Long Term Follow-up of Deep Brain Stimulation for Treatment-Resistant Depression
Phase: NA
Conditions: Treatment Resistant Depression, Depressive Disorder, Treatment-Resistant, Depression, Bipolar
Sponsor: Dartmouth-Hitchcock Medical Center

1
Study Protocol
TITLE:
Long Term Follow-up of Deep Brain Stimulation for Treatment-
Resistant Depression (LTF of DBS for TRD)
PRINCIPAL INVESTIGATOR:
Paul Holtzheimer, MD (Psychiatry and Surgery)
CO-INVESTIGATORS:
Josh Aronson, MD (Neurosurgery)
Laurie Waterman 
DRAFT DATE:
August 4, 2022
NCT03360942

2
Schema
Recruitment: Patients enrolled in DBS for TRD will be informed of the option to enroll 
in the naturalistic follow-up study. Patients will be informed of the option 
during the screening phase of the DBS for TRD study as well as a 
reminder 2 weeks prior to completion of the study
Study Visits:
Assessment by study psychiatrist once per year

3
1.0
INTRODUCTION
Major Depression is one of the most common and costly of all psychiatric 
disorders 1. It ranks among the top causes of worldwide disease burden and is the 
leading source of disability in adults in North America under the age of 50 2.  
While depression can be effectively treated in the majority of patients by either 
medication or some form of evidence-based psychotherapy 3, up to 20% of 
patients fail to respond to standard interventions 4,5. For these patients, trial-and-
error combinations of multiple medications and electroconvulsive therapy are 
often required 6,7.  For patients who remain severely depressed despite these 
aggressive approaches, new strategies are needed.
Converging clinical, biochemical, neuroimaging, and post-mortem data suggest 
depression is unlikely to be a disease of a single brain region or neurotransmitter 
system.  Rather, it is now generally viewed as a systems-level disorder affecting 
integrated pathways linking select cortical, subcortical and limbic sites and their 
related neurotransmitter and molecular mediators 8-12.  While mechanisms driving 
this ‘system dysfunction’ are not yet characterized, they are likely to be multi-
factorial, with important and synergistic contributions from genetic vulnerability, 
developmental insults, and environmental stressors 13-15.  Treatments for 
depression can be similarly viewed within this limbic-cortical system framework, 
where different modes of treatment modulate specific regional targets, resulting in 
a variety of complementary, adaptive chemical and molecular changes that re-
establish a normal mood state 12,16,17.
Functional neuroimaging studies have played a critical role in characterizing these 
limbic-cortical pathways 17-20.  Previous studies have demonstrated consistent 
involvement of the subgenual cingulate (Cg25) in both acute sadness and 
antidepressant treatment effects, suggesting a critical role for this region in 
modulating negative mood states 21,22.  In support of this hypothesis, a decrease in 
Cg25 activity is reported with clinical response to different antidepressant 
treatments including specific serotonin reuptake inhibitor (SSRI) antidepressant 
medications, electroconvulsive therapy (ECT), repetitive transcranial magnetic 
stimulation (rTMS), and ablative surgery 23-28. In addition, Cg25 connections to 
the brainstem, hypothalamus, and insula have been implicated in the disturbances 
of circadian regulation associated with depression (sleep, appetite, libido, 
neuroendocrine changes) 29-33.  Reciprocal pathways linking Cg25 to orbitofrontal, 
medial prefrontal, and various parts of the anterior and posterior cingulate cortices 
form the neuroanatomical substrates by which primary autonomic and 
homeostatic processes influence various aspects of learning, memory, motivation 
and reward – core behaviors altered in depressed patients 31,34-36.
Recent advances in the surgical treatment of Parkinson’s disease have 
demonstrated that chronic high frequency deep brain stimulation (DBS) in 
pathologically active brain circuits produces profound clinical benefits 37-39.  It has 
also been shown that clinically effective DBS in the basal ganglia produces both 
local and remote changes in neural activity as assessed by positron emission 
tomography (PET) 40,41. 

4
A second sham-controlled pilot study at Emory University assessed the safety and 
efficacy of bilateral SCC DBS in 10 TRD patients with major depressive disorder 
(MDD) and 7 TRD patients with bipolar II disorder (BP). Dr. Holtzheimer was 
the lead psychiatrist on this study. Rates of response (≥50% decreased in 
depression severity from baseline) were 41% at 6 months, 36% at 1 year and 92% 
at 2 years following onset of chronic stimulation. Rates of remission (virtually no 
depressive symptoms) were 18% at 6 months, 36% at 1 year and 58% at 2 years 
following onset of chronic stimulation. There was a very modest but statistically 
significant decrease in depression severity following 4 weeks of sham stimulation, 
but this was largely accounted for by a decrease in depression severity following 
surgery but prior to the onset of sham stimulation. In three patients in whom 
blinded discontinuation was performed after 24 weeks of active stimulation, all 
had a full return of depressive symptoms within two weeks and antidepressant 
benefit returned with re-initiation of stimulation. There was only one patient who 
experienced a serious adverse event (infection requiring removal of the system) 
related to surgery. There were no adverse events associated with acute or chronic 
stimulation. In this study, a longer duration of a euthymic (no depression) period 
since illness onset, fewer adequate antidepressant treatments in the current 
episode, fewer lifetime psychotropic medications and fewer depressive episodes 
each predicted response/remission at various time points in the study. It was also 
demonstrated that functional connectivity of the BA25/SCC region (derived from 
pre-operative resting state functional magnetic resonance imaging [rfMRI] data) 
predicted 6 month treatment response. If validated, this would support using 
clinical variables related to illness stability (number of episodes, time between 
episodes and number of treatments) as well as pre-operative rfMRI to help with 
patient selection if SCC DBS is introduced clinically. 
In both of these prior SCC DBS studies, all patients initially received bilateral 
stimulation; this decision was made based on previous imaging studies implicating 
both left and right BA25/SCC in TRD; however, both sides were rarely implicated 
in the same study. In the Toronto cohort, it was discovered that one patient had a 
greater antidepressant response with left-sided stimulation only. At Emory, one 
patient was eventually found to have a greater antidepressant response to right-
sided stimulation alone compared to bilateral stimulation. A single case report from 
an Argentinean group also described antidepressant benefit from right-sided 
stimulation alone 18. Further evidence supports differential roles for left- and right-
sided brain regions in the pathophysiology of depression 19 but also suggests the 
nature of this laterality may differ across depressed patients. These data suggest 
that certain TRD patients may require right-sided stimulation, others may require 
left-sided stimulation and some may require stimulation bilaterally. If unilateral 
stimulation is comparable to bilateral stimulation, then this would allow the overall 
procedure to be safer since the major risk of implantation comes from the potential 
for an intracranial hemorrhage with each passage of a DBS lead. Additionally, this 
would speak to both the mechanism of action of DBS and potential neurobiological 
differences between TRD patients.

