, and that critical neurotransmitters—chemicals used by nerve 
cells to communicate—are out of balance (Nestler et al. 2002).  Genetic research 
indicates that vulnerability to depression results from the influence of multiple 
genes acting together with environmental factors (NIMH Genetics Workgroup).  
Ongoing studies of brain chemistry and of mechanisms of action with 
antidepressant medications continue to inform the development of new and better 
treatments.  
Antidepressant medications are widely used and often partially effective treatments 
for depression (Mulrow et al. 1998).  Available antidepressant drugs influence the 
functioning of certain neurotransmitters in the brain, primarily serotonin and 
norepinephrine, known as monoamines. Older medications such as tricyclic 
antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), affect the 
activity of both of these neurotransmitters simultaneously. The disadvantage of 
these older medications is that they can be difficult to tolerate due to side effects 
or, in the case of MAOIs, dietary and medication restrictions.  Newer medications, 
such as the selective serotonin reuptake inhibitors (SSRIs) or selective 
serotonin/norepinephrine reuptake inhibitors (SNRIs), appear to have fewer side 
effects than the older drugs, making it easier for patients to adhere to treatment. 
Unfortunately, no single medication is effective for all depressed patients as 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 7 
various groups of patients will respond to one drug while other patients will require 
different agents.  Fava (2003) states that treatment resistant depression typically 
refers to an occurrence of an inadequate response following adequate 
antidepressant therapy among patients suffering from unipolar depressive 
disorders; which further shows that adequate treatment strategy is extremely 
difficult for this group of depressed patients. A recent, overall assessment of the 
nation’s largest real world study of treatment-resistant depression (Sequenced 
Treatment Alternatives to Relieve Depression – STAR*D) suggests that a patient 
with persistent depression can get well after trying multiple treatment strategies, 
but his or her odds of “beating” depression lessen as additional strategies are 
needed (Rush et al. 2006).  The STAR*D study, which has studied thousands of 
patients, further proves that the task of finding the correct treatment for severely 
depressed patients, can be extremely daunting.   
Certain types of psychotherapy can be an effective treatment option for 
depression. Cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT) 
have shown to be particularly useful. Approximately two thirds of adults with 
depression improve when they receive appropriate treatment with medication, 
psychotherapy, or the combination (Hollon et al. 2006), whereas only one third of 
treatments result in a full remission. 
Despite available pharmacologic and psychotherapeutic treatments, a large 
number of depressed patients do not have an acceptable or sustained response to 
these treatments.  Despite the advances in brain-neurobiology research and the 
growing number of available antidepressant therapies, fewer than 50% of these 
patients achieve remission, and up to 20% develop treatment resistant depression 
(Kennedy & Lam, 2003). Not only do these patients remain treatment resistant, 
they are also chronically and severely disabled.   
For these severely ill patients who do not respond to psychotherapy and 
medication, Electroconvulsive Therapy (ECT), is often prescribed.  Although this 
therapy has been shown to have short-term efficacy, many patients experience 
acute or sustained side effects as a result of the feature (Fink, 2001).  Some 
patients indicate memory loss which can occur for days, weeks and even months 
after ECT sessions. More recently, other somatic interventions such as 
Transcranial Magnetic Stimulation (rTMS) and Vagus Nerve Stimulation (VNS) 
have become available, although sustained response rates are relatively modest 
according to research studies.   
Although still investigational, the rTMS method appears to only provide temporary 
relief of symptoms; thus many aspects will need to be refined for programming 
parameters and targeting of regional locations when utilizing this technology, if it is 
ultimately approved by FDA.  A recent FDA panel meeting addressing rTMS’ 
safety and efficacy, showed that rTMS has a favorable safety profile but did not 
show efficacy at the specific primary endpoint of the clinical trial.  The FDA panel 
recommended to FDA that this therapy not be approved for the treatment of Major 
Depressive Disorder (FDA Panel Meeting, January 2007).   
Alternatively, vagus nerve stimulation has been used for the indication of Epilepsy 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 8 
in the United States since 1997 (George 2000 and Sackeim et al. 2007).  Due to 
the fact that many epileptic drugs also work for bipolar depressed patients, there 
was belief that there may be a correlation in the disease process between these 
two conditions (Elger 2000).  These hypotheses led to clinical trials researching the 
use of the VNS system for major depressive disorder.   VNS was ultimately 
evaluated and approved by the FDA in July of 2005, for the adjunctive long-term 
treatment of chronic or recurrent depression for patients 18 years of age and older, 
who are experiencing a major depressive episode and have not had an adequate 
response to four or more adequate antidepressant treatments (Cyberonics 
Labeling).  VNS is now one of the limited new options for this depressed, treatment 
resistant patient population.  Although this therapy was recently approved by the 
FDA, longer-term, well designed clinical trials are needed to confirm the safety and 
efficacy of this treatment alternative.  Furthermore, since the VNS device has 
shown limited efficacy in small numbers of patients, it has certainly not proven to 
be the ultimate solution for treatment of these severely depressed patients.  
For the most severely, treatment resistant of these patients, several invasive 
ablative neurosurgical procedures have also been available; although they are now 
infrequently used due to perceived side effects and the unfortunate irreversibility of 
the treatment.  Well-established procedures involve the production of lesions that 
interrupt distinct frontal-cingulate, fronto-striatal, and thalamo-frontal white matter 
tracts, resulting in therapeutic benefit for some patients (Cosgrove et al. 1995; and 
Sachdev and Sachdev, 2005). Several of these procedures, including subcaudate 
tractotomy, cingulotomy and anterior capsulotomy have been found to be effective 
in some patients, although all involve the permanent destruction of neural 
structures.  Furthermore, there is also a considerable time delay between surgery 
and symptom improvement.   
Recently, destructive procedures to treat Parkinson’s disease, such a 
thalamotomies and paladotomies have been replaced by applying high frequency 
electrical stimulation to these targets. Deep brain stimulation (DBS) has been 
found to have distinct advantages over ablation with the major advantage being its 
reversibility, as well as the option to modify specific stimulation parameters when 
necessary.  Pathological studies further demonstrate that chronic DBS produces 
little to no tissue damage (Haberler et al. 2000). In theory, DBS can be seen as a 
potentially safe, effective, flexible and reversible alternative to ablative surgery for 
treatment resistant depression, if the optimal target can be defined and evaluated.  
Functional neuroimaging studies have revealed changes in cortical (frontal, 
parietal), paralimbic (cingulate, insula) and subcortical (caudate, thalamus) activity 
following various types of treatments [medication, psychotherapy, sleep 
deprivation, ECT, repetitive transcranial magnetic stimulation (rTMS), ablative 
surgery] (Mayberg, 2003).  Normalization of frontal abnormalities (both increases 
and decreases) is the best-replicated finding. Decreases in paralimbic regions, 
while variable, are also consistently reported. While there is not yet a common 
pattern that characterizes depression remission across all of the available 
treatment modalities, medications and all of the available somatic treatments such 
as ablative surgery, TMS and VNS, changes have been seen in the paralimbic 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 9 
regions. Specifically, changes have been found in the hippocampus and ventral 
medial frontal/cingulate areas, having known projections through specific 
subcaudate tracts (Mayberg et al. 2000).   
Regions affected by these white matter interruptions are widespread, as the 
subcaudate tractotomy is quite large.  Specific tracts are less well characterized, 
but likely involve connections linking orbital frontal, subgenual cingulate, ventral 
striatum/caudate, thalamus brainstem, hypothalamus and hippocampus/amygdala.  
The precise optimal target(s) within the subcaudate that mediate antidepressant 
response is not known at this time. However, imaging studies suggest that 
disturbances involving more specific connections between the subgenual cingulate 
and 
medial 
frontal, 
ventral 
striatum, 
anterior 
thalamus, 
hippocampus, 
hypothalamus and brainstem may be particularly critical (Seminowicz et al. 2004).  
Brodmann Area 25WM (BA25WM), also known as the subgenual cingulate region, 
subgenual white matter, or Cg25, has been shown to be involved in both acute 
sadness and antidepressant treatment effects; hence indicating its role in 
modulating mood states (Mayberg et al. 1999).  These findings further suggest that 
DBS may be most effective if these medial pathways are selectively modulated, as 
this hypothesis has been further verified in a preliminary study in treatment-
resistant depressed patients.  Mayberg et al. 2005, reported that in a small group 
of severe refractory depressed patients, DBS induced clinical response in 4 out of 
6 patients, with 2 patients achieving full remission. Although these preliminary 
findings are encouraging, much larger, controlled clinical trials are necessary to 
show the safety and efficacy of deep brain stimulation of Brodmann Area 25WM.    
Deep brain stimulation is considered safe, non-destructive and reversible. The 
frequency and severity of procedural risks and complications with DBS 
implantation for depression are expected to be similar to those for Parkinson’s 
Disease and Essential Tremor.  An extensive review of Manufacturer and User 
Facility Device Experience (MAUDE) reports, regarding deep brain stimulation 
from 1997 to present, has shown no evidence of tissue damage due to excessive 
electrical stimulation.  To date, over 30,000 Deep Brain Stimulation devices have 
been implanted worldwide. Furthermore, a recent paper by Haberler et al. (2000) 
concluded that chronic DBS, defined as continuous deep brain stimulaton for up to 
70 months, does not cause damage to neural tissue in Parkinson’s Disease 
patients when applied at therapeutic levels.   
Unfortunately, there are a limited number of new treatment options for the 
treatment resistant patient population.  Considering the severity of treatment 
resistant depression and its debilitating effect on patients’ and family’s lives, Deep 
Brain Stimulation provides an optimistic opportunity for significant symptom relief 
and potential quality of life improvement, with minimal risk.  Further, this evaluation 
of DBS’ safety and efficacy, gives patients with treatment resistant depression an 
additional treatment option.  The purpose of this proposed clinical study is to 
evaluate safety and efficacy of subgenual white matter (Brodmann Area 25WM) 
deep brain stimulation for the treatment of single or recurrent, Major Depressive 
Disorder, using standard psychiatric rating scales and questionnaires as outcome 
measures.   

