Burst Suppression Anesthesia for Treatment of Severe Depression
Phase: PHASE1
Conditions: Major Depressive Disorder
Sponsor: University of Utah

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Date April 2017  
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NCT Number:  
NCT02935647 
 
Brief Title:  
 
Anesthesia for Treatment of Depression 
 
Principal Investigator: Brian Mickey, MD, PhD 
Associate Professor of Psychiatry 
 
 
 
501 Chipeta Way 
 
 
 
Salt Lake City, UT 84108 
 
 
 
brian.mickey@utah.edu 
 
 
 
(801) 581-7952 
 
Core 
 
 
Howard Weeks, MD, Associate Professor of Psychiatry 
Co-Investigators: 
Kathleen Light, PhD, Research Professor of Anesthesiology 
 
 
 
Alan Light, PhD, Research Professor of Anesthesiology 
 
 
 
Scott Tadler, MD, Associate Professor of Anesthesiology 
 
 
 
Kelly Smith, MD, Associate Professor of Anesthesiology 
 
 
 
Andrea White, PhD, Adjunct Associate Professor, Anesthesiology 
 
Co-Investigators: 
Michael Beck, MD, Assistant Professor of Anesthesiology 
 
 
 
Lowry Bushnell, MD, Assistant Professor of Psychiatry 
 
 
 
Michael Cahalan, MD, Professor of Anesthesiology 
 
 
 
Laura Gilley Hensley, MD, Assistant Professor of Psychiatry 
 
 
 
Jacob Jessop, DO, Assistant Professor of Anesthesiology 
 
 
 
Jeremy Kendrick, MD, Assistant Professor of Psychiatry 
 
 
 
Adam Larson, MD, Adjunct Assistant Professor of Anesthesiology 
 
 
 
David Odell, MD, Associate Professor of Anesthesiology 
 
 
 
Nathan Pace, MD, MStat, Professor of Anesthesiology 
 
 
 
Matthew Pierson, MD, Assistant Professor of Psychiatry 
 
 
 
Andrew Prescot, PhD, Assistant Professor of Radiology 
 
 
 
Perry Renshaw, MD, PhD, Professor of Psychiatry 
 
 
 
Derek Sakata, MD, Associate Professor of Anesthesiology 
 
 
 
Sara Whittingham, MD, Adjunct Assistant Professor, Anesthesiology 
 
 
 
 
 
Supported by: 
 
Department of Psychiatry 
University Neuropsychiatric Institute 
Department of Anesthesiology 
University of Utah 
 
Burst Suppression Anesthesia for Treatment of Severe Depression 

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Table of Contents 
1. 
Schedule of Activities ..........................................................................................................3 
2. 
Study Objectives .................................................................................................................4 
2.1 
Study 1 ................................................................................................................................... 4 
2.2 
Pilot Study 2 ........................................................................................................................... 4 
3. 
Background .........................................................................................................................5 
4. 
General Study Design ..........................................................................................................8 
4.1 Inclusion Criteria ........................................................................................................................... 8 
4.2 Exclusion Criteria .......................................................................................................................... 8 
4.3 Study Recruitment Procedures ..................................................................................................... 9 
4.4 Informed Consent Procedures ...................................................................................................... 9 
4.5 Study Visits ................................................................................................................................. 10 
Costs and Compensation .................................................................................................................. 11 
Subject Withdrawal and Study Completion ...................................................................................... 11 
5. 
Clinical and Laboratory Evaluations ..................................................................................11 
5.1 Study Drug Administration and Duration .................................................................................... 11 
5.2 Study Drug Management ............................................................................................................ 13 
5.3 Clinical Assessments ................................................................................................................... 13 
5.4 Tissue Banking ............................................................................................................................ 13 
6. 
Data and Safety Monitoring..............................................................................................14 
6.1 Data Collection ........................................................................................................................... 14 
6.2 Data Storage ............................................................................................................................... 14 
6.3 Safety and Efficacy Monitoring ................................................................................................... 15 
7. 
Statistical Considerations .................................................................................................15 
7.1 Aim 1. ......................................................................................................................................... 15 
7.2 Aims 2 and 5 ............................................................................................................................... 16 
7.3 Aim 4 .......................................................................................................................................... 16 
8. 
Training and Resources .....................................................................................................16 
9. 
Protection of Human Subjects ..........................................................................................17 
9.1 Potential Risks ............................................................................................................................ 17 
9.2 Potential Benefits ....................................................................................................................... 19 
10. 
References ....................................................................................................................20 

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1. Schedule of Activities 
Visits 
Screening 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Post 
Tx 
Follow-up5 
(Repeated) 
Assessments 
 
 
Week
1 
 
 
 
Week
2 
 
 
Week 
3 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric Interview 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HRSD, MoCA, WSAS, GAD7 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
MRI / MRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
QIDS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
EEG 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood Sample 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Anesthetic Induction2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Anesthetic Emergence3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
QIDS, WSAS, Study XP4 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1  Study 1 only 
2  High ISO/BS+, Low ISO/BS-, or propofol 
3 Time to eye opening, time to sitting without dizziness, and time to ambulation and ingestion of liquids without vomiting. Occurrence 
rates of nausea and vomiting, presence of EKG abnormalities and somatic complaints, and total time for each will also be recorded.  
Orientation time will be assessed as the earliest time post-treatment at which a participant is able to recall 4 of 5 orientation items 
(name, date of birth, age, place, day of the week). 
4 An opened ended question about the participant’s experience during the study  
5 Follow-up measures will take place monthly after the end of treatment series and will continue for 6 months. 
 
