Conditions: Major Depressive Disorder Alcohol Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
The investigators will compare 3 treatment groups (ketamine plus naltrexone vs. ketamine alone vs. placebo) for treating major depressive disorder (MDD) and alcohol use disorder (AUD) in an 8-week randomized, double-blind, placebo-controlled, between-subjects trial. First, prior to the double-blind trial, the investigators will conduct an open-label trial that will include 5 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a follow-up of 4 weeks. Second, after reviewing the safety and efficacy of repeated ketamine treatment from the open-label trial, the investigators will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will include 60 patients with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) plus naltrexone with a follow-up of 4 weeks. The 4-month follow-up session will also occur.

Detailed description:

Arms:
arm 1: Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular naltrexone once a month (a total of 2 injections). arm 2: Subjects in this arm will receive (1) intravenous ketamine treatment once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections). arm 3: Subjects in this arm will receive (1) intravenous placebo treatment (psychoactive placebo midazolam) once a week for 4 weeks (a total of 4 infusions) with a follow-up of 4 weeks and (2) intramuscular placebo once a month (a total of 2 injections).

Interventions: intervention 1: Ketamine + Naltrexone intervention 2: Ketamine + Placebo intervention 3: Placebo (psychoactive placebo midazolam) + Placebo
Intervention descriptions: intervention 1: Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular naltrexone (380 mg) once a month (a total of 2 injections). intervention 2: Subjects in this arm will receive (1) intravenous ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections). intervention 3: Subjects in this arm will receive (1) intravenous psychoactive placebo midazolam (0.045 mg/kg) once a week for 4 weeks (a total of 4 infusions) and (2) intramuscular placebo once a month (a total of 2 injections).

Protocol document:
Prot_SAP_000.pdf: 
1  
v. 09/29/2022  GY0002 
 
NCT number: NCT02461927 
 
 
1. Title 
Ketamine for the Rapid Treatment of Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) 
 
2. Principal Investigator 
 
Gihyun Yoon, M.D. 
VA Connecticut Healthcare System 
Phone: 203-932-5711 x7421 
E-mail: gihyun.yoon@va.gov 
 
3. Objectives  
We propose a novel use of ketamine for the treatment of comorbid major depressive disorder (MDD) and 
alcohol use disorder (AUD) in veterans and civilians. Although MDD and AUD are two of the top 4 leading 
sources of disease burden among all medical diseases, the efficacy of current pharmacotherapy is only 
modest. In recent years, the rapid-acting antidepressant ketamine has shown efficacy and safety for the 
treatment of depression. Since up to 40% of all depressed patients have AUD in their lifetime, it would be 
important to test ketamine in treating comorbid MDD and AUD—instead of targeting only MDD. Since most 
AUD patients have been excluded in clinical trials testing antidepressants, little is known about proper 
pharmacotherapy for patients with comorbid AUD and MDD. Thus, there is a critical need to develop effective 
pharmacotherapy for comorbid AUD and MDD. Also, ketamine has been suggested for potential treatment of 
AUD itself (Krystal, Petrakis, Krupitsky, et al., 2003; Krystal, Petrakis, Mason, Trevisan, & D'Souza, 2003). 
 
Based on these scientific data, we recently tested a single intravenous (IV) infusion of ketamine in veterans 
with comorbid MDD and alcohol dependence. Our pilot data in a crossover trial shows that a single dose of IV 
ketamine at 0.5 mg/kg IV infusion is safe and effective in reducing both depression and alcohol craving. 
Recently, several research groups have shown that repeated ketamine infusions (up to 6 infusions) are even 
more effective than single ketamine infusion (Murrough, et al., 2013; Rasmussen, et al., 2013; Shiroma, et al., 
2014).  
 
To further (a) increase treatment efficacy for AUD and (b) minimize abuse potential of ketamine in patients with 
MDD and AUD, we have tested naltrexone plus ketamine treatment for safety and efficacy in our recent pilot 
study (GY0004). This pilot study showed that combination therapy of naltrexone and ketamine was safe and 
effective in reducing depression and alcohol consumption. 
 
In order to expand our preliminary work, we propose an 8-week, randomized, double-blind, placebo-controlled, 
between-subjects trial in which repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 
ketamine infusions) plus naltrexone will be evaluated for safety and efficacy. First, prior to the double-blind trial, 
we will conduct an open-label trial that will include 5 veterans with comorbid MDD and AUD to test safety and 
efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) 
with a follow-up of 4 weeks. Second, after reviewing the safety and efficacy of repeated ketamine treatment 
from the open-label trial, we will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will 
include 60 veterans and civilians with comorbid MDD and AUD to test safety and efficacy of repeated ketamine 
treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) plus naltrexone with a follow-
up of 4 weeks and a 4-month follow up. This is the first study examining the therapeutic potential of repeated 
ketamine for the treatment of comorbid MDD and AUD. We will compare 3 groups (ketamine plus naltrexone, 
ketamine alone, and placebo) for treating MDD and AUD as follows. 
 