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
l 
Page 10 
2 
Objective 
2.1 
Primary Objectives 
To demonstrate the safety and efficacy of deep brain stimulation (DBS) to the 
subgenual white matter (Brodmann Area 25WM) as an adjunctive treatment 
for Major Depressive Disorder (MDD), single or recurrent episode. 
2.2 
 Secondary Objectives 
To evaluate changes in the following:  Hamilton Rating Scale for Depression 
(HRSD-17), the 30-item Inventory of Depressive Symptomatology (IDS-C30), 
Quick Inventory of Depressive Symptomatology (QIDS-SR), Young Mania 
Rating Scale (YMRS), Work and Social Adjustment Scale (WSAS), Quality of 
Life and safety.  
2.3 
Primary Variable 
Primary Efficacy:  Change from Baseline (defined as mean of 3 Montgomery 
and Asberg Depression Rating Scale (MADRS) scores) to the mean of 
months 4, 5, and 6 between treatment groups. 
The primary endpoint
2.4 
Secondary Variables 
 will be defined as at least a 40% reduction in MADRS 
and no worsening in Global Assessment of Functioning (GAF). 
• Change from baseline in GAF over time;  
• Change from baseline in the MADRS over time; 
• Change from baseline in the Hamilton Rating Scale for Depression - 17 
item (HRSD-17) over time; 
• Change from baseline in the Inventory of Depressive Symptomatology 
(IDS-C30) over time; 
• Change from baseline in Quick Inventory of Depressive Symptomatology 
(QIDS-SR) over time; 
• Change from baseline in the Work and Social Adjustment Scale (WSAS) 
over time; 
• Change from baseline in Patient Global Impression of Severity over time; 
• Change from baseline in Clinician Global Impression of Improvement over 
time; 
• Change from baseline in quality of life over time; 
• The incidence of all adverse events (i.e. hospitalization due to worsening 
depression, suicidal ideation or behavior, medical treatment, and device 
related events) that occur over study duration. 
• Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) over 
time. 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 11 
2.5 Other Variables 
• Number of patients who have a 40% reduction in Baseline HRSD-17 over 
time; 
• Number of patients who have a 40% reduction in IDS-C30 over time; 
• Number of patients who have a 40% reduction in QIDS-SR over time; 
• Number of patients in Remission (as defined by a score of ≤ 14 on the 
IDS-C30) over time; 
• Number of patients in Remission (as defined by a score of ≤ 5 on the 
QIDS-SR) over time; 
• Number of patients in Remission (as defined by a score of ≤ 10 on the 
MADRS) over time; 
• Number of patients in Remission (as defined by a score of ≤ 7 on the 
HRSD-17) over time.  
• Change from baseline in the Young Mania Rating Scale (YMRS) over 
time; 
• Number of patients with hypomania (defined as present when YMRS > 
15.); 
• Change in the Neuropsychological Battery test results at 6 and 12 months; 
• Change from baseline in the Health and Labor Questionnaire (HLQ) over 
time; 
• Change from baseline in the Columbia Suicide-Severity Rating Scale (C-
SSRS) over time 
3 
Study Design 
3.1 Design 
This study is designed as a prospective, multi-centered, double-blind, 
randomized, controlled 12-month pivotal study to evaluate the safety and 
efficacy of the ANS Libra®
 
 Deep Brain Stimulation System for patients with 
major depressive disorder who have failed at least 4 treatments in the current 
episode. The primary outcome assessment will occur at 6 months: however, 
all patients will be followed for 1 year. A total of 201 patients will be 
randomized from up to 20 sites. 
Each 
potential 
patient 
will 
be 
pre-screened 
according 
to 
the 
inclusion/exclusion criteria.  A narrative of what study participation entails, will 
be used to educate potential participants on study requirements. Prior to on-
site baseline evaluations, the patient will sign the informed consent. Patients 
will then undergo 3 baseline evaluations, with each of these evaluations to 
occur no less than 2 weeks apart from each other. The first 2 baseline visit 
evaluations will be performed by separate psychiatrists in order to confirm the 
patient’s diagnosis.  The patient must score an average ≥ 22 on the MADRS, 
across 3 evaluations.  All patients will be scheduled for surgery, to occur no 
less than two weeks and no more than 1 month after final baseline evaluation, 
to implant the ANS Libra® Deep Brain Stimulation system.  After device 
implantation, patients will be randomly assigned to 1 of 2 groups in a 2:1 ratio 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 21 
5 
 Patient/Subject Selection  
5.1 Inclusion Criteria 
Patients enrolled in this study must comply with the following inclusion criteria: 
 
1.   Men and women (non-pregnant) age is 21-70 years; 
2.   Diagnosed with non-psychotic major depressive disorder, single or 
recurrent episode by DSM-IV-TR criteria derived from the MINI;  
3.  First episode onset before age 45; 
4. 
Current episode > 12 months duration; 
5.    In the current episode: Documented resistance (i.e. persistence of the 
major depressive episode) to a minimum of 4 adequate depression 
treatments from at least 3 different treatment categories (e.g. SSRI’s, 
SNRI’s, TCA’s, MAO-inhibitors, Mirtazipine, Nefazodone, Trazodone, 
Bupropion, lithium augmentation, thyroid augmentation, ECT); Adequacy 
of treatments as defined by a score of at least 3 according to the 
amended Antidepressant Treatment History Form (ATHF) criteria; 
6. 
In Lifetime:  Received a course of psychotherapy for depression; 
7. 
Montgomery Asberg Depression Rating Scale (MADRS) of > 22 at 3 
separate baseline visits, rated by 2 separate psychiatrists, Baseline 2 
and Baseline 3 MADRS scores cannot be separated by > 6 weeks and 
cannot improve ≥ 20%; 
8.   Global Assessment of Function, score <50; 
9.  Modified mini-mental state examination (MMSE) score >24; 
10.   No change in current antidepressant medication regimen or medication 
free >4 weeks prior to study entry (with exception to sleep, cholesterol, 
blood pressure, sexual dysfunction, non-migraine headache medication, 
or medication for other medical reasons not related to depression, in 
which changes to dose or type will be allowed during course of study); 
11.  Able to give informed consent in accordance with institutional policies; 
12.   Able to comply with all testing and follow-up requirements as defined by 
the study protocol; 
13.   Must be determined medically stable by surgeon, to undergo deep brain 
stimulation surgical procedure.  
14.    Must have platelet count, PT and PTT within normal limits of the 
laboratory. 
15.    During last 6 months in the current episode documented treatment 
under the care of a licensed psychiatrist/psychologist. 
 