  

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2. Study Objectives 
 
2.1 Study 1  
Study 1 will test the central hypothesis that high dose isoflurane anesthesia inducing EEG burst 
suppression (High ISO/BS+) is a more effective intervention for severe depression when 
compared to a low dose isoflurane anesthesia that does not induce EEG burst suppression (Low 
ISO/BS-). The proposed study is a randomized, double-blind trial that will evaluate 30 actively 
depressed participants with moderate to severe depression.  Depression outcomes will be 
compared between two groups of participants (n=15 per group) who have received 10 
treatment applications over a period of three weeks of either High ISO/BS+ or Low ISO/BS-. 
 
Aim 1. To determine whether High ISO/BS+ is more effective than Low ISO/BS- in producing 
either a treatment response (defined as 50% reduction in depression scores) or full remission of 
depressive symptoms. We hypothesize that significantly more depressed participants 
randomized to receive 10 treatments of High ISO/BS+ compared to Low ISO/BS- will show a 
positive treatment response or full remission by treatment end. Based on the STAR*D Trial, a 
responder is a participant showing 50% reduction in depression score and full remission is 
defined as a score of 0-10 on the HRSD-24 scale and score of 0-5 on the QIDS-SR16. 
 
Aim 2. Preliminary data on neural and immune pathways that are differentially affected by the 
2 treatments and associated with antidepressant effects will be explored by comparing changes 
from pre-treatment to post-treatment in full transcriptome leukocyte gene expression (using 
the RNA Seq method). 
 
Aim 3.  To measure the central neurochemical effects of isoflurane treatment, we will quantify 
neurotransmitter levels (GABA and glutamate) using magnetic resonance spectroscopy. 
 
2.2 Pilot Study 2  
Study 2 is designed to complement Study 1 in providing additional support for the hypothesis 
that burst suppression is an important mechanism for antidepressant treatment effects of 
anesthesia in moderate to severe depression. If Study 1 demonstrates that more participants 
receiving High ISO/BS+ undergo remission than those receiving Low ISO/BS-, this could be 
interpreted as a dose response effect for isoflurane that is not specifically a result of burst 
suppression. Demonstrating that a different anesthetic administered at doses producing 80% 
burst suppression for 10 treatment session is also effective in producing depression remission 
would add support for the hypothesis that the underlying mechanism is burst suppression. 
Therefore, Study 2 will be an open-label trial to provide preliminary data that propofol, an 
intravenous anesthetic with a favorable safety profile, administered for 10 treatment sessions 
at levels to induce 80% burst suppression, also is effective in producing depression remission in 
50% or more of the pilot sample of 10 depressed participants. 
 
Aim 4. To determine whether propofol anesthesia at a level to produce 80% EEG burst 
suppression is effective in producing remission of depressive symptoms. We hypothesize that 

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the majority of depressed participants (n=10) receiving 10 treatments of propofol anesthesia 
will achieve remission of symptoms by treatment end. 
 
Aim 5. Preliminary data on neural and immune pathways that are differentially affected by the 
2 treatments and associated with antidepressant effects will be explored using full 
transcriptome leukocyte gene expression (RNA Seq). 
 
Aim 6.  To measure the central neurochemical effects of propofol treatment, we will quantify 
neurotransmitter levels (GABA and glutamate) using magnetic resonance spectroscopy. 
 
3. Background 
Major Depressive Disorder is a prevalent, chronic, recurring disorder that is becoming 
increasingly burdensome both to individuals and society at large.  Despite the increasing 
burden of this disease, we have seen a plateau in development and establishment of effective 
treatments, particularly for those who are refractory to conventional medications. 
Electroconvulsive therapy (ECT) is typically regarded as the treatment of choice for the most 
treatment resistant depression (TRD) as it rapidly reduces symptoms and yields high remission 
rates (about 55-90%) even after multiple medication failures. 8, 9, 17, 18, 20 Though effective, ECT is 
associated with significant adverse cognitive effects such as retrograde amnesia, problems with 
concentration and attention, and other cognitive sequelae. 6, 15 There is also a widespread 
public misunderstanding that the seizure induced by ECT may be painful, and carries risk of 
brain damage and personality change. These fears make patients and family members reluctant 
to approve this treatment option. 15, 16 For these reasons, this effective therapy is often used a 
treatment of last resort (relegated to 5th, 6th or 7th step after the failure of other therapies per 
American Psychiatric Association guidelines) and ECT is administered to only about 100,000 of 
the millions of TRD patients each year. For TRD patients, there is a great need for alternative 
therapies with similar efficacy to ECT but wider social acceptability and less adverse cognitive 
effects. 
 
One such treatment alternative that may be both efficacious and have a better side effect 
profile is deep inhalation anesthesia with isoflurane.  Like ECT, deep anesthesia with isoflurane 
induces a brief state of electrocortical quiescence (flat electroencephalogram), but does not 
induce convulsions or other seizure symptoms.  Anesthesia-induced cortical burst suppression 
was first suggested as a potential alternative to ECT for treatment resistant depression in the 
1980’s. Recent research, both clinical and preclinical, has renewed interest in this hypothesis. 
 
Langer et al 11, 12 originally hypothesized that high dose isoflurane anesthesia (High ISO) might 
be an effective antidepressant therapy based on certain similarities to the physiological effects 
of ECT. The feature shared by High ISO and ECT was a reduction in electrocortical activity, which 
occurs after the seizure in ECT and without any seizure in High ISO anesthesia. In their study of 
ECT treatments, Kranaster et al 10 noted that post-ictal burst suppression index correlated with 
seizure duration, and thus was predictive of antidepressant effectiveness. The hypothesis that 
cortical burst suppression (BS+) is important in anesthesia-induced antidepressant effects has 

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not been rigorously studied in patients, but has been reinforced by recent findings using animal 
models of depression including research by our co-investigators. 19, 21  Murrell et al 14 had 
previously reported that at equivalent anesthetic concentrations, isoflurane had greater 
potency to induce BS+ than 2 related anesthetic drugs, sevoflurane and desflurane, and that 
another inhaled anesthetic, halothane, did not induce burst suppression (BS-). Using the forced 
swim test, Tadler et al 19 found that High ISO anesthesia had antidepressant effects in mice 
similar to the antidepressant desipramine. Similarly, using a shuttle box-based test of learned 
helplessness in rats, Wang et al 21 found that 2 hours of isoflurane at 2% prevented this 
depressive behavior while halothane-treated rats (who experienced no EEG burst suppression) 
showed no preventive antidepressant effects. Whether cortical burst suppression is the 
mechanism for the antidepressant effect of isoflurane anesthesia in patients and animal models 
remains an important and unresolved research question. 
 