3 groups 
1 
IV Ketamine (0.5 mg/kg) + IM Naltrexone (380 mg) (n=20) 
2 
IV Ketamine (0.5 mg/kg) + IM Placebo (n=20) 
3 
IV Placebo (midazolam 0.045 mg/kg) + IM Placebo (n=20) 
 


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v. 09/29/2022  GY0002 
 
4. Hypothesis 
We predict that IV ketamine will significantly reduce the symptoms of MDD and AUD compared with active 
placebo (midazolam) in veterans and civilians with MDD and AUD.   
 
Specific Aim #1: To evaluate if serial IV ketamine is superior to placebo in reducing depression. We 
hypothesize that serial IV ketamine is superior to placebo in reducing depression. 
 
Specific Aim #2: To evaluate if serial IV ketamine is superior to placebo in reducing alcohol consumption. We 
hypothesize that serial IV ketamine is superior to placebo in reducing alcohol consumption. 
 
Exploratory Aims: 
Specific Aim #3: To evaluate if serial IV ketamine is superior to placebo in reducing alcohol craving. We 
hypothesize that serial IV ketamine is superior to placebo in reducing alcohol craving. 
 
Specific Aim #4: To evaluate if serial IV ketamine is superior to placebo in reducing suicidal ideation. We 
hypothesize that serial IV ketamine is superior to placebo in reducing suicidal ideation. 
 
Specific Aim #5: To evaluate the safety and tolerability of serial IV ketamine in patients with comorbid MDD 
and AUD. We hypothesize that serial IV ketamine is safe and well tolerated in this population. 
 
Specific Aim #6: To evaluate whether naltrexone plus ketamine is superior to ketamine alone in reducing 
abuse potential of ketamine. We hypothesize that naltrexone plus ketamine is superior to ketamine alone in 
reducing abuse potential of ketamine as measured by the Drug Abuse Potential Scale. 
 
5. Background 
 
1) MDD and AUD are serious mental illnesses and frequently co-occur 
MDD and alcohol use disorder AUD are two of the top 4 leading sources of  disease burden among all medical 
diseases in the Americas as reported by the World Health Organization (World Health Organization, 2008). 
They are both relatively common, with lifetime prevalence rates of 13.2% and 30.1%, respectively, in the adult 
U.S. population (Hasin, Goodwin, Stinson, & Grant, 2005; Hasin, Stinson, Ogburn, & Grant, 2007). These two 
disorders frequently co-occur (Kessler, et al., 1997; Regier, et al., 1990). According to the National Longitudinal 
Alcohol Epidemiologic Survey in the United States, 40% of patients with MDD have comorbid AUD in their 
lifetime (Grant & Harford, 1995). The prevalence rates of MDD and AUD are even higher in some groups, such 
as veterans. The National Vietnam Veterans Readjustment Study reported that both prevalence rates of MDD 
and AUD are higher in theater veterans than in civilians (Jordan, et al., 1991). 
 
In recent years, there has been widespread public concern about depression, suicide, and alcohol abuse 
among military personnel and veterans. A 2012 report by the Institute of Medicine acknowledged the 
seriousness of alcohol use problems in the U.S. military by noting that binge drinking by active duty service 
members increased from 35% in 1998 to 47% in 2008 (Institute of Medicine, 2012). Another report by IOM 
described that military personnel and veterans usually have more than one health problem, including AUD and 
MDD (Institute of Medicine, 2013). In addition, suicides in the U.S. military surged to a record high of 349 in 
2012 (Burns, 2013). Veterans frequently have co-occurring alcohol problems and depression (Stecker, 
Fortney, Owen, McGovern, & Williams, 2010; Thomas, et al., 2010). In combat veterans, depression 
significantly increases alcohol misuse (Heltemes, Clouser, MacGregor, Norman, & Galarneau, 2014) with two 
studies showing veterans with concurrent depression were 2.1 to 4.2 times more likely to misuse alcohol 
(Heltemes, et al., 2014; Jakupcak, et al., 2010). 
 
Previous studies have reported that individuals with comorbid MDD and AUD have more severe health 
conditions than those with MDD alone. In a general population sample, individuals with comorbid depression 
and AUD had more serious episodes of depression and suicidal behaviors than those with MDD alone (Grant, 
Hasin, & Dawson, 1996). In a prospective study of young adults (Briere, Rohde, Seeley, Klein, & Lewinsohn, 
2014), comorbid MDD and AUD doubled the risk of alcohol dependence compared with AUD only. In this 


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study, the comorbidity also increased life dissatisfaction and lowered global level of functioning. In another 
study using a clinical sample comparing patients with single and dual disorders, dually diagnosed patients with 
MDD and AUD had higher suicidality, impulsivity, functional impairment, and lower self-esteem (Cornelius, et 
al., 1995). In addition to these indicators of more severe pathology and symptoms, dual diagnosis of MDD and 
AUD has also been associated with poorer treatment outcomes (Rounsaville, Dolinsky, Babor, & Meyer, 1987) 
presumably because each disorder increases the risk and severity of the other disorder in a bidirectional way 
over time (Briere, et al., 2014).  
 