 
 
 
 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 22 
5.2 Exclusion Criteria 
Patients will be excluded from participation in this study if they meet any one 
of the following criteria: 
 
1. 
A diagnosis of a bipolar I or bipolar II disorder by DSM-IV-TR criteria, 
derived from the MINI; 
2. 
Meets criteria for borderline or antisocial personality disorder in the last 
12 months by DSM-IV-TR criteria, derived from the Cluster B Personality 
Disorders Sections 301.7 – 301.83, and screened via SCID-II at 
Baseline visit; 
3. 
In the current depressive episode, has been diagnosed with General 
 
Anxiety Disorder (GAD) -  as defined by the DSM-IV-TR, and GAD is the 
 
primary diagnosis; 
4. 
Has an intracranial Central Nervous System (CNS) disease that impairs 
motor, sensory or cognitive function or that requires intermittent or 
chronic medication (e.g., Parkinson’s Disease, chronic migraine, stroke, 
Huntington’s, head trauma, etc.) with exception to non-migraine 
headaches; 
5. 
Has been diagnosed with fibromyalgia or has a current condition which 
requires chronic pain narcotic usage (e.g. morphine, methadone); 
6. 
Has been currently diagnosed with chronic fatigue syndrome; 
7. 
Substantial suicidal risk as defined by (1) MADRS item 10 score of 5 or 
6, (2) a current plan and intent, (3) clinician judgment that there is a clear 
immediate intent for self-harm, (4) more than 3 suicide attempts within 
the last 12 months; 
8. 
Co-morbid obsessive compulsive disorder, post-traumatic stress 
disorder, panic disorder, bulimia or anorexia nervosa if previously 
present, must be in remission for 6 months as defined by DSM-IV-TR 
criteria, derived from the MINI; 
9. 
Alcohol, medication, or illegal substance dependence or abuse within 
last 12 months derived from the MINI; 
10. Diagnosis of sleep apnea confirmed by a sleep test that is not 
adequately treated; 
11. Advanced cardiovascular disease which renders anesthesia and surgery 
as unsafe as determined by neurosurgeon;  
12. Clinically relevant abnormality (e.g. tumor or growth) on study MRI; 
13. Has cardiac pacemaker/defibrillator or other implanted active stimulator; 
14. Has a medical condition requiring a repetitive MRI body scan;  
15. Requires chemotherapy for the treatment of malignancy or requiring 
chronic oral or intravenous (immunosuppressive or)  steroid therapy; 
16. Is unable to comply with study visit schedule and timeline; 
17. Past ablative or relevant intracranial surgery; 
18. A female lactating or of child bearing potential, with a positive pregnancy 
 
test or not using adequate contraception;  
19. Lifetime psychotic disorders, schizophrenia, or schizoaffective disorder 
 
defined by DSM-IV-TR; 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 24 
7 
Methods and Procedures 
7.1  Informed Consent 
Written Informed Consent will be obtained from each patient prior to 
enrollment into the study. All potential patients/subjects will be properly 
informed as to the purpose of the study and the potential risks and benefits 
known, or that can be reasonably predicted or expected. The Investigator will 
retain the original copy of the Informed Consent Form signed by the patient, a 
duplicate will be provided to the patient and a document signed by the 
Investigator confirming receipt of patient consent will be returned to the 
Sponsor. Only the consent form approved by the IRB/IEC will be used. 
(Appendix A: Sample Informed Consent) 
7.2 Screening/Baseline 
Study candidates will be screened according to the inclusion/exclusion criteria 
prior to enrollment in the study. All study participants must provide informed 
consent. Evaluations will include the following: 
 
• Confirmation of MDD via DSM-IV-TR criteria will occur combined with 
extensive medical record review by evaluating psychiatrist;  
• Montgomery and Asberg Depression Rating Scale (MADRS); 
• Demographics and prior history; 
• Medical system review; 
• Brief physical exam, neurological exam;  
• Pregnancy test (if necessary); 
• Family history, medication history – antidepressant treatment history form 
(ATHF - modified);  
• MINI Plus; 
• HRSD-17; 
• SAFTEE; 
• Mini Mental State examination (MMSE); 
• Subsection for cluster B personality disorder of the Structured Clinical 
Interview for DSM-IV Personality Disorders (SCID-II) ; 
• Inventory of Depressive Symptomatology (IDS-C30); 
• Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR);  
• Work and Social Adjustment Scale (WSAS); 
• Short form Quality of Life Enjoyment and Satisfaction Questionnaire 
(QOL); 
• Young Mania Rating Scale (YMRS); 
• Clinical Global Impression of Severity and Improvement (CGI); 
• Patient Global Impression Index (PGI); 
• Health Labor Questionnaire (HLQ); 
• Hamilton Anxiety Rating Scale (HAM-A); 
• Columbia Suicide-Severity Rating Scale (C-SSRS). 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 25 
7.2.1 Baseline 2/Baseline 3  
A second baseline will be performed no less than 2 weeks and no more 
than 4 weeks after Baseline #1. Evaluations will include the following: 
 
• 
Confirmation of MDD via DSM-IV-TR criteria will occur combined with 
 
extensive medical record review by evaluator;  
• 
Montgomery and Asberg Depression Rating Scale (MADRS); 
• 
The Quick Inventory of Depressive Symptomatology (QIDS); 
• 
Systematic Assessment for Treatment Emergent Events (SAFTEE-SI); 
• 
Hamilton Anxiety Rating Scale (HAM-A); 
• 
Columbia Suicide-Severity Rating Scale (C-SSRS). 
 
A third baseline will be performed no less than 2 weeks and no more than 
6 weeks after Baseline #2. Evaluations will include the following: 
 
• 
Montgomery and Asberg Depression Rating Scale (MADRS); 
• 
The Quick Inventory of Depressive Symptomatology (QIDS); 
• 
Systematic Assessment for Treatment Emergent Events (SAFTEE-SI); 
• 
Hamilton Anxiety Rating Scale (HAM-A); 
• 
Columbia Suicide-Severity Rating Scale (C-SSRS); 
• 
Neuropsychological Battery – performed only if
• 
MRI scan will be performed after patient has meet eligibility 
requirements (to exclude brain abnormalities, plan for surgery, and 
targeting); 
 patient meets eligibility 
 
for study participation after scoring ≥ 22 on three baseline MADRS 
 
evaluations. 
 
The patient will also be assigned a case manager to follow each patient’s 
care for the duration of the study. 
 
*If the patient does not have three MADRS values ≥ 22, they will be 
considered a screen failure and may not
 
 be re-evaluated for study 
participation for a minimum of 6 months.  
7.2.2 Outcome measures 
 
The Montgomery and Asberg Depression Rating Scale is a 10 item 
severity scale constructed to be sensitive to change with treatment. It was 
designed to be sensitive for individual items and is therefore useful for 
measuring differential profiles of action. Ratings of patients on a 65 item 
comprehensive psychopathology scale were used to identify the 17 most 
commonly occurring symptoms in primary depressive illness, and ratings 
on these 17 items for 64 patients participating in studies of four different 
antidepressant drugs were used to create a depression scale consisting of 
Montgomery and Asberg Depression Rating Scale (MADRS) 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 26 
the 10 items which showed the largest changes with treatment and the 
highest correlation to overall change. (Montgomery & Asberg 1979)  An 
interrater evaluation will also be performed on multiple study visits to 
increase consistency and reduce variability. 
 