Initial trials examining the antidepressant efficacy of High ISO were promising. Langer et al 11, 12 
conducted two preliminary studies that demonstrated comparable efficacy between 6 sessions 
of High ISO vs. ECT, with High ISO having the advantage of not causing memory loss. 
Antidepressant efficacy was also supported by Engelhardt et al 3 who used High ISO treatments 
followed by ECT and by Carl et al 1 who again found comparable antidepressant efficacy with 
the 2 treatments. These positive findings were followed by two negative trials. Greenberg et al 5 
treated 6 elderly individuals with High ISO, with little improvement.  Garcia-Toro et al 4 
examined the efficacy of 4 low dose treatments of a related anesthetic, sevoflurane, in another 
pilot trial, and saw a 24% reduction in depressive symptoms. Since sevoflurane is less effective 
in inducing BS+ than isoflurane, the dose could have been too low to achieve consistent BS+. 
Moreover, 4 treatments are fewer than are recommended for ECT (8-12 sessions) and thus it is 
not surprising that the effect size was small. Unfortunately, further investigations of High ISO as 
an antidepressant halted for quite some time. 
 
Because of its early success and the design limitations associated with the negative trials, our 
group conducted a small open-label study to renew investigation of the potential 
antidepressant efficacy of High ISO. 22 In the study, 8 patients with treatment resistant 
depression were treated with 10 sessions of high dose ISO with confirmed EEG burst 
suppression (High ISO/BS+).  The comparison group was 20 patients treated with bifrontal ECT. 
High ISO/BS+ led to an antidepressant response (defined as a 50% reduction in HRSD score) in 
75% of participants and a rate of full remission of depressive symptoms identical to ECT (50%). 
Furthermore, the response rates for the High ISO/BS+ and ECT treatments were comparable, as 
measured by QIDS self-report.  In addition, improvement was maintained for 4 weeks after 
treatment for most participants in the High ISO/BS+ group. Furthermore, participants treated 
with High ISO/BS+ showed significantly less neurocognitive impairment following their 
treatments than was shown by ECT-treated patients. 
 
The central question in the proposed research is whether isoflurane-induced cortical burst 
suppression (BS+) is necessary for antidepressant efficacy in patients with severe depression. 
We demonstrated that BS+ (defined as ≥80% burst suppression ratio (BSR) using the Bispectral 
Index BIS Monitor) can be reliably induced at high isoflurane concentrations that are clinically 

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safe in our target population while on various psychotropic medications. 22 However, to date, 
there has been no rigorous randomized, blinded trial comparing antidepressant effects of High 
ISO/BS+ to an appropriate control condition. The present study is designed to provide this 
rigorous test using a control condition involving a lower isoflurane dose that predictably 
produces unconsciousness in this same patient population without causing burst suppression 
(BS-, defined as ≤20% BSR).  Thus, we will determine if high dose ISO anesthesia inducing EEG 
burst suppression (High ISO/BS+) is a more effective intervention for severe depression when 
compared to a low dose ISO that does not induce EEG burst suppression (Low ISO/BS-). 
 
As an additional test of whether cortical burst suppression is a possible mechanism underlying 
anti-depressive effects of deep anesthesia, we will also examine the antidepressant effects of 
burst suppression induced by propofol, an intravenous anesthetic with a favorable safety 
profile that is routinely used by anesthesiologists. This closely associated study will be an open-
label trial to provide preliminary data that may support the use of propofol for this group of 
depressed patients. Propofol is the agent of choice to induce burst-suppression for brain 
protection during neurosurgical procedures and is used routinely for this purpose. Propofol 
does not promote post treatment nausea; however, like isoflurane, propofol is associated with 
dose dependent hypotension. This is well tolerated by patients without cardiovascular disease 
and is easily treated as described for isoflurane. Although anecdotal data support some anti-
depressant effects with propofol, these effects have not been specifically or systematically 
examined. If effective, its use may be an even better option than isoflurane for patients, for the 
reasons described above. 
 
If evidence from these studies support deep anesthesia with BS+ (High ISO/BS+ and/or 
propofol/BS+), it would point to a possible mechanism of action for the antidepressive effects 
of deep anesthesia.  Treatments that evoke burst suppression, in theory, could have all the 
benefits of ECT without the neurocognitive deficits and the associated social stigma.   
 
As detailed above, even in the minority of cases when initial pharmacological treatment for 
depression is effective, it usually requires months before symptoms show satisfactory 
remission, and during that time patients and physicians have no objective test to use to verify 
that the intervention is or is not likely to be successful. Even with ECT, where improvement can 
be noted in days rather than weeks or months, initial signs of improvement are based on 
relatively soft non-objective measures such as global improvement that rely heavily on the 
physician’s individual clinical insight and experience. Thus, there is a great need to establish 
convenient, reliable and objective biomarkers for treatment-induced changes that reliably 
predict clinical improvement in cases of depression. 
 