Using administrative data from the Veterans Health Administration (VHA), we recently identified 58,173 
veterans who had a diagnosis of comorbid MDD and AUD nationally during a 12-month period (October 1, 
2011 - September 30, 2012). Based on the VHA data, we have reported that dually diagnosed veterans with 
MDD and AUD, relative to veterans with MDD alone, had a greater number of comorbid health conditions, such 
as liver disease, drug use disorders, and bipolar disorder as well as greater likelihood of homelessness and 
higher health service utilization (Yoon, et al., 2014). Since there have been reports that (1) the prevalence of 
comorbid major depressive episodes and substance use disorders has increased significantly from the 1990s 
to the 2000s (Compton, Thomas, Stinson, & Grant, 2007) and (2) MDD is projected to be the number one 
cause of burden of disease in the 2030s worldwide (World Health Organization, 2008), future demand for 
services for veterans with comorbid MDD and AUD will likely grow. In addition, more veterans are already 
presenting to VA facilities for the treatment of this comorbidity (Milliken, Auchterlonie, & Hoge, 2007). Given the 
severe pathology and morbidity associated with comorbid MDD and AUD, it is important to develop effective 
treatments for dually diagnosed veterans with MDD and AUD. 
 
2) Ketamine for the Rapid Treatment of MDD and AUD 
Despite the enormous suffering, morbidity, and mortality in patients with MDD and AUD, the efficacy of current 
pharmacotherapy is only modest. Remission rates following current antidepressants are low (only 30%). Also, 
current antidepressants require a delay of weeks or months before the onset of antidepressant effect. Four 
medications approved for AUD do not treat depression or suicidality. Since most AUD patients are excluded in 
clinical trials for testing antidepressants, little is known about proper pharmacotherapy for patients with 
comorbid AUD and MDD. Thus, there is a critical need to develop effective pharmacotherapy for comorbid 
AUD and MDD. 
 
Recently, a single intravenous infusion of ketamine, an NMDA receptor antagonist, has shown a rapid 
treatment effect on depression and suicidality (0.5 mg/kg IV infusion over 40 minutes). This rapid-acting 
antidepressant effect of IV ketamine was replicated by other ketamine studies, including our data. A meta-
analysis including 8 double-blind, randomized controlled trials showed that effect size was large (standardized 
mean difference = 0.90), indicating the efficacy of ketamine in the rapid treatment of depression (McGirr, et al., 
2014). Recently, several research groups have shown that repeated ketamine infusions (up to 6 infusions) are 
even more effective than single ketamine infusion (Murrough, et al., 2013; Rasmussen, et al., 2013; Shiroma, 
et al., 2014) for the treatment of depression. Currently, ketamine is an FDA approved medication for human 
use as an anesthetic. Many researchers have reported that ketamine has the potential to revolutionize clinical 
treatment of depression (Krystal, Sanacora, & Duman, 2013). However, all of these ketamine studies excluded 
patients with AUD.  
 
Emerging evidence indicates that ketamine has the potential to treat AUD (Krystal, Petrakis, Krupitsky, et al., 
2003; Krystal, Petrakis, Mason, et al., 2003) as other similar glutamatergic medications have been shown to 
reduce craving for alcohol (Hölter, Danysz, & Spanagel, 1996; Krupitsky, et al., 2007). The NMDA receptor 
antagonist ketamine could be an effective treatment by stabilizing glutamatergic system, suppressing alcohol 
withdrawal, and decreasing the development of alcohol tolerance. Chronic alcohol drinking upregulates NMDA 
receptor function, which can cause alcohol tolerance and withdrawal. NMDA receptor antagonist ketamine 
dose-dependently reduced alcohol self-administration in rats. This anti-alcohol effect of ketamine was 
mediated by the activation of mTOR. In a human lab studies, detoxified alcohol-dependent patients had less 
side effects to ketamine compared with healthy subjects. Additionally, ketamine was more effective for treating 
depression in patients with a family history of AUD. Several lines of evidence suggest that both AUD and MDD 
share many similar neurobiological features, such as disruption of glutamate neurotransmission and impaired 


4  
v. 09/29/2022  GY0002 
 
astroglial cell function. Based on these scientific data, we recently tested a single intravenous infusion of 
ketamine in patients with comorbid MDD and alcohol dependence. Our pilot data shows that a single dose of 
IV ketamine at 0.5 mg/kg IV infusion is safe and effective in reducing both depression as measured by the 
Hamilton Depression Rating Scale and alcohol craving as measured by the Alcohol Urges Questionnaire.  
 