The Hamilton Rating Scale for Depression is a 17-item scale that 
evaluates depressed mood, vegetative and cognitive symptoms of 
depression, and comorbid anxiety symptoms. The HRSD-17 was one of 
the first rating scales developed to quantify the severity of depressive 
symptomatology. First introduced by Max Hamilton in 1960, it has since 
become the most widely used and accepted outcome measure for 
evaluating depression severity. It provides ratings on current DSM-IV 
symptoms of depression, with the exceptions of hypersomnia, increased 
appetite, and concentration/indecision. The HRSD-17 was designed to be 
administered by a trained clinician using a semi-structured clinical 
interview. The 17-items are rated on either a 5-point (0-4) or a 3 point (0-
2) scale.   
Hamilton Rating Scale for Depression (HRSD-17) 
 
The construction of the IDS-C30 was intended to remedy deficits in the 
Hamilton Scale for Depression (HRSD-17) and Montgomery and Asberg 
(MADRS) depression rating scales by, among others, including all nine 
symptom domains needed to diagnose a DSM-IV major depressive 
episode in order to assess symptom remission, improve ability to detect 
milder levels of symptoms than the HRSD-17, and provide unconfined and 
more equivalent weighting among items. There are two versions of the 
IDS with identical items: a clinician rating (IDS-C30) and a self-report 
(IDS-SR30). Items were selected to represent mood, cognitive, vegetative, 
anxious, and endogenous symptoms common in depression. Each of the 
30 items is rated from 0 to 3, with increasing severity represented by a 
higher rating. (Rush et al. 1996) 
Inventory of Depressive Symptomatology (IDS-C30) 
 
The Quick Inventory of Depressive Symptomatology Self Report
 
 (QIDS-
SR) is a 16-question shortened self-test, derived from the 30-item IDS, 
which measures 9 different criterion domains of major depression.  Each 
of the 4 possible answers to each quiz is given an ascending numerical 
value from 0-3.  
The SAFTEE is a structural clinical interview developed by the National 
Institute of Mental Health which exams possible treatment-emergent side 
effects for clinical studies.  The SAFTEE-SI looks at specific adverse 
symptoms for a particular treatment. 
Systematic Assessment for Treatment Emergent Events (SAFTEE-SI) 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 27 
 
The MINI is a short structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM-IV 
and ICD-10 psychiatric disorders. With an administration time of 
approximately 15 minutes, it was designed to meet the need for a short 
but accurate structured psychiatric interview for multi-centered clinical 
trials and epidemiology studies and to be used as a first step in outcome 
tracking in non-research clinical settings.  The MINI Plus is a more 
detailed edition of the MINI.  
The Mini-International Neuropsychiatric Interview (M.I.N.I.) Plus 
 
The mini-mental state examination (MMSE)
 
 or Folstein test is a brief 30-
point questionnaire test that is used to assess cognition. It is commonly 
used in medicine to screen for dementia.  In the time span of about 10 
minutes, it samples various functions, including arithmetic, memory and 
orientation.  It was introduced by Folstein et al in 1975 and is widely used 
with small modifications. 
 
The SCID-II is a semi-structured interview for making DSM-IV Axis II 
(Personality Disorder) diagnoses and is designed to be administered by a 
clinician or trained mental health professional. A SCID II takes 1/2 to 1 
hour to administer. There are 3 components to the SCID-II. The interview 
itself covers the 11 DSM-IV Personality Disorders. The SCID-II Personality 
Questionnaire is available as a screening tool to shorten the time it takes 
the clinician to administer the SCID-II. After the subject fills out the 
Personality Questionnaire (which usually takes 20 minutes), the clinician 
simply circles the numbers to the left of the SCID-II items that correspond 
to items answered "yes" on the questionnaire. When the SCID-II is 
administered, the clinician needs only to inquire about the items screened 
positive on the questionnaire. The assumption is that a subject who 
responds with a "no" on the questionnaire item would also have answered 
"no" to the same question had it been read aloud by the interviewer.  For 
this study, only the subsection for Cluster B will be administered. 
Structural Clinical Interview for Personality Disorders (SCID II) 
 
The YMRS is an 11-item instrument used to assess the severity of mania 
in patients with a diagnosis of bipolar disorder. The 11 items are: Elevated 
Mood, Increased Motor Activity Energy, Sexual Interest, Sleep, Irritability, 
Speech (Rate and Amount), Language - Thought Disorder, Content, 
Disruptive - Aggressive Behavior, Appearance, and Insight. 
The Young Mania Rating Scale (YMRS) 
Ratings are based on patient self-reporting, combined with clinician 
observation (accorded greater score).  (Young 1978) 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 28 
 
 
The short form of the Quality of Life Enjoyment and Satisfaction 
Questionnaire is a self-report form composed of 16 items each rated on a 
5-point scale that indicates the degree of enjoyment or satisfaction 
experienced during the past week.  A total score of items 1 to 14 is 
computed and expressed as a percentage of the maximum possible score 
of 70.  The 14 items evaluated each subjects’ satisfaction with his or her 
physical health, social relations, ability to function in daily life; ability to get 
around physically; mood; family relations; sexual drive and interest; ability 
to work on hobbies, work, leisure time activities; economic status; 
household activities; living/housing situation; and overall sense of well 
being.  (Rapaport et al. 2005) 
Quality of Life Enjoyment and Satisfaction Questionnaire (QOL) 
 
The WSAS-SR is used to measure functional impairment attributed to a 
identified problem (Mundt, 2002).  There are 5 questions that are 
associated with work, home, social leisure, private leisure and ability to 
form and maintain relationships.  
Work and Social Adjustment Scale Self Report (WSAS) 
 
The Global Assessment Scale is a hypothetical continuum of mental 
health illness that looks at psychological, social and occupational 
functioning. The GAF scale is divided into 10 ranges of functioning in 
which the clinician picks a single value that best reflects the individual’s 
overall level of functioning. The GAF does not include “impairment in 
functioning due to physical (or environmental) limitations.” (American 
Psychiatric Association – APA, 1994) 
Global Assessment of Functioning (GAF) 
 
The CGI is used to measure the global impression of a treatment 
response in a psychiatric patient’s illness by a clinician (Guy 1976).  Two 
of three sub-scales are being used to measure severity of the illness and 
improvement of the illness. Items in the two-subscales being administered 
are rated on a seven-point scale ranging from “1=normal” to “7=extremely 
ill” for severity subscale and “1=very much improved” to “7=very much 
worse” for improvement sub-scale. 
Clinical Global Impression of Severity and Improvement (CGI) 
 
The PGI is used to measure the global impression of a treatment 
response in a psychiatric patient’s illness by the patient.  Two sub-scales 
are being used to measure severity of the illness and improvement of the 
illness. Items in the two-subscales being administered are rated on a 
seven-point scale ranging from “1=normal not ill at all” to “7=among the 
Patient Global Impression Index (PGI) 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 29 
most extremely ill” for severity sub-scale and “1=very much improved” to 
“7=very much worse” for improvement sub-scale. 
 
 
Health and Labor Questionnaire (HLQ)
The HLQ is designed to collect quantitative data on the relation between 
illness and treatment and work performance. The HLQ data permits the 
estimation of production losses (costs) of paid and unpaid labor. It 
contains also an indicator for impediments for paid and unpaid labor, one 
of the indicators for quality of life. The HLQ is divided into 4 modules to 
collect data about absence from work, reduced productivity at paid work, 
unpaid labor production and impediments to paid and unpaid labor. The 
modular structure permits the omission of questions that are not 
applicable to the study population. The questionnaire is suitable for self-
assessment.  
  