By comparing changes in full transcriptome leukocyte gene expression from pre- to post-
treatment in these 40 participants treated with High ISO/BS+ vs. Low ISO/BS-, and 
propofol/BS+, this investigation will explore the neural and immune pathways through which 
anesthetic-induced antidepressant effects are produced, and will be able to identify candidate 
neural pathways that can later be reconfirmed in larger samples. In particular, we will examine 
the possible role of NMDA receptor subunits, GABA-ergic and ATP-responsive ion channel 

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pathways as well as other putative depression- or suicidality-linked neuroimmune pathways 
previously associated with refractory depression or suicidality by our group and others. 2 7 13 
 
Burst suppression anesthesia is thought to strongly engage the brain's major inhibitory and 
excitatory neurotransmitter systems, GABA and glutamate, respectively.  Indeed, both isoflurane 
and propofol are thought to directly bind GABA and glutamate receptors.  To better understand 
the brain mechanisms through which burst suppression causes antidepressant effects, we will 
measure GABA and glutamate concentrations in vivo using magnetic resonance spectroscopy, a 
type of MRI.   
 
 
4. General Study Design 
To determine if the antidepressant effects of deep anesthesia are related to burst suppression 
(BS+) we will conduct two concurrent studies: 1) prospective, randomized, double-blind study 
will evaluate the role of burst suppression using isoflurane treatments at 2 doses (high dose 
ISO/BS+ vs low dose ISO/BS-) on symptoms in participants with moderate to severe depression, 
and 2) an open-label pilot study examining the anti-depressive effects of propofol anesthesia, 
BS+ same as high dose ISO/BS+ on symptoms in participants with moderate to severe 
depression. 
 
 
4.1 Inclusion Criteria 
We will recruit depressed patients referred to the University Neuropsychiatric Institute for an 
ECT consult.  
 Diagnosis of Major Depressive Disorder (MDD) or bipolar Disorder (I or II, most recent 
episode must be depression 
 Failed at least 2 anti-depressant treatments and no ECT in past 6 months 
 Age between 18-55 years 
 BMI < 40 
 Hamilton Rating Scale for Depression (HSRD) score > 18  
 Quick Inventory of Depression Scale (QIDS) score > 10. 
 
 
4.2 Exclusion Criteria  
 Diagnosis of other current and/or active DSM-5 disorders with the exception of anxiety 
disorders  
 Significant pre-morbid cognitive impairment  
 Hypertension and current use of ACE inhibitor or AR blocker medications  
 Symptomatic coronary artery disease or congestive heart failure 
 History of transient ischemic or neurologic signs during the past year 
 History of or susceptibility to malignant hyperthermia 
 Contraindication to isoflurane or propofol anesthesia (as determined by 
anesthesiologist) 
 Diabetes requiring insulin 
 Poor kidney function 
 Chronic use of benzodiazepines or opioids 

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 Individuals incompetent to provide consent (e.g. catatonic, psychotic).  
 
 
4.3 Study Recruitment Procedures 
Potential participants will be recruited to the study through one of three ways: chart review, 
referral, or direct enrollment.  
 
Recruitment via chart review: Potential participants will first be identified through review of 
medical records by trained study staff; specifically, examination of the records of patients who 
have been scheduled for an ECT consultation at the University Neuropsychological Institute 
(UNI). Participants who may be eligible for screening will be told about the study toward the 
end of their consultation. Interested patients will be screened and consented either right after 
the ECT consultation or during a separate appointment.  
 
Recruitment via referral: Physicians from the Department of Psychiatry who have been 
informed of this study may also refer patients for screening. Patients who are referred will be 
contacted by study staff to arrange for screening and consent. 
 
Direct enrollment: Psychiatrists listed on the study protocol may identify potential research 
volunteers during their ECT consultations. These patients will be informed of the research, and if 
interested, will be screened and consented. 
 
Participants will be informed that there are two study options and that they will be able to 
decide which one they will participate in. For the isoflurane study, we will explain that some 
preliminary evidence shows that high dose isoflurane is effective in reducing depression 
symptoms. However, if the isoflurane study is chosen, there is a 50:50 chance of being in the 
low dose isoflurane treatment, and the individual will not know what treatment group (high vs 
low dose) they are in. We do not know whether low dose isoflurane will reduce depression 
symptoms. For the propofol study, we will explain that this arm of the study is open-label, 
meaning they will know they are receiving propofol treatment at a dose that produces burst 
suppression. We will also inform participants that we do not know if propofol treatment will be 
effective in reducing symptoms of depression. 
 
We hope to enroll at least 1 participant per week and have a maximum capacity of 4 
participants per week with a total of 45 participants enrolled in the study (30 in Study 1 and 10 
in Study 2).  
 
 
4.4 Informed Consent Procedures 
Trained research staff will screen potential participants and obtain consent. Participants will be 
consented in the physician's office (if consent is after the ECT consult); otherwise, consent will 
take place in a private meeting room near the ECT Clinic at UNI. No other language than English 
will be used to obtain consent.  
 
Participants and study coordinator (and/or physician) will go over each section of the consent 
form together. They will then be given time to read/ think about/ discuss/ and ask questions 

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about the study before they sign. Thus, they may sign at that time, or we may schedule another 
visit to sign and enroll into the study. Most of these patients have a support person with them 
who will be included in the consent process (provided the participant is fine with it). A legally 
authorized representative (LAR) will NOT be used to consent the participant.  
 
We will make certain the participant understands that the experimental treatments may or may 
not be effective. We are not offering any financial inducement for participation. Participants are 
not required to sign the consent right after we explain it. If necessary, we will schedule a later 
date for consent to allow adequate time for participants to ask questions and think about 
whether to participate in the study. 
 
Psychiatrist Investigators on this protocol may consent patients if they see an eligible patient in 
a context other than an ECT consult. We don't anticipate that many participants will be enrolled 
via this route. 
 
 
4.5 Study Visits 
Screening: Patients who have been referred or have volunteered for the study will be screened 
in person or by phone to verify that inclusion and exclusion criteria have been met. 
 