The primary goal of this proposal is to test repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; 
a total of 4 ketamine infusions) for comorbid AUD and MDD. First, prior to the double-blind trial, we will conduct 
an open-label trial that will include 5 veterans with comorbid MDD and AUD to test safety and efficacy of 
repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a 
follow-up of 4 weeks. Second, after reviewing the safety and efficacy of repeated ketamine treatment from the 
open-label trial, we will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will include 
60 veterans and civilians with comorbid MDD and AUD to test safety and efficacy of repeated ketamine 
treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a follow-up of 4 months. 
Midazolam will be used as an active placebo (instead of regular placebo saline), as suggested by VA grant 
reviewers, to enhance blinding in placebo-treated subjects. Midazolam has been safely used as an active 
placebo in other ketamine studies (Afridi, Giffin, Kaube, & Goadsby, 2013; Galvez, et al., 2017). In our study, 
we will use a smaller dose of midazolam (0.045 mg/kg), as compared to Galvez’s study that used 4.5 mg of 
midazolam. Also, to further enhance safety, (1) we will limit a maximum dosage of midazolam at 4.0 mg (4 mg 
of midazolam is equivalent to only 8 mg of diazepam) and (2) midazolam will be administered over 40 minute 
(a much longer duration) than other studies.  
 
To further (a) increase treatment efficacy for AUD and (b) minimize abuse potential of ketamine in patients with 
MDD and AUD, we have tested naltrexone plus ketamine treatment for safety and efficacy in our recent pilot 
study (GY0004). This pilot study showed that combination therapy of naltrexone and ketamine was safe and 
effective in reducing depression and alcohol consumption. 
 
Thus, we will compare 3 groups (ketamine plus naltrexone, ketamine alone, and placebo) for treating MDD and 
AUD as follows. 
 
3 groups 
1 
IV Ketamine (0.5 mg/kg) + IM Naltrexone (380 mg) (n=20) 
2 
IV Ketamine (0.5 mg/kg) + IM Placebo (n=20) 
3 
IV Placebo (midazolam 0.045 mg/kg) + IM Placebo (n=20) 
 
 
6. Significance 
There is a critical need to develop new drugs to treat MDD and AUD. In recent years, ketamine has shown a 
large effect size for the treatment of depression. Since up to 40% of all depressed patients have AUD in their 
lifetime, it would be important to test ketamine in treating patients with comorbid MDD and AUD—instead of 
targeting only MDD. Also, ketamine has been suggested for potential treatment of AUD (Krystal, Petrakis, 
Krupitsky, et al., 2003; Krystal, Petrakis, Mason, et al., 2003). The proposed research will yield important 
information on ketamine for the treatment of comorbid MDD and AUD. This study has the potential to improve 
the treatment of comorbid MDD and AUD. 
 
7. Subjects 
A total of 110 depressed and recently-detoxified alcohol dependent subjects between the ages of 21-65 will be 
recruited with the goal of reaching 60 people who enroll and complete all study procedures. Subjects will be 
accepted into the protocol after an opportunity to review and provide voluntary written informed consent and 
completion of a comprehensive medical and psychiatric history, physical examination, mental status 
examination, and routine laboratory assessments. Patients will be recruited in outpatient settings. Participants 
will be enrolled if they meet the following criteria. 
 
Inclusion Criteria: 
1. Male or female veterans and civilians,  21-65 years old 


5  
v. 09/29/2022  GY0002 
 
2. Current major depressive disorder without psychotic features by DSM-5 (antidepressant regimens can 
be allowed and changed during the trial) 
3. Montgomery–Åsberg Depression Rating Scale (MADRS) ≥ 20  
4. A minimum of 4 of 11 current alcohol use disorder symptoms by DSM-5 
5. Heavy drinking at least 4 times in the past month (‘heavy drinking’ defined as ≥ 5 standard drinks per 
day for men and ≥ 4 standard drinks per day for women)  
6. Able to provide written informed consent  
      
Exclusion Criteria: 
1. Current substance use disorder by DSM-5 in the past 3 months (except alcohol, tobacco, or cannabis) 
2. Current or past history of psychotic features or psychotic disorder 
3. Current dementia  
4. Current uncontrolled hypertension (systolic BP > 170 mm Hg or diastolic BP > 100 mm Hg)  
5. Unstable medical condition or allergy to ketamine, midazolam, naltrexone, or lorazepam---clinically 
determined by a physician 
6. Imminent suicidal or homicidal risk 
7. Pregnant or nursing women, positive pregnancy test, or inadequate birth control methods in women of 
childbearing potential 
8. Positive opioid or illicit drug screen test (except marijuana) 
9. Opioid use within 10 days prior to study medication (injectable naltrexone) or risks for opioid use during 
the study 
10. Liver enzymes that are three times higher than the upper limit of normal 
11. Current use of benzodiazepine 
12. Acute narrow-angle glaucoma 
13. Severe sleep apnea---clinically determined by a physician 
 