 
A 14 item test designed to assess the severity of anxiety symptoms.  All 
questions are rated on a 5 point (0-4) scale, with 7 questions on psychic 
anxiety and 7 questions on somatic anxiety.  Total scores range from 0 to 
56.  Patients with anxiety and panic disorder tend to have a score greater 
than 20.    
Hamilton Anxiety Rating Scale (HAM-A) 
 
The C-SSRS is a semi-structured clinical interview that utilizes a set of 
prompts and questions to help an interviewer get more complete 
information on events suggestive of suicidality.  This prospective tool aims 
to standardize terminology and articulate suicidality assessment in a 
straightforward manner. 
Columbia Suicide-Severity Rating Scale (C-SSRS) 
7.2.3 
Neuropsychological Battery 
 
Neuropsychological Examination: 
 
The following neuropsychological 
tests will be performed and evaluated at or after baseline #3, 6 
months, and 1 year visits during the study to assess the safety of 
Deep Brain Stimulation.  The following is a description of all the tests 
to be performed:   
 
Attention/Working Memory 
Wechsler Memory Scale –Working Memory Index Test (Wechsler, 
1997) 
 
Letter-Number Sequencing  
Examinees are presented with strings of alphanumeric sequences 
(e.g., 6-B-3-Z) of increasing length (2-8 letter-number pairs). The task 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 30 
of the examinee is to repeat the letters and then the numbers in 
alphabetical and numerically ascending order. This test of working 
memory thus requires re-sequencing of information while holding in 
memory the original sequence. This task takes 3-5 minutes to 
complete. 
 
Stroop Color and Word Test (Golden, 1978) 
This version of the well-known Stroop test has 3 parts, each 
consisting of 1 page of 100 stimuli (arranged in 5 columns of 20 
items). The first sheet contains the words red, green, and blue, printed 
in black ink, in random order with the constraint that a word cannot be 
followed by the same word. The examinee is asked to read the words, 
and the variable of interest is how many items are completed correctly 
in 45 sec. On page 2 are 100 “XXXX” printed in either red, green or 
blue ink, with the constraint that a given item number could not 
correspond to the same color on the first page, and the same color 
cannot occur on consecutive items. The examinee is given 45 sec to 
name the color of the ink in which each stimulus is printed. On the 
final part, the page consists of the words red, green, and blue, and 
each word is printed in red, green, or blue ink, but in a manner that 
the word and color ink are always incongruent. The score is the 
number of items completed correctly in 45 sec. The whole test takes 
about 5 minutes. 
 
Ruff 2 & 7 Selective Attention Test (Ruff & Allen, 1996) 
This test of sustained and selective attention consists of 20 15-second 
trials during which patients cross out 2 target stimuli (the numbers 2 
and 7) among three rows of either numeric or alphabetic stimuli (each 
row contains 10 targets and 40 distracters in quasi-random order). 
The targets embedded among letters are considered “automatic” 
conditions (because the patient can identify targets simply by the 
category they belong to), whereas the tasks embedding the targets 
among numbers are considered “Controlled” conditions requiring 
effort and working memory since targets and distracters belong to the 
same stimulus category (numbers). The test evaluates both accuracy 
(considering errors of omission and commission) and speed.  
Normative data (based on 360 persons) are available for ages 16-70 
years, stratified by education. Test-retest reliability is estimated to be 
.89 for speed, and .59 to .69 for accuracy on automatic and controlled 
search tasks (with stability coefficients ranging from .76 to .93). The 
test is typically completed in 5 minutes. 
 
 
Executive Functions 
Delis-Kaplan Executive Function System (D-KEFS) Verbal 
Fluency Tests 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 31 
The D-KEFS contains 3 verbal fluency tests assessing timed oral 
production of items from lexical and semantic categories. In the Letter 
fluency task the patient is asked to say as many words as possible 
(excluding proper names and numbers) beginning with a given letter 
of the alphabet. There are 3 trials, each using a different letter, of 60 
seconds each. In the Category Fluency task, the examinee is asked to 
say as many words as possible belonging to a category (such as 
animals) in 60 seconds.  There are 2 trials using different categories. 
On the final task (Category Switching), the patient is asked to orally 
generate consecutive words from 2 alternating categories for 60 
seconds.  The tasks can be completed in about 8-10 minutes. 
 
The tests are normed on over 2000 individuals, are standardized, are 
applicable to persons up to 89 years of age, and are co-normed with 
the WASI. This co-norming feature means that cognitive strengths 
and weaknesses can be ascertained with confidence given 
comparability of scores and normative data. Another strength of this 
instrument is the availability of alternate forms, thus minimizing 
practice effects (although not eliminating possible familiarity and 
carry-over effects). Test-retest data are available to facilitate 
interpretation of score changes over time. 
 
 
Memory 
Hopkins Verbal Learning Test – Revised (HVLT-R; Brandt & 
Benedict, 2001) 
This verbal learning test has six equivalent, alternate forms, making it 
ideal for repeat administration. It is normed on persons aged 16-92 
years and was designed to be tolerated by even significantly impaired 
individuals. The examinee is provided 3 learning trials to remember an 
orally presented 12-word list (four nouns from each of 3 semantic 
categories). Following a 20-25 minute interval, delayed recall and 
yes/no recognition are assessed. The test takes about 15 minutes 
excluding the delay interval which is preferably filled with intervening 
visuospatial tasks. Test-retest reliability is weaker for recognition and 
retention (.40 and .39; probably limited by skewed 
Score distributions), but adequate for recall (.66-.74). Test-retest 
gains, even when persons were tested as little as 2 weeks apart, were 
only about 0.5 standard deviations. 
 
Brief Visual Memory Test – Revised (BVMT-R; Benedict, 1997) 
Like any of its word list learning analogs (e.g., the HVLT-R), this test 
involves multiple trial learning followed by delayed recall and 
recognition trials. However, the stimuli are abstract line drawings 
rather than words. The patient is shown a set of 6 abstract line 
drawings (in a 2x3 array) for 10 seconds and is then asked to draw 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 32 
them in their correct location. This procedure is repeated for a total of 
3 learning trials. After 25 minutes, delayed recall and recognition 
(identifying which 6 of 12 drawings were seen) trials are administered. 
The brevity of the task and the availability of 6 alternate forms make 
the test useful for repeated administrations. It is normed for persons 
aged 18-79 years. Reliability coefficients exceed .90, and test-retest 
reliability ranges from .60 to .84. Excluding the delay, which is filled 
with verbal tests, the BVMT-R can be completed in 15 minutes. 
 
 
Self and Informant Rating of Executive Functions 
Behavior Rating Inventory of Executive Function – Adult Version 
(BRIEF-A; Roth et al. 2005) 
The self-and informant-report forms consist of 75 items asking the 
person to report the frequency (never, sometimes, or often) with which 
certain behaviors have occurred during the month prior to evaluation. 
The behaviors measured relate to a variety of executive functions 
(e.g., self-monitoring, emotional control, behavioral inhibition and 
shifting, planning and organization) and are expressed in 2 indices 
(Behavioral Regulation Index and Metacognition Index) and an overall 
summary score (Global Executive Composite). There are also 3 
response validity scales. Normative data are available for 1,050 
persons for self-report and 1,200 informant reports. The test can be 
used with adults aged 18-90 years. Test-retest reliability for self-report 
clinical scores ranged from .82 to .93 over an average re-test interval 
of about 4 weeks, while informant report test-retest reliability ranged 
from .91 to .94. Test-retest values were still higher for the summary 
indexes. Patients and informants usually complete these forms in 
about 15 minutes. 
 
 
Testing order: 
The above tests should be performed in the following order: 
 
1. HVLT-R immediate recall (3 trials); 
2. Ruff 2 & 7; 
3. Stroop; 
4. Fill rest of 20-25 minute delay with starting the BRIEF; 
5. HVLT-R Delayed recall and recognition; 
6. BVMT-R Immediate recall (3 trials); 
7. DKEFS verbal fluency tests; 
8. Letter-Number Sequencing; 
9. Continue the BRIEF as needed to fill the BVMT-R delay; 
10. BVMT-R Delay recall and recognition; 
11. Finish BRIEF. 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 33 
7.3 
DBS System Implantation 
 
The DBS system implant visit should be performed no less than 2 weeks and 
no more than 1 month after the baseline #3 visit.  
 