Consent procedures: Each patient will be given a full verbal explanation of the study 
procedures, including risks, benefits, and alternatives, and will be given a copy of the approved 
written consent form. The patients will be given the opportunity to review the consent form 
and to discuss any questions or concerns with their own psychiatrist, our study investigators, or 
others if necessary prior to beginning study treatment procedures. 
 
Baseline: Prior to the first treatment, depression severity will be assessed via a psychiatric 
interview, including completion of the HRSD-24 and MoCA, which will also verify inclusion and 
exclusion criteria. Immediately before treatment 1, the participant will complete the QIDS and a 
blood sample will be obtained from the IV line. 
 
Randomization (Study 1 only): Participants who meet study criteria will be randomly assigned 
in blocks of 4 to either high or low dose isoflurane (High ISO/BS+ vs. Low ISO/BS-). We 
anticipate up to 15 participants in each arm; this sample size was defined by our prior study in 
which 8 participants were adequate to show significant antidepressant effects. 
 
Leukocyte Gene Expression: Although our study is designed with EEG burst suppression as our 
primary target mechanism, we acknowledge that its effects must be mediated via specific 
neural pathways. Thus, we will explore possible neural and immune pathways associated with 
the antidepressant effects of deep anesthesia. Changes in full transcriptome leukocyte gene 
expression from pre- to post-treatment will be assessed from blood samples drawn before the 
first treatment and within 48 hours of the final (10th) treatment. In particular, we will examine 
the possible role of GABA-ergic and ATP-responsive ion channel pathways as well as other 
putative depression- or suicidality-linked neuroimmune pathways. We will also evaluate other 
ATP-responsive ion channels (purinergic, acid sensing and transient vanilloid receptor) or other 

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genes including IL-10 and other cytokines, SAT1, PTEN, MARCKS and MAP3K3 previously 
associated with refractory depression or suicidality by our group and others. 42918 
Magnetic resonance imaging:  GABA and glutamate concentrations will be quantified in the 
prefrontal cortex and a posterior cortical control region using 2-dimensional J-resolved proton 
magnetic resonance spectroscopy (MRS) and prior knowledge fitting (Prescot & Renshaw, 2013) 
on the Siemens Prisma 3T scanner at the Imaging & Neurosciences Center in Research Park.  In 
case that scanner is unavailable, images will be acquired using an identical scanner at the 
University Neuropsychiatric Institute.  Time in the scanner is expected to be 60-75 minutes 
(maximum: 90 minutes). The scans will be completed prior to beginning the treatments, before 
treatment #6, and 48-72 hours post treatment #10. 
Costs and Compensation 
There are no costs to participate. No compensation will be provided to participants.  
 
Subject Withdrawal and Study Completion 
Subject compliance will be monitored throughout the trial by study staff. If any 
contraindications to the study are identified, participants may be withdrawn by the 
investigators. Participants can be withdrawn at any point if the investigators feel it is in the 
participant’s best interest or in the interest of study integrity. No information will be collected 
from withdrawn participants unless it is related to a continuing AE or SAE. 
 
5. Clinical and Laboratory Evaluations 
 
 
5.1 Study Drug Administration and Duration 
All treatment groups, High ISO/BS+, Low ISO/BS- (Study 1) and propofol (Study 2) will receive 10 
treatments over 3 weeks. All treatment procedures will take place in the ECT Procedure Room 
at the University of Utah Neuropsychiatric Institute.  All participants will receive standard 
monitoring as recommended by the American Society of Anesthesiologists that includes EKG, 
pulse oximetry, blood pressure by noninvasive cuff, temperature, respiratory rate, and end-
tidal carbon dioxide. If monitoring reveals significant hemodynamic alteration the 
anesthesiologist will manage the study participant by one or more of the following: IV fluid 
loading; Trendelenburg positioning; small bolus doses of ephedrine, phenylephrine, or 
epinephrine; or stopping the anesthesia. The course of action will be at the discretion of the 
anesthesiologist based on initial hemodynamics, absolute MAP change, and condition of the 
study participant.   IV fluids will also be co-loaded at induction with the goal of replacing any 
deficit that resulted from fasting.  The above noted anesthetic practices are routine and carried 
out on a daily basis in both the operating room and in the ECT suite.  
 
 
5.1.1 Study 1. High vs Low Dose Isoflurane (ISO): The route and doses of isoflurane 
(both high and low doses) fall within the normal range of standard clinical practice. Details of 
induction follow, below: 
 

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Anesthetic Induction (High and Low Dose ISO): Anesthetic induction will be achieved with 
methohexital (1-3mg/kg IV).  If there is a contraindication to methohexital, etomidate or 
propofol will be administered at the discretion of the anesthesiologist.  General anesthesia will 
be administered via facemask. Patients will be co-loaded with IVF to offset any dehydration 
from fasting. Patients will be ventilated while under anesthesia using an LMA or ET tube as 
appropriate for safety and comfort. 
 
High ISO/BS+ (n=15): The High ISO/BS+ group will receive isoflurane at the same level used in 
our previous study, with the initial vaporizer setting at 4%. End-tidal isoflurane concentration 
will measured continually and is the best measure of alveolar concentration.  Alveolar 
concentration will approximate effect site concentration.  In this study we are directly 
measuring isoflurane effect on CNS electrical activity via the EEG (BIS) and burst suppression 
ratio is continually calculated and displayed.   As the end tidal isoflurane concentration 
increases and the burst-suppression ratio increases, the vaporizer setting will be decreased.  
The goal is a burst-suppression ratio of 80%.  Some burst suppression is seen at concentrations 
as low as 1MAC of isoflurane (1.15%) and most patients will achieve 80% BSR at 2 MAC or less 
(2.3%).   These doses are well within the normal range for isoflurane use and are achieved on a 
daily basis in the O.R.s at this institution.  As in the prior study by Weeks et al 51, this condition 
of isoflurane-induced electrical quiescence will be maintained for 15 minutes. 
 