 
8. Privacy 
All research records will be kept as confidential as possible. Only a code number will identify research records. 
The master list linking names to code numbers will be kept separately from the research data. In case of a 
medical emergency, the medication group blinding can be broken by the principal investigator or a designated 
covering staff member, in order to supply information required for emergency medical care of research 
subjects. If a subject shows clinical deterioration (worsening of MDD or AUD symptoms), Dr. Yoon will 
determine whether: 1) the subject can remain in the study, or 2) a higher level of care (e.g. referral back to a 
treating psychiatrist or referral to emergency or inpatient care) is needed. 
 
10. Recruitment 
Subjects will be recruited in traditional ways through flyers, posters, and research boards at the VA 
Connecticut Healthcare System. In addition, we will also be using online posting through Trialfacts in order to 
recruit individuals that traditional methods are not able to reach. Subjects will be identified via their response to 
advertisements and/or internal recruiting through the research clinics and mental health clinics. Subjects will be 
asked to call us (West Haven VA Alcohol Research Center) at the number provided on the flyers if they are 
interested in participating in the research study. In addition, subjects will be identified via internal recruiting 
through the research clinics and mental health clinics. Our research staff will review CPRS records only to 
identify potential participants and alert treatment providers in the VA Clinics regarding veterans who may meet 
criteria for our study. In this case, our research staff will make initial contact with potential subjects in person or 
by letter prior to initiating any telephone contact, unless there is written documentation from the patient’s 
clinician that the subject is willing to be contacted by telephone about the study.  Additionally, under a HIPAA 
waiver, IRB-approved letters of invitation can be mailed to prospective participants with a past diagnosis of 
AUD or Major Depressive Disorder (or episode) who otherwise might meet eligibility criteria. When an invitation 
letter is mailed out and there is no response from potential participant, study staff may contact the potential 
participant by telephone. However, no more than three attempts will be made, no more than one call a day, 
unless instructed otherwise by potential participant. There will be a “do not contact” log maintained by site staff 
for participants who decline to be contacted.  


6  
v. 09/29/2022  GY0002 
 
 Subjects will be briefly screened over the phone for eligibility, and, if the subject seems suitable, he or she will 
present for an in-person evaluation that will be preceded by the consent process. All information obtained for 
the purposes of recruiting subjects, completing questionnaires, and processing data are confidential. 
Designated research staff will be responsible for recruiting potential subjects.  
 
• All data will be obtained exclusively for research purposes and will be at no cost to the 
patients. They will be paid a nominal but fair amount of money for their time and participation, 
up to $520 (i.e., enough money to fairly compensate and encourage follow-up without being 
coercive or encouraging risk taking).  The payment schedule is as follows: $40 baseline 
assessments ($40; visit 1) 
• $80 for infusion days ($80 x 4 = $320; visit 3, 4, 5, 6) 
• $20 weekly visits ($20 x 3 = $60; visit 7, 8, 9)     
• $50 for final 2 visits ($50 x 2 = $100; visit 10, 4-month F/U) 
 
Payment will be made through electronic funds transfer (EFT).  Participants will need to provide us 
with your banking information by completing a special payment form.  Alternatively, if participants do 
not have a bank account, a check will be mailed to them instead.  This check(s) will be mailed to the 
address they provide us with.  Alternatively, patients may choose to receive gift certificates issued to 
them for use at the VCS canteen (retail store) or VCS cafeteria here at the VACHS.   Study payments 
are subject to withholding for outstanding federal debts (i.e., defaulted student loans, interstate child 
support, back taxes etc) without notification. 
 
 
11. Research Design  
The primary goal of this proposal is to test repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; 
a total of 4 ketamine infusions) plus naltrexone for comorbid AUD and MDD. First, prior to the double-blind trial, 
we will conduct an open-label trial that will include 5 veterans with comorbid MDD and AUD to test safety and 
efficacy of repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) 
with a follow-up of 4 months. This open-label trial will allow us to examine the safety and tolerability of the 
ketamine treatment in this population.  
 
Second, after reviewing the safety and efficacy of repeated ketamine treatment from the open-label trial, we 
will conduct an 8-week, randomized, double-blind, placebo-controlled trial that will include 60 veterans and 
civilians with comorbid MDD and AUD to test safety and efficacy of repeated ketamine treatment (0.5 mg/kg; 
once a week for 4 weeks; a total of 4 ketamine infusions) plus naltrexone with a follow-up of 4 weeks and a 4-
month follow up. All patients will receive usual standard care during this trial. This study will be conducted at 
the West Haven VA. 
 