Implantation of the DBS system will be performed according to standard 
surgical procedure for Brodmann Area 25WM (Cg25) DBS implantation. 
 
Pre-Operative Imaging:
 
 High resolution, 3D T1 weighted images will be 
obtained.  On or before the day of surgery patients will have a stereotactic 
frame or appropriate bone fiducials applied using local anesthesia.  Additional 
CT imaging for fusion is optional, as is the use of IV contrast.   
Pre-Operative Planning:
 
 Standard software (e.g. Framelink, Brainlab, or 
other) is used to reconstruct the images in axial, coronal, and sagittal views, 
relative to the AC-PC plane.    
The sagittal images will be used first.  Surgeon will select an image several 
millimeters (mm) off midline clearly showing the white and gray matter of the 
cingulate gyrus.  A tentative target point is selected at the center of the 
subgenual cingulate (Brodmann Area 25WM).  
 
Next, the surgeon will convert to the coronal images perpendicular to the AC-
PC plane.  The midpoint of the subgenual cingulate gyrus is typically found in 
the coronal image containing the anterior-most section of the caudate 
nucleus.  Thus the A-P position of the target can be confirmed by scanning a 
few images anterior and posterior to confirm proximity to this section.  
 
Precise targets can then be selected bilaterally in this same coronal section.  
A point is selected on each side at the border of the white and grey matter, 
midway between the superior and inferior banks of the cingulate gyrus. The 
intended site is approximately 5-7 mm from the midline and 10 mm below the 
corpus callosum. After targets have been selected, the appropriate frame 
coordinates can be calculated and used for the stereotactic procedure. 
 
Entry points can also be selected on the stereotactic planner if desired.  This 
practice is variable at different centers.  If entry planning is performed it is 
recommended that an entry site that is slightly anterior to the more typical 
burr hole used for STN-DBS. This is necessitated by the more anterior nature 
of this target.  Anterior entry (~2cm anterior to the coronal suture) will avoid a 
difficult approach angle.   
 
DBS Implantation: After sterile preparation of the operative field, burr holes 
are placed under local or general anesthesia.  Again the slightly more anterior 
entry is recommended. A lateral position of 2-3cm from midline is also 
recommended. Dura and pia are opened under direct visualization.  The 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 34 
remainder of the operation is performed using an appropriate stereotactic 
frame or frameless guidance system. 
  
One or more cannulas are inserted to the target coordinate. Microelectrode 
recording may be performed, at this point, to confirm the location of the grey-
white junction within the target area.  This procedure is optional.  
 
A DBS electrode will be inserted into the target under fluoroscopic 
visualization.  Once the electrode has been placed in the calculated target 
intra-operative diagnostic testing will be performed; however, no active deep 
brain stimulation will be delivered to the patient in order to protect the study 
blinding process.  After confirmation of position the end of the lead is 
protected and excess lead is coiled in a sterile subgaleal pocket made by 
blunt dissection. The procedure is then repeated for the contralateral side.  
 
Intraoperative Device Diagnostic Testing:
 
 The implanted leads will be tested 
for proper connectivity as well as impedance; however, no active stimulation 
will be delivered, so as to not break the blinding of the study.   
IPG Implantation:
 
 The second stage of the operative procedure involves the 
implantation of lead extensions and the IPG. This will be performed 
immediately following the above procedure. The patient is given a general 
anesthetic and a sterile preparation is performed. The lead ends are 
accessed either by reopening the scalp incision or by making a smaller 
incision over the subgaleal pocket.  The lead extension is then tunneled 
subcutaneously to a second incision just below the clavicle (can be left or 
right depending on patient preference). The extension wire is attached to the 
DBS leads proximally and to the battery distally.  The implantable pulse 
generator is placed in a subcutaneous pocket that is made below the clavicle.  
Excess wire is coiled behind the IPG.  Once again, a device diagnostic test 
will occur but no active stimulation will be delivered to the patient at this time. 
Lead Localization
7.4 Concomitant Treatments 
:  The lead will be imaged post-implantation to confirm lead 
location according to current neurosurgical procedures and/or CT scans.  
These images must be given to the Sponsor for future analysis. 
 
All patients will have the ability to maintain their depression medication 
regimen as well as regularly scheduled psychotherapy to ensure study and 
therapy controls are maintained.  For the 1-year study, all psychiatric 
care/decisions must be transferred to the study psychiatrist.  For the first 6 
months of the study, patients will not be able to add new medications 
(excluding sleep aids and other meds to manage non-depression related 
conditions) nor increase current antidepressant medication doses.  
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 35 
 
Medication additions: 
For temporary insomnia, zaleplon, zolpidem, zopiclone, or chloral hydrate (a 
single dose nightly) or trazodone (< 100 mg) may be used, for a maximum of 
14 nights during the study. Lorazepam (< 2 mg/d) may also be administered 
for treatment emergent anxiety for up to 14 days. 
 
Rescue medications: 
The study psychiatrist should first identify a need for a rescue based on 
his/her clinical judgment of worsening depression.  In the event that a patient 
needs to be “rescued” due to a severe worsening of their depression (defined 
as patients who score 25% worse than their baseline average on the MADRS 
or worsening of suicidal ideation), prior to the completion of 6 months in the 
study, appropriate intervention may be initiated at the principal investigator’s 
discretion considering the protocol-specified guidance.  The following 
guidance should be adhered to when the rescue protocol is initiated: 
 
 
 
If a patient is rescued based on a 25% worsening of their MADRS score 
compared to the average MADRS Scores: 
• The patient will be considered a treatment failure. 
• The visit will serve as the patient’s endpoint data and the patient will be 
exited from the study.  All end-of-study procedures should be 
performed. 
• At the principal investigator discretion, medications may be added or 
changed as deemed in the best medical interest of the patient. 
• Patients who were in either the control group or received active 
stimulation should enter a separate open-label protocol for long-term 
follow-up. 
 
 
If a patient is rescued based on a worsening of suicidal ideation 
• A patient who shows imminent suicidal intent but does not attempt 
suicide will be treated for the acute exacerbation of their symptoms.  If 
the event can be treated with an acute intervention (less than 7 days) 
then the patient should resume participation in the trial and not be 
unblinded as to treatment. 
• After the acute intervention, the patient must have a MADRS item 10 
score of less than 5 to resume participation in the trial. 
• After the acute intervention, the patient must resume their previous 
medication regimen if medications were changed. 
• Patient’s medications must be stable for a minimum of 7 days prior to 
an effectiveness visit 
• If the patient attempts suicide, or requires a long-term medication 
change he/she will be considered and followed as a treatment failure.  

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 41 
Patient evaluation will take place 52 weeks after the system is 
implanted. This visit will include the following: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.5.2  Control Group (Non-Active Stimulation): 
 
 
At the end of the 6 month visit, patients will be given the option to have 
 
device programmed and activated for DBS.  Patient will then be 
 
followed monthly, until the end of the 52 week study.  
7.6 Long-Term Follow-Up 
All patients will be encouraged to enroll in a long-term follow-up study under a 
separate protocol sponsored by ANS to monitor the continued efficacy and 
safety of this system. Efficacy assessments and device related adverse 
events will be collected on all willing participants at specific intervals after they 
exit the currently proposed study.  A separate study protocol and patient 
informed consent will be signed for this long term follow up study. 
 
All study patients may have access to the device at no cost for battery 
replacement and or revision(s) until the device is commercially available in the 
United States.  The patients/physicians must make a request to the study 
sponsor to have the device shipped to the appropriate location.  
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 42 
8 
Adverse Events (AEs)  
8.1  AE Definitions 
 
An ADVERSE EVENT is “Any change, undesired, noxious or pathological in a 
patient or subject illustrated by signs, symptoms and /or laboratory changes 
that occur during a clinical trial, whether or not considered drug/treatment 
related.” 
 