Low ISO/BS- (n=15): ISO concentration will be titrated to maintain unconsciousness with burst 
suppression of ≤20%. This condition will be maintained for 15 minutes. 
 
 
5.1.2 Study 2. Open-Label Propofol Treatment: Participants in the propofol treatment 
group will receive an induction dose of 2-3 mg/kg IV bolus, followed by propofol infusion at  
100-400 mcg/kg/min.  Additional boluses (0.5-2 mg/kg), administered every 2-3 minutes, may 
be necessary to achieve and maintain 80% burst suppression on EEG. At the end of the 
treatment, propofol administration will be discontinued and the participant will be allowed to 
awaken. Similar means of propofol induced burst-suppression is commonly and safely 
administered during neurosurgical procedures.  Monitoring and supportive treatment will be 
consistent with clinical standards outlined by the American Society of Anesthesiologists as 
discussed above for participants in the main study.  We will enroll up to 10 participants in the 
propofol pilot study. 
 
 
5.1.3 Anesthetic Emergence (All Treatments): Emergence from isoflurane anesthesia 
into consciousness will be facilitated by the Aneclear device (QED 100TM) according to FDA 
approved guidelines and as routinely used in the University of Utah operating rooms.  
 
The time from discontinuing the intervention to when the participant responds to the repeated 
(every minute) command “Open your eyes” will be recorded.  Participants will be monitored for 
AEs such as nausea, vomiting, and sore throat during anesthetic emergence. Orientation will be 
assessed repeatedly, beginning 3 minutes after eye opening, until the participant answers the 
questions correctly, e.g. “What day is it”, “Do you know where you are?” Perception of drug 

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effects during recovery will be assessed using the Drug Effects Questionnaire (DEQ). The total 
time for each session (estimated at 1.5 to 2.5 hours) will also be recorded. 
 
 
5.2 Study Drug Management 
Study drug will be managed by staff at the University Neuropsychiatric Institute. Subjects will 
be issued a subject ID number. This number will be used to randomize subjects into High 
ISO/BS+ or Low ISO/BS- arms of the study. Randomization will be conducted by a designated 
un-blinded member of the study team. Emergency un-blinding information will be maintained 
by a designated custodian. Subjects’ un-blinding information will only be accessed by the study 
team in case of a medical emergency. If a drug disclosure is made, a record must be made by 
the Investigator detailing the purpose, date, and personnel involved.  
 
 
5.3 Clinical Assessments 
 
5.3.1 Primary Response Assessments: The primary outcome measure is change in 
depressive symptoms assessed by the Hamilton Rating Scale for Depression (HRSD-24), which is 
the most widely used method of evaluating the effectiveness of treatments to relieve 
depression. HRSD-24 will be administered as part of a clinical interview by blinded investigators 
prior to beginning the treatments, then repeated before treatment #6 and at the end of 
treatments. 
 
 
5.3.2 Secondary Response Assessments to be acquired before each treatment: Also as 
standard of care for patients receiving ECT, the participant will fill out the Quick Inventory of 
Depressive Symptomatology (QIDS-SR) which is a patient self-report measure of depressive 
symptoms prior to each treatment session. QIDS scores will also be used as a safety measure. If 
2 consecutive QIDS scores indicate worsening of depressive symptoms, below pre-treatment 
values, the study participant will meet with one of the study Psychiatrists to discuss treatment 
alternatives. The Montreal Cognitive Assessment (MoCA), Generalized Anxiety Disorder scale 
(GAD-7), and Work and Social Adjustment Scale (WSAS) will be administered prior to beginning 
the treatments, then repeated before treatment #6, and 48-72 hours post treatment #10.  
 
5.3.3 Follow-up Assessments to be acquired monthly for up to 6-months post 
treatment period: Follow-up assessments will include QIDS-SR, WSAS, and an opened ended 
question about the participant’s experience during the study. Follow-up assessments will be 
administered over the phone or by email with a link to an electronic survey housed on REDCap 
(a secure online database). A voicemail may be left (with prior permission) regarding the follow-
up assessments. 
 
 
5.4 Tissue Banking 
Blood samples will be drawn from participants and analyzed for biomarkers of depression and 
response to treatment. Samples will be stored in a -80 freezer in Dr. Mickey’s laboratory at 383 
Colorow or in Dr. Alan Light's laboratory in the Department of Anesthesiology, U of U School of 
Medicine. 
 

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Participants who consent to bank de-identified samples will be assigned a study code that is 
linked to their identifying information during the study period. After all study blood analyses 
are performed, the study coordinator will determine which samples (by code) need to be de-
identified. When these samples are located, they will be assigned a new code that is not linked 
to personal identifiers. This de-identification process will happen after all study blood analyses 
are completed.  
 
Participants who want their samples to be removed from the bank must contact Dr. Mickey. If 
their samples are still linked to identifying information, they will be located and destroyed. De-
identified samples will not be removed, as it will not be possible to identify their source. 
 
De-identified banked samples will be available to researchers within the University of Utah and 
at the institutions of research collaborators. All researchers must contact Dr. Mickey to receive 
permission to conduct IRB approved research on depression and response to treatment using 
these samples. 
 
6. Data and Safety Monitoring 
We will monitor study data and documentation after the first 2 participants have completed 
treatment and then every 6 months thereafter. The monitoring group will consist of Ken 
Johnson, MD, MS, Professor of Anesthesiology; Shane Brogan, MD, Associate Professor 
(Clinical) of Anesthesiology; and Jim Ashworth, MD, Associate Professor (Clinical) of Psychiatry. 
This group is well qualified to review data and safety reports for the study. 
 