5
This pilot study supports the hypothesis that high-frequency DBS in Cg25 white 
matter can be used to treat depression, but further data is needed to confirm these 
findings.  The long-term effects of DBS are not known.  The following study will 
evaluate right versus left-sided DBS in Cg25 over the course of ten years.  Patients 
who are enrolled in the DBS for TRD study at DHMC will be given the opportunity 
to enroll in the ten year follow-up study at the end of the study in which they are 
currently enrolled.
2.0
OBJECTIVES
We propose to test whether long-term high frequency DBS of the subgenual 
cingulate white matter (Cg25-DBS) is a safe and efficacious antidepressant 
treatment in five (5) TRD patients. We will address the following specific aims.
Specific Aim 1. To assess the long term effects including efficacy and safety of 
Cg25 DBS in patients with Major Depressive Disorder.
3.0
PATIENT SELECTION
Patients who are enrolled in the DBS for TRD study at DHMC will be given the 
opportunity to enroll in the ten year follow-up study at the end of the DBS for 
TRD study in which they are currently enrolled.  Patients will be informed of the 
option during the screening phase of the DBS for TRD study as well as a 
reminder 2 weeks prior to completion of the study.  A total of five (5) patients 
will be enrolled in this study.
3.1
Eligibility Criteria
3.1.1
Have received DBS for TRD
3.1.2
Ability to provide written informed consent
3.1.3
Willing to comply with all necessary study visits
4.0
CLINICAL ASSESSMENTS
During this phase, patients will be evaluated every 12 months by the study 
psychiatrist (via in-person, phone or video call visit) to assess device functioning, 
adverse events and current status of depression. This visit will be documented in a 
note to file. Specific areas to be assessed:
1. Current status of depression and overall functioning
2. Changes in medications
3. Adverse events
4. Status of DBS system including any changes or problems
5. If a patient chooses to have the DBS system explanted or turned off, they 
will be monitored weekly (by telephone, video call or in person as 
appropriate) for 12 weeks following explantation for adverse events. After 
that time, their participation in the study will be concluded. 
5.0
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

6
Data collected in this phase are purely descriptive and no formal analysis is 
planned. 
6.0
DATA SAFETY AND MONITORING
6.1
Data and Safety Monitoring Board (DSMB). We will continue to use the 
Data Safety Monitoring Board (DSMB) for the Department of Psychiatry as 
a third-party oversight committee as we have done for the DBS for TRD 
study.
6.2
Frequency of meetings/review. The frequency of DSMB review for this 
protocol will follow recommendations from CPHS based on the assessed 
risk status of the study. Currently, it is expected that the DSMB will meet 
annually. 
6.3
This protocol will be submitted to the DSMB simultaneously with this 
initial submission to CPHS. The DSMB will review the research protocol 
and plans for data and safety monitoring. The DSMB will review a report 
from the study’s data manager that includes the following information: the 
number of participants who signed consent forms for the study and were 
subsequently randomized to study arms, the number of post-randomization 
dropouts, the reasons for withdrawal from the study, and any safety 
concerns, adverse events, an up-to-date consent form, and measures taken 
to protect confidentiality (e.g., data and tape storage, use of coded ID 
numbers, etc.). The DSMB will also review the Principal Investigator’s 
summary of any new data or evidence that might alter the risk/benefit ratio 
for participating in the study (e.g., newly published studies, etc.). After 
reviewing this information, the DSMB will issue its own report 
summarizing any serious and unexpected adverse events or other 
unanticipated problems that involve risk to study participants, and whether 
these appear related to the study-based interventions or research assessment 
protocols. 
6.4
There will be regular, ongoing communication between the PI, CPHS, and 
the DSMB. The PI will take responsibility for reporting any serious and 
unexpected adverse events or other unanticipated study problems to CPHS 
within 24 hours, according to standard regulations. A copy of each report 
will be sent to the DSMB. Actions taken by CPHS in response to adverse 
event reports will be immediately reported to the DSMB, which will review 
all serious adverse events as they arise. DSMB reports will be shared with 
CPHS.
6.5
A Serious Adverse Event (SAE) in this study will be defined as an event 
that results in death, is life-threatening, requires hospitalization or 
prolongation of existing hospitalization, or results in persistent or 
significant disability or incapacity. The degree of probable relation between 
study procedures and the SAE will be carefully evaluated and documented. 
6.6
Unexpected adverse events in this study will be defined as any adverse 
events for which the nature and severity are not consistent with expected 
adverse events resulting from the surgery, pre- or post-operative evaluation, 
or deep brain stimulation. 

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6.7
The DSMB will have the authority to stop the study at any point.
7.0
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