12. Procedures 
 
Table 1. Procedures involved from screening visit to visit 10 
Visit 
1 
Screening 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
4-mo 
F/U 
Day 
-30-0 
-9-1 
0+ 
7+ 
14+ 
21+ 
28+ 
35+ 
42+ 
49+ 
120+ 
IM naltrexone or placebo 
 
X 
 
 
 
 
X 
 
 
 
 
Ketamine or Midazolam 
 
 
X 
X 
X 
X 
 
 
 
 
 
Informed Consent  
X 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
SCID 
X 
 
 
FHAM 
X 
 
 


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v. 09/29/2022  GY0002 
 
A three day window is recommended for scheduling and completion of the weekly study visits; thus, subjects 
may be seen within 6-9 days of their last weekly visit. All evaluations and consent can be conducted in-person 
or by telephone (including video call, such as VVC). However, subjects need to come and meet with study staff 
to receive ketamine (or midazolam) and IM naltrexone (or placebo). The initial physical exam can be replaced 
by other physician's or clinician’s CPRS notes documented in the past 3 months. However, a research 
physician can still conduct a physical exam if needed to examine any medical issues. Subjects are encouraged 
to come within 9 days from the designated date. a. Day -30-0 refers to the period between signing consent and 
completion of screening. As such Visit 1 refers to one or multiple screening visits. b. Informed consent will be 
obtained prior to any study procedure. c. psychotherapies will be allowed during the study. d. IM injections will 
be given by an unblinded nurse who is not involved in ratings or evaluations, due to the distinctive appearance 
of naltrexone suspension. Abbreviations: Structured Clinical Interview (SCID), Family History Assessment 
Module (FHAM), Columbia-Suicide Severity Rating Scale (C-SSRS), Montgomery- Åsberg Depression Rating 
Scale (MADRS), Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR), Hamilton Anxiety 
Rating Scale (HAM-A), Time Line Follow Back (TLFB), Clinical Global Impression (CGI), Brief Psychiatric 
Rating Scale (BPRS), Clinician-Administered Dissociative States Scale (CADSS), Visual Analog Scale (VAS) 
of Mood States, Obsessive Compulsive Drinking Scale (OCDS), Quality of life enjoyment and satisfaction 
survey (Q-LES-Q), Electrocardiogram (EKG), Complete Blood Count (CBC), Ethyl glucuronide (EtG), Yale 
Craving Scale (YCS), Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar), Drug Abuse 
Potential Scale (DAPS) 
 
Initial Telephone Screening 
Subject eligibility will first be assessed via telephone screening. If medical record is available, medical record 
can be reviewed as well. However, medical record review is not required. Telephone screening will occur by 
experienced research personnel adept with this process. If the subject seems to be a likely candidate for 
inclusion in this protocol, he or she will be invited to a screening visit for study eligibility.  
 
Screening Visit 
At the screening visit, our research team will explain the overall study plan to potential subjects and go over the 
consent form. Subjects will have an initial screening evaluation that will include psychiatric history, medical 
history, mental status examination, physical examination, and laboratory assessment. Other detailed 
Psychiatric Eval 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
EtG, Liver Profile, GGT 
X 
 
X 
X 
X 
CBC, Chemistry 7 
X 
 
X 
 
Urine Tox/Preg 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
BP, Pulse, Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS, QIDS-SR, HAM-A 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
YCS, OCDS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPRS, CADSS, VAS 
 
 
X 
X 
X 
X 
 
 
 
 
 
Concomitant Meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLFB 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CIWA-Ar 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Breathalyzer 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
DAPS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Q-LES-Q 
 
 
X 
 
 
X 
 
 
 
X 
X 
Genotyping 
 
 
X 
 
 
 
 
 
 
 
 


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procedures are described in Table 1. If the examination and test results are acceptable and the subject meets 
the inclusion/exclusion criteria, the subject will be invited to the baseline visit. Our research team may provide 
transportation by arranging a car service for any visits if needed. 
 
Two Injectable Naltrexone Visits 
Subject will receive injectable naltrexone or placebo twice, (1) first at visit 2 (between the screening visit and 
the first ketamine infusion session [1-9 days prior to the first ketamine infusion preferred]) and (2) second at 
visit 7. 
 