 
6.1 Data Collection 
Discussion of the study with participants will take place individually instead of in front of a 
group. The data collected through research interventions will be conducted in a private place. 
The information collected about participants will be limited to the amount necessary to achieve 
the aims of the research so that no unneeded information will be collected. Gene expression 
data gathered during this study will not be shared with the participant or family members.  
 
 
6.2 Data Storage 
Research data will be stored on password protected computers or in locked cabinets or offices. 
All participant identifiers will be stored separately from the coded, participant data.  
 
Any data that will be transferred or transported outside of the institution will be encrypted. Any 
research information shared with outside universities or entities will be de-identified. 
 
Periodic review and confirmation of participant eligibility and informed consent documentation 
will take place. This review will also include confirmation that all appropriate information has 
been reported to the oversight agencies (IRB).  
 

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6.3 Safety and Efficacy Monitoring 
All serious adverse events will be reported within 5 days to the Data and Safety Monitoring 
Board (DSMB) and IRB by the Principal Investigator or study coordinators. These would include 
life-threatening cardiac arrhythmias, respiratory arrest, myocardial infarction, stroke, and 
death. Moderate adverse events including worsening of depressive symptoms will be reported 
to the DSMB. An interim data analysis will be performed at the midpoint of this pilot 
investigation, after data is obtained from 5 participants in each of the treatment conditions. 
The study will be terminated if significantly greater negative outcomes are associated with 
either isoflurane treatment or propofol treatment. 
 
Prior to each treatment, participants will fill out the QIDS-SR.  HRSD-24 will be obtained at 
baseline, before treatment 6, and after treatment 10. All participants will be assessed before 
the 6th treatment.  If participants in Low ISO/BS- or propofol treatment groups show clinical 
deterioration (defined by 2 consecutive QIDS scores below baseline OR a decrease in HSRD-24 
before the 6th treatment), they will be offered treatment at the 80% burst suppression level 
(High ISO/BS+) as it has proven effective in reducing depression or ECT as the standard of care 
treatment. Participants in High ISO/BS+ treatment who show clinical deterioration, as defined 
above, will be offered ECT.  All serious adverse events will be reported within 5 days to the 
DSMB by the Principal Investigator or study coordinators. The DSMB will also be notified 
within 10 business days if a study participant is showing signs of clinical deterioration (defined 
as 2 consecutive QIDS scores below baseline OR HRSD-24 below baseline). Progress reports will 
be submitted every 6 months. If a participant has a serious reaction to anesthesia, they will be 
withdrawn from the study.  
 
As exploratory biomarkers, we will evaluate whether quantitative cortical EEG changes early in 
treatment (obtained from dual lead BIS data in each treatment session) are associated with 
subsequent remission in depressive symptoms.  
 
7. Statistical Considerations 
Statistical analyses will employ a statistical mediation model framework. Any participant 
missing necessary information will be excluded from statistical analysis. Only participants with 
usable data will be included in the analyses. If the original statistical plan becomes infeasible, 
the original plan and the modifications made will be reported.   
 
 
7.1 Aim 1. To determine if significantly more depressed participants randomized to 
receive 10 treatments of High ISO/BS+ will show a positive treatment response (defined as 50% 
reduction in depression scores) or achieve full remission of symptoms by treatment end 
compared to those in the Low ISO/BS-group, odds of treatment response and remission will be 
compared between groups using logistic regression analysis with positive response at 
treatment end (yes/no) as the dependent variable, and treatment group (High ISO/BS+ vs Low 
ISO/BS-) as the independent variable. Positive treatment response is defined as 50% reduction 
in depression scores, and remission will be defined as a score of 0-10 on the HRSD-24 scale. 

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Covariates will include baseline depression severity and possibly other baseline demographic 
and clinical measures as needed. 
 
 
7.2 Aims 2 and 5. Using RNA SEQ methods, we will also explore whether participants 
who respond to treatment show blood-based changes in gene expression of neural and 
immune pathways previously associated with refractory depression or suicidality by our group 
or others.  A t-test or non-parametric Wilcoxon test will be used, as appropriate.  Change from 
baseline to end of treatment in gene expression levels will be correlated with change from 
baseline to end of treatment in HRSD-24.  
 
 
7.3 Aim 4. In the open-label trial of propofol, initial evidence of efficacy will be defined 
by the percent of participants who show at least a 20% reduction in both HRSD and QIDS scores 
(initial improvement, as employed in the STAR D investigation) and who are propofol/BS+ 
responders  (defined as 50% or more reduction in both HRSD-24 and QIDS scores). Secondary 
evidence of efficacy will be defined by comparing the percent of participants who are 
responders to propofol/BS+ vs. to the Low ISO/BS- control condition in the randomized trial. 
 
8. Training and Resources 
Brian Mickey MD, PhD, Principal Investigator, is trained in Psychiatry and is an established 
researcher in the area of neuroscience and treatment-resistant depression. He will oversee the 
project. 
 
All anesthetic treatments will be administered by experienced Anesthesiologists from the 
Department of Anesthesiology (Drs. Tadler, Smith, Sakata, Odell, Jessop, Larson, Whittingham,  
and Beck).  Drs. Tadler and Smith will coordinate the anesthesiology team. 
 
Psychiatric evaluations (HSRD-24 interviews) will be performed by experienced psychiatrists 
from the Department of Psychiatry (Drs. Weeks, Mickey, Kendrick, Gilley, Pierson, and 
Bushnell). 
 
Kathleen Light, PhD, Department of Anesthesiology, has over 30 years of NIH-funded research 
and will assist the PI with data analysis, publications, and preparation of a larger grant proposal 
using data from this project. 
 
Alan Light, PhD, Department of Anesthesiology, will supervise the gene expression assays for 
the biomarker portion of the study. 
 