A SERIOUS/SEVERE AE is where the event is/causes: 
Life threatening or fatal 
Requires or prolongs hospitalization 
The patient to be disabled 
 
A DEVICE RELATED AE is an anticipated (those events listed in section 8.4) 
or unanticipated (those events that occur that are not listed in section 8.4) 
event that occurs that is considered device related.  A device-related event is 
one that the Investigator feels that the device (i.e. IPG, extension or lead) 
contributed in any way to the adverse event occurring.  A stimulation-related 
event is one that resolves when stimulation is turned off or turned down. 
 
A NON SERIOUS AE is an event other than one described above. 
8.2 AE Recording 
All Adverse Events volunteered by the Subjects/Patients or elicited 
by 
the 
Investigator must be recorded on the AE forms provided.  All serious/severe 
AEs must be recorded whether or not considered device/treatment related.  
All device related complications that occur during the study duration and/or 
malfunctions of study device should be recorded on the AE forms provided.  
Device complications are defined as those complications relating directly to 
the functioning of the stimulation system (i.e. IPG, extension or lead). 
8.3 Reporting AEs 
Throughout the course of the proposed study, all serious/severe adverse 
events and device related adverse events would be recorded and monitored 
by the Sponsor and the Investigator. Every effort will be made to remain alert 
to possible adverse experiences and unexpected findings. If adverse 
experiences occur, the first concern will be the safety of the subject. 
Appropriate medical intervention will be made.  All completed suicides and 
suicide attempts (defined by the Columbia Suicide Severity Rating Scale 
(CSSRS) > 3) must be reported to the Sponsor immediately (less than 10 
days) upon discovery.  Once the Sponsor is notified of these events, the 
Sponsor will report these events to the FDA within 10 days. 
 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 43 
Individual reports of device related complications will be documented and 
reported appropriately.  The investigator must report all serious AEs to the 
Sponsor immediately upon discovery by telephone and forward the completed 
AE form as soon as it is available. The Investigator must also promptly report 
the resolution to all reported serious or device related AEs. 
8.4  Anticipated Adverse Events and Complications 
Implantation of a deep brain stimulation lead is a surgical procedure that may 
expose the patient to the risks of post-operative pain, stress, or discomfort, 
intracranial hemorrhage, subcutaneous hemorrhage, intracranial infarctions, 
venous air embolism (air entering the veins), venous infarctions, symptomatic 
neumocephalus (intracranial air causing confusion requiring an extra day stay 
in the hospital), seizure or convulsions, seroma, infection, aphasia, paralysis, 
stroke, death, cerebrospinal fluid leakage or abnormality.  An additional 
neurosurgical procedure may be necessary to manage one of the above 
complications or to replace a fractured lead or to replace the pulse generator 
 
The anticipated adverse events associated with the use of this device may 
include the following: 
  
• Neuropathy;  
• Neuralgia;  
• Headache; 
• Asthenia, hemiplegia or hemiparesis; 
• Cognitive impairment, including confusion, abnormal thinking, 
hallucinations, alteration of mentation, amnesia, delusions, or dementia; 
• Infection; 
• Fever; 
• Disequilibrium; 
• Ataxia;  
• Myoclonus;  
• Hearing and visual disturbance; 
• Paresis;  
• Dystonia; 
• Attention deficit; 
• Dysarthria; 
• Sleep disturbance; 
• Suicide or Suicide attempt; 
• Increase in drug side effects; 
• Autonomic instability (change in vital signs); 
• Urinary incontinence; 
• Worsening depression symptoms (will not be considered an AE); 
• Anxiety; 
• Ruminativeness; 
• Hypomania; 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 44 
• Mania; 
• Panic attacks; 
• Obsessive compulsive disorder (OCD) symptoms; 
• Psychosis; 
• Seizure; 
• Apathy; 
• Eye disorder; 
• Sweating; 
• Diarrhea;  
• Sensory deficit; 
• Drowsiness; 
• Difficulty breathing; 
• Increased salivation; 
• Nausea and/or vomiting; 
• Rapid heart rate; 
• Pneumonia; 
• Skin disorder; 
• Edema including periorbital; 
• Syncope; 
• Persistent pain or redness at the IPG site or the surgery site/extension; 
• Pulling sensation along extension site; 
• Allergic or rejection response to implanted materials; 
• General erosion or local skin erosion over the pulse generator (IPG), burr 
hole cap, and/or extension; 
• Undesirable changes in stimulation possibly related to cellular changes in 
tissue around the electrodes, changes in the electrode position, or loose 
electrical connections and/or lead fracture; 
• Initial jolt or tingling during stimulation; 
• Paresthesia;  
• Loss of therapeutic benefit as a result of change in electrode positions, 
lead fracture, loose electrical connections, DBS system battery failure, 
DBS system malfunction, or inadvertent turning off of device; 
• Lead fracture; 
• Lead migration; 
• System dislodgement; 
• DBS battery failure; 
• DBS system malfunction. 
 
8.5  AE Classification 
Each adverse event will be classified by the Investigator and reported to the 
Sponsor using the Adverse Event Form of the patient’s Case Report Form. 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 50 
12 
Modification of Protocol 
Any amendments to this protocol must be prepared by the study monitor and 
approved by ANS, the Investigator and the local authority (FDA/IRB/IEC) before 
implementation. 
13 
Discontinuation of Study 
ANS reserves the right to discontinue any study for administrative reasons at any 
time, such as but not limited to, a decision to discontinue further clinical 
investigations with the test article, improper conduct of the study by the 
Investigator, inability to obtain the number of patients required by the protocol, etc.  
Reimbursements for reasonable expenses will be made if such action is 
necessary. 
This study may be terminated by the DSMB if an unacceptable number of 
intracranial hemorrhages or an unacceptable number of completed suicides or 
suicide attempts is reached without an appropriate explanation.  Guidance 
regarding event evaluation is provided in the DSMB Plan 
 
Study enrollment will be suspended if the following criterion is met until the Data 
Safety Monitoring Board and FDA can review the safety and effectiveness data to 
determine whether the study should be halted, modified, or continued. 
 
• If the lower bound of the two-sided 95% confidence interval (based on the normal 
approximation) for the rate of completed suicides in the combined patient 
population exceeds 2% at any point during the study. 
 
This study may be terminated if the number of the following events is reached 
without an appropriate explanation by the 6 month primary endpoint: 
 
• If greater than 24 patients experience an intracranial hemorrhage. This would 
assume that during the study at the specified interval the rate of intracranial 
hemorrhage would exceed 12% then the study would be terminated. 
 
 
14 
Administrative Requirements and Quality Assurance 
 
14.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
 
Before the study can begin the Investigator must provide the Sponsor with a 
copy of the approval notice for the protocol and informed consent forms,   
signed by the appropriate committee chairperson. 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 51 
 
14.2 Clinical Supplies 
 
The Investigator agrees to keep all test articles in a secure location with 
restricted access.  The Investigator will maintain an inventory of test article 
receipt and distribution.  The Sponsor will provide an itemized inventory of all 
supplies dispatched.  The Investigator or appropriate designee will provide 
written confirmation of receipt.  Investigational devices and device 
accessories required for maintenance of the implanted devices will be made 
available to all patients enrolled in this study, at the request of the study 
Investigator, during the period the patient has completed study participation 
and prior to PMA approval.   
 
14.3 Reporting and Recording of Data 
 
All study data will be recorded on electronic Case Record Forms (eCRF).  
Electronic data capture (EDC) will also be utilized to monitor, correct, and 
store the collected data. 
 