Four infusion sessions (Day #0, 7, 14, 21) 
T-60: Intravenous lines started 
Vital signs (sitting/standing blood pressure, sitting/standing pulse, respiratory rate, oxygen saturation), 
Urine Tox/Preg 
YCS, MADRS, QIDS-SR, VAS, HAM-A, BPRS, CADSS* 
T0: 
INFUSION BEGINS (approximately 40 minutes in duration) (ketamine or placebo midazolam) 
T+60: Vital signs, YCS, MADRS, QIDS-SR, VAS, HAM-A, BPRS, CADSS, DAPS 
T+240: Vital signs, YCS, MADRS, QIDS-SR, VAS, HAM-A, BPRS, CADSS 
 
-If breathalyzer is positive for alcohol, ketamine (or placebo) infusion session will be cancelled and 
rescheduled. 
-Vital signs will be continuously monitored during the 40-minute infusion. Vital signs will be also monitored at -
60, 0, +60, +90, +120, +150, +180, +240. 
- Dosage of midazolam will be 0.045 mg/kg (maximum dosage of midazolam = 4.0 mg). 
-*Items that could not change within a session, e.g. sleep, appetite, will be rated only at T-60 and at follow-up 
sessions. 
-After the subject receives study medication at the WHVA, he or she will receive lunch and be medically 
cleared before leaving.  
-If necessary, intravenous lorazepam (ativan) at 1 mg will be available to reduce the behavioral effects of 
ketamine. This will be determined by a research physician.  
-If necessary, intravenous flumazenil will be available to reduce the sedative effects of midazolam. This will be 
determined by a research physician.  
-Subjects are not permitted to drive to and from the VA on ketamine treatment days, and subjects must make 
their own arrangements for a ride. However, if subjects cannot make their own arrangements for a ride, our 
research team may provide their transportation by arranging a car service on four ketamine/midazolam infusion 
days. 
 
Four follow-up sessions (Day #28, 35, 42, 49) 
A total of 4 weekly follow-up sessions will be performed on Day #28, 35, 42, and 49. All evaluations can be 
conducted in-person or by telephone (including video call, such as VVC). 
 
4-month follow-up sessions (Day #120): The 4-month follow-up session will occur at day 120. After the 
study, participants will be provided with psychiatric and/or substance abuse treatment referrals to continue 
treatment at their discretion.  All evaluations can be conducted in-person or by telephone (including video call, 
such as VVC). 
 
13. Measures 
Clinical Assessments 
The proposed measures were successfully employed in previous ketamine studies where the rationale for their 
implementation was discussed in great detail (J. H. Krystal, et al., 1994). 
 
Assessments and Ratings  
1) Medical Assessments:  Physical examination (including vital sign determination) and clinical laboratories 
(discussed in greater detail previously) will be completed at the first visit. Urine toxicology screen and 
breathalyzer will be performed on the morning of each infusion day, and the results will be determined before 


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proceeding with the infusions. The subject will not receive ketamine on the day if urine toxicology results are 
positive for any illicit drugs (except marijuana) or if his/her breathalyzer is positive for alcohol. A pregnancy test 
will also be administered to all reproductive age females enrolled in the study prior to participation. 
      
2) Psychiatric Assessments:  Ratings are performed by trained research assistants at the WHVA whose 
performance is evaluated routinely in inter-rater reliability sessions.  Administration of clinical measures is 
supervised by the primary investigator. Each of the psychiatric assessment instruments is briefly described 
below. 
1. Montgomery- Åsberg Depression Rating Scale (MADRS): The MADRS is a standardized instrument to 
ascertain depressed mood and neurovegetative signs and symptoms of a major depressive episode. 
2. Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR): The QIDS-SR is a patient-
rated depression instrument. 
3. Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a standardized instrument to evaluate anxiety 
severity. 
4. Clinical Global Impressions Scale (CGI): The CGI is a widely-used instrument which assesses overall 
severity of illness on a 1 to 7 point scale with 1 indicating “normal, not at all ill” and 7 indicating “among 
the most extremely ill patients.”  It also assesses global improvement on a 1-to-7 point scale with 1 
indicating “very much improved,” 4 indicating “no change” and 7 indicating “very much worse.” 
5. Brief Psychotic Rating Scale (BPRS): The BPRS is a standardized instrument that contains scales 
assessing psychotic symptoms including positive and negative symptoms, activation and emotional 
distress. 
6. Clinician-Administered Dissociative States Scale (CADSS): The CADSS has self and interviewer-
administered items including 5 subscales, generated a priori, evaluating dissociation including altered 
environmental perception, time perception, spatial/body perception, derealization and memory 
impairment. 
7. Visual Analog Scale (VAS) of Mood States: The VAS includes scales for anxiety, drowsiness, high 
irritability, anger and sadness.  The scales are 100 mm lines marked by subjects at a point 
corresponding to the apparent intensity of the feeling state (0 = none, to 100 = most ever). 
8. Time Line Follow Back (TLFB): The TLFB is a standardized measure utilized for collecting information 
on daily alcohol use as well as other substance use 
9. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS has both lifetime/recent and since last 
visit versions.  The “Lifetime/Recent” version gathers information on lifetime history of suicidality and 
recent suicidal ideation/self-injurious behavior.  The “Since Last Visit” version of the C-SSRS asks 
about any suicidal thoughts or behaviors the subject has exhibited since the last time administered the 
C-SSRS.  
10. Obsessive Compulsive Drinking Scale (OCDS): The OCDS is a self-report measure of craving which 
consists of two subscales that measure obsessions and compulsions associated with craving for 
alcohol.  
11. Quality of life enjoyment and satisfaction survey (Q-LES-Q): The Q-LES-Q is a self-report measure of 
quality of life.  
12. Yale Craving Scale (YCS): The YCS will measure acute alcohol cravings. 
13. Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar): The CIWA-Ar is a reliable and 
valid 10-item assessment for monitoring alcohol withdrawal symptoms. 
14. Drug Abuse Potential Scale (DAPS): The DAPS will be used to assess abuse liability of study drugs. 
 