Andrea White, PhD, Department of Psychiatry, will be responsible for coordinating patient 
screening and scheduling participant visits. She will oversee collection and initial processing of 
blood samples for the biomarker portion of the study. She will be responsible for 
randomization, maintaining the subject coding key, and monitoring study progress. 
 

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Anna Arp, study coordinator, Department of Psychiatry, will assist with participant recruitment, 
screening, and management of study records. 
 
Core members of the study team will meet regularly (typically weekly) to discuss study 
progress, including recruitment, data management, and participant status. 
 
All study personnel have current CITI training. Personnel who are responsible for data 
monitoring and study reports will have had appropriate RATS training. All personnel who will 
consent study participants have experience with this process and have received specific 
guidance regarding the details of this protocol. 
 
All treatments will take place in the ECT suite at the University Neuropsychiatric Institute. 
Screening, consent, and psychiatric interviews will take place in office space adjacent to the ECT 
suite. 
 
Participants will undergo psychiatric evaluation at baseline, after treatment #5, and after 
treatment #10. In addition, before each treatment, depression will be assessed using the QIDS. 
If a participant is in need of immediate psychiatric care, the UNI CrisisLine is available 24/7. 
 
9. Protection of Human Subjects 
 
 
9.1 Potential Risks 
Isoflurane is a standard anesthesia induction agent.  Its use has been shown to be effective in 
standard surgical care.  Isoflurane is contraindicated if: 1) the participant is sensitive to 
isoflurane or other halogenated anesthetics, or 2) if the participant or a family member have 
had previous complications from anesthesia, specifically malignant hyperthermia.  
 
Propofol is a well-tolerated, routinely administered anesthetic. Its use has been shown to be 
effective in standard surgical care.  Propofol is contraindicated if the participant has an allergy 
to soy or peanuts. 
 
The following risks are associated with anesthesia: 
 
Common (1-10%): The participant may experience nausea, vomiting, and/or shivering from the 
anesthesia. Medications can be given to help with nausea and vomiting. These symptoms 
normally resolve within 60 minutes. Participants may also experience a mild sore throat from 
the breathing tube. For propofol group only: burning sensation at the injection site. 
After each anesthesia treatment, activities requiring mental alertness may be impaired for 2-4 
hours. Therefore, we require participants to have someone accompany them home and 
recommend that they do not make any important decisions for 24 hours after treatment. 
 
Both isoflurane and propofol anesthesia are associated with dose-dependent decreases in 
blood pressure. If monitoring reveals significant hemodynamic alteration, the anesthesiologist 

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will manage the study participant by one or more of the following: IV fluid loading; 
Trendelenburg positioning; small bolus doses of ephedrine, phenylephrine, or epinephrine; or 
stopping the anesthesia. The course of action will be at the discretion of the anesthesiologist 
based on initial hemodynamics, absolute MAP change, and condition of the study 
participant.”IV fluids will also be co-loaded at induction with the goal of replacing any deficit 
that resulted from fasting. Blood pressure typically returns to normal after anesthesia is 
stopped. 
 
Very Rare (less than 1/10,000): Complications including life-threatening cardiac arrhythmias, 
respiratory arrest, myocardial infarction, stroke, and even death are possible. These events are 
much less likely in adults who are younger than age 55 and who have low cardiovascular 
risk.  Malignant hyperthermia is another very rare complication of isoflurane anesthesia. We 
are excluding participants who have a known susceptibility to this condition. 
  
The physicians performing these procedures are experienced anesthesiologists and will be 
closely monitoring responses to the anesthesia and all vital functions, and will take all 
appropriate steps to minimize these risks. 
 
Risks of Worsening Depression 
During the psychiatric and HSRD-24 interviews, participants will be asked to answer questions 
about their symptoms that may be upsetting. The interviews will be conducted by experienced 
clinicians in Psychiatry who have expertise in managing emotional situations. If participants 
require additional support, they will be referred to their clinical provider or the UNI CrisisLine at 
(801) 587-3000. 
 
The study physicians will be monitoring participants' depressive symptoms at frequent 
intervals, and if symptoms get worse, we will discuss other treatment options available outside 
of the study.  Treatments available after leaving the study may include ECT or medications. 
 
Risks of Blood Sampling 
Blood samples will typically be obtained through the participant's IV line, but we may have to 
do an additional needle stick in some cases. Thus, there is the risk of pain, bruising, and in rare 
cases infection. Sampling will be performed by skilled personnel to minimize these risks. 
 
Risks of MRI 
Standard questionnaires and screening procedures will be performed prior to MRI scanning to 
rule out MRI contraindications (e.g., pacemakers, surgical clips, metallic devices).  Subjects and 
all investigators will be screened for metallic objects prior to entering the scanner room.  
Subjects will wear hearing protection to prevent hearing damage due to scanner noise.   
 
 
REPRODUCTIVE RISKS 
The effects of isoflurane and propofol on the embryo or fetus are currently unknown.  It is 
possible that if either of these is given to a pregnant woman it will harm the unborn child. 
Pregnant women must not take part in this study, nor should women who plan to become 

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pregnant during the study. Women who are at risk of pregnancy will be asked to have a 
pregnancy test before taking part to exclude the possibility of pregnancy. If you could become 
pregnant you must use an effective contraceptive during the course of this study. Acceptable 
methods of birth control include abstinence, oral contraceptives, the contraceptive patch, the 
contraceptive ring, condoms, etc.  
 
 
9.2 Potential Benefits 
There may be no direct benefits to participants who volunteer for this research, although 
evidence suggests that participants receiving High ISO/BS+ may realize a clinical benefit. 
Information obtained from this work may provide insight into the role of burst suppression as a 
possible mechanism underlying the anti-depressant effects of deep anesthesia. The gene 
expression analyses may in turn identify potential neuro-immune pathways associated with 
depression treatment. 
 
 
 
 

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