14.4 Monitoring 
 
The Investigator will permit the Study Monitor to visit the Investigational Site 
at regular intervals to review all the CRFs, study related adjunctive data, and 
study management.  These reviews are for the purpose of verifying the 
adherence to the protocol and the completeness and exactness of the data 
being entered as required by Federal Regulations.  The Study Monitor must 
be kept informed of all issues pertinent to the study.  The Study Monitor will 
be available to discuss by telephone questions regarding adverse events, 
removal of patients/subjects from the study, conduct of the study or any other 
questions that should arise.  At the final monitoring visit the Study Monitor 
must resolve any outstanding data deficiencies and retrieve all used and 
unused test articles. 
 
14.5 On-site Audits 
 
The various National Regulatory Authorities (including the United States Food 
and Drug Administration) in the person of a scientifically trained and properly 
authorized employee of the department, may request access to all study 
records, including source documents, for inspection and copying.  Similar 
auditing procedures may also be conducted by a representative of the 
Sponsor. 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 54 
15 References 
1. 
Murray CJL, Lopez AD, eds. Summary: The global burden of disease: a comprehensive 
 
assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and 
 
projected to 2020. Cambridge, MA: Published by the Harvard School of Public Health on 
 
behalf of the World Health Organization and the World Bank, Harvard University Press, 1996. 
 
http://www.who.int/msa/mnh/ems/dalys/intro.htm 
2. 
World Health Organization, http://who.int/mental health/management/depression/definition/en/  
 
Accessed October, 2006. 
3. 
Narrow W E. One-year prevalence of depressive disorders among adults 18 and over in the 
 
U.S.: NIMH ECA prospective data. Population estimates based on U.S. Census estimated 
 
residential population age 18 and over on July 1, 1998. Unpublished. 
4. 
American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders, 
 
fourth edition (DSM-IV). Washington, DC: American Psychiatric Press, 1994. 
5. 
Nestler EJ, Varrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron, 2002; 34(1):13- 
25. 
6. 
NIMH Genetics Workgroup. Genetics and mental disorders. NIH Publication No. 98-4268. 
 
Rockville, MD: National Institute of Mental Health, 1998. 
7. 
Mulrow CD, Williams JW Jr., Trivedi M, et al. Evidence report on treatment of depression-
 
newer pharmacotherapies. Psychopharmacology Bulletin, 1998; 34(4): 409-795. 
8. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biological Psychiatry, 
2003; 53:649-659. 
9. 
Rush A J et al.  Acute and longer-term outcomes in depressed outpatients who required one 
 
or several treatment steps: a STAR*D report.  American Journal of Psychiatry. 2006; 163: 
 
1905-1917. 
10. 
Hollon S, Stewart M, Strunk D, Enduring effects for cognitive behavior therapy in the treatment 
of depression and anxiety. Annual Review of Psychology, 2006; 57:285-315. 
11. 
Kennedy S, Lam R. Enhancing outcomes in the management of treatment resistant 
depression: a focus on atypical antipsychotics. Bipolar Disorders, 2003; 5(Suppl. 2):36-47. 
12. 
Fink, M. (2001). Convulsive therapy: a review of the first 55 years. Journal of Affective 
 
Disorders, 63, 1-15. 
13. 
George M et al. Vagus Nerve Stimulation: A new tool for brain research and therapy. Biol. 
 
Psych. 2000; 47:287-295. 
14. 
Sackeim H, Brannan S, Rush AJ, et al. Durability of antidepressant respone to vagus nerve 
stimulation (VNSTM
15. 
Elger G, Hoppe C, Falkai P, et al. Vagus nerve stimulation is associated with mood 
improvements in epilepsy patients. Epilepsy Research, 2000; 42:203-210. 
). International Journal of Neuropsychopharmacology, 2007. (unpublished). 
16. 
Cyberonics Labeling – Brief summary of safety information for the VMS Therapy™ System 
 
[epilepsy and depression indications]. August 2006. 
17. 
Cosgrove GR., Rauch SL.  Psychosurgery.  Neurosurg Clin North America 1995; 6:167-176 
18. 
Sachdev P, Sachdev J. Long-term outcome of neurosurgery for the treatment of resistant 
depression. Journal of Neuropsychiatry Clinical Neuroscience, 2005; 17(4): 478-485. 
19. 
Haberler C, Alesch F, et al. No Tissue damage by chronic DBS in Parkinson’s disease.  Ann 
 
Neurol 2000; 48:372-6 
20. 
Mayberg H. Modulating dysfunctional limbic-corical circuits in depression : towards 
development of brain-based algorithms for diagnosis and optimised treatment. British Medical 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 55 
Bulletin, 2003 ; 65 :193-207. 
21. 
Mayberg H, Brannan S, et al. Regional metabolic effects of fluoxetine in major depression: 
 
Serial changes and relationship to clinical response. Biol Psych 2000; 48:830-43 
22. 
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple KK, Kennedy S, Segal Z, Rafi-Tari S.  
 
Limbic-Frontal Circuitry in Major Depression: A Path Modeling Metanalysis. Neuroimage 2004; 
 
22: 409-18. 
23. 
Mayberg H. Limbic-cortical dysregulation: A proposed model of depression. J Neurop Cl 
 
Neurosc, 1997; 9:471-81  
24. 
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, 
 
Kennedy SH  Deep brain stimulation for treatment-resistant depression Neuron. 2005 Mar 3; 
 
45(5):651-60. 
25. 
Rush AJ, Thase M, Dubé S. Research issues in the study of difficult-to-treat depression. 
Biological Psychiatry, 2003; 53: 743-753. 
26. 
Nahas Z, Marangell L, Husain M, et. al. Two-year outcome of vagus nerve stimulation (VNS) 
for treatment of major depressive episodes. Journal of Clinical Psychiatry, 2005; 66(9):1097-
1104, 
27. 
Montgomery S, Asberg M, A new depression scale designed to be sensitive to change. British 
Journal of Psychiatry, 1979; 134: 382-389. 
28. 
Hamilton M. A rating scale for depression. J Neurol Neursurg Psychiatry. 1960; 23:56-62. 
 
29. 
Rush, Gullion, Basco, Jarrett, & Trivedi, The Inventory of Depressive Symptomatology (IDS): 
 
psychometric properties. Psychol Med. 1996 May;26(3):477-86 
30. 
Folstein M, Folstein S, McHugh P. Mini-Mental State. A practical method for grading the 
 
cognitive state of patients for the clinician. J Psych Res 1975; 12:189–198. 
31. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and 
 
sensitivity. Br J Psychiatry. 1978; 133:429-435. 
32. 
Rapaport M, Clary C, Fayyad R, et al. Quality-of-life impairment in depressive and anxiety 
disorders. American Journal of Psychiatry, 2005; 162(6): 1171-1178. 
33. 
Mundt J, Marks I, Shear K, et al. The work and social adjustment scale: a simple measure of 
impairment in functioning. British Journal of Psychiatry. 2002; 180: 461-464. 
34. 
Watson D, Clark LA, Tellegen A.Development and validation of brief measures of positive and 
 
negative affect: the PANAS scales.J Pers Soc Psychol. 1988 Jun;54(6):1063-70. 
35. 
Landis, JR and Koch, GG, The Measurement of Observer Agreement for Categorical Data.  
 
Biometrics 1977 33
36. 
Guy W. ECDEU Assessment manual for psychopharmacology. Rockville, MD: US Department 
of  Health and Human Services publication (ADM) 1976; pp 218–22. 
, 159-174. 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 56 
16 Appendices  
16.1 Appendix A:  Product Labeling 
16.2 Appendix B:  Sample Informed Consent 
16.3 Appendix C: Case Report Forms (CRFs) 
16.4 Appendix D: Study Visit Schedule 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 57 
 
16.1  Appendix A: Product Labeling 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 58 
16.2  Appendix B:  Sample Informed Consent 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 59 
 
16.3 Appendix C:  Case Report Forms (CRFs) 
 
 
 

C-07-01 L bra® IPG DBS 
10/05/2011 
Major Depressive Disorder Pivotal Study 
Final 
 
 
 
Page 60 
 
16.4 Appendix D:  Study Visit Schedule