3) Termination Criteria:  If a subject develops active suicidal and/or homicidal plan during the protocol, he or 
she will be terminated from the study, and, based on a risk assessment performed by a licensed psychiatrist, 
will be observed in the most appropriate milieu, e.g. psychiatric emergency room and/or inpatient psychiatric 
unit, until the suicidality and/or homicidality resolves. All data on such subjects will be carried forward in an 
intention-to-treat analysis (see “Data Analysis” below for additional details).   
      
14. Power Analysis 
A power analysis was performed using the comparison of means from two independent samples. The 
published randomized placebo-controlled trials of 0.5mg/kg ketamine administered to treatment-resistant 


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depressed subjects with unipolar depression (Berman, et al., 2000; John H Krystal, et al., 1994; Valentine, et 
al., 2011; Zarate, et al., 2006) and bipolar depression (Diazgranados, et al., 2010) were used for this 
calculation. These studies all had moderate-to-large effect sizes. At 72 hours post-infusion, we calculated a 
minimum sample size of 18 subjects (at an α=0.05 and β=0.8) for a minimal detectable difference of 6 
Hamilton Depression Rating Scale points considering a 6 point standard deviation. 
 
15. Data Analysis 
Study data will be collected and managed using REDCap electronic data capture tools hosted at VA CT 
Healthcare System. REDCap (Research Electronic Data Capture) is a secure, web-based application designed 
to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external sources 
 
 
 All continuous outcomes will be summarized descriptively and assessed for normality prior to analysis using 
normal probability plots and Kolmogorov test statistics. Transformations or nonparametric analyses will be 
performed as necessary.  
1) Specific Aim 1 (MDD): Our primary analysis will be to compare the proportions of subjects with clinical 
response, measured by the MADRS between the ketamine and midazolam groups at the end-of-treatment time 
point (Day 21, visit 6, T+240 minutes) using chi-square tests. All primary analyses will be intent-to-treat. For 
missing data, we will perform sensitivity analyses where response status is determined based on multiple 
imputations of the outcome to check the robustness of the results. As a secondary analysis we will use 
generalized linear mixed models for repeated binary data with medication condition as a between-subject 
factor, assessment time-point as a within-subject factor, logit link and subject as a clustering factor. This 
analysis will include all available data on an individual across assessment time points, does not require data 
imputation and will provide a test of the group and time main effects and the group by time interaction. In the 
primary analysis we expect to see significantly higher response rate in the ketamine group compared to the 
midazolam group. In the secondary analysis we expect both significant group effect and significant group by 
time effect.  
2) Specific Aim 2 (AUD): Our primary analysis will be to compare the proportions of subjects with complete 
abstinence, measured by the TLFB between the ketamine and midazolam groups during the 4-week treatment 
(Day 28) using the same approach as outlined for specific aim 1. In the primary analysis we expect to see 
significantly higher abstinence rate in the ketamine group compared to the midazolam group. In the secondary 
analysis we expect both significant group effect and significant group by time effect.  
3) Exploratory Aim 3: Alcohol craving, measured by the YCS, will be compared between medication conditions 
using linear mixed models with treatment (ketamine vs. midazolam) as a between-subject factor, time point as 
a within-subject factor and subject as a clustering factor. The best-fitting variance-covariance structure will be 
selected based on Schwartz’ Bayesian Information criterion. A significant treatment main effect and possibly a 
treatment by time interaction, where alcohol craving is reduced during ketamine vs. midazolam, will be 
supportive of our hypothesis.  
4) Exploratory Aim 4: Suicidal ideation, measured by the C-SSRS Suicidal Ideation category scores, will be 
compared between medication conditions using the same approach as outlined for exploratory aim 3. A 
significant treatment main effect and possibly a treatment by time interaction, where suicidal ideation is 
reduced during ketamine vs. midazolam, will be supportive of our hypothesis.  
5) Exploratory Aim 5: Safety measures (adverse events profile) will be compared between medication 
conditions using Fisher’s exact tests (ketamine vs. midazolam). 
 
 
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