Clinical trial NCT01657760
Conditions: Alcohol Dependence
Keywords: craving dopamine citalopram ssri
Sponsor: VA Office of Research and Development
Start date: 2014-05-01; Completion date: 2017-09-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Alcohol use disorders (AUDs) are highly prevalent among U.S. civilians, and even more prevalent in the U.S. Veteran population. AUDs are frequently co-morbid with depressive symptoms in psychiatric clinical populations, resulting in an increased severity of both conditions. Indeed, returning Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) Veterans have extraordinarily high rates of alcohol misuse and co-morbid psychiatric symptoms, indicating that future Veteran clinical populations will be particularly affected by AUDs. While FDA-approved medications are available to treat AUDs, their efficacy is low compared to available psychosocial treatments. Despite the lack of evidence for efficacy from controlled trials, antidepressants are frequently prescribed to clinical populations (including Veterans) with active AUDs. A better understanding of patient-level clinical variables that may confer poor response to treatment with antidepressants would allow clinicians better tools to distinguish those alcohol-dependent Veterans likely to do worse with antidepressant treatment.

Detailed description:
Description of Proposed Study A. Scientific Basis: Alcohol abuse and dependence represent a spectrum of maladaptive behaviors with enormous public health impact, especially for the U.S. Veteran population. Depressive symptoms are frequently comorbid with alcohol use disorders, but despite the frequent use of serotonin reuptake inhibitors (SSRIs) in clinical practice, clinical trials with these agents for alcohol use disorders have yielded mixed results concerning their impact on drinking behavior.

The characterization of alcohol-dependent subjects on the basis of demographic variables, severity of addiction, and psychiatric symptomatology has revealed a divergence in response to treatment with SSRIs among different subtypes of alcoholics (less severe "Type A" vs. more severe "Type B" alcohol dependence. Type A alcoholics have exhibited a trend toward decreased drinking behavior in clinical trials with SSRIs, whereas type B alcoholics showed a trend in the opposite direction. The literature does not offer an explanation for this divergence, and therefore, it is not clear how these research findings can be applied clinically.

As intravenous (iv) citalopram infusion (40 mg) bypasses hepatic metabolism, a single infusion produces a clinically relevant concentration in human brain, and the brain concentration remains stable for up to 4 h post-infusion, and is well-tolerated. A single infusion reduces striatal dopamine receptor binding potential by a magnitude comparable to the effect of chronic oral citalopram treatment, as measured by positron emission tomography (PET). The subjective experience of craving for alcohol in alcohol-dependent individuals has been associated with decreased dopamine receptor availability in the striatum via PET.

Significance of the research: Alcohol abuse and dependence occur at a higher rate in Veterans than in the overall U.S. population, and the presence of comorbid depressive symptoms amplifies the health risks to affected Veterans. While FDA-approved medications are available to treat alcohol dependence, their overall efficacy is low compared to available psychosocial treatments. Given that SSRIs are frequently utilized in Veteran populations with depressive symptoms and alcohol use disorders, there is the certainty that many Veterans with Type B alcohol dependence are receiving a pharmacological intervention that may exacerbate their drinking behavior, thereby increasing morbidity. A better understanding of patient-level clinical variables that may confer poor response to treatment with SSRIs would allow clinicians better tools to distinguish those alcohol-dependent Veterans likely to do worse, and prevent what was intended to be a beneficial medical intervention from worsening a Veteran's clinical course. This research is well-suited to a Veteran population because of the high proportion of Veterans with alcohol dependence.

C. Program Objectives: The nominee has a strong background in clinical addiction psychiatry, and he seeks to accomplish two objectives through the proposed training program: 1) to become an expert in the field of human alcohol addiction research, and 2) to learn techniques of PET research. The nominee's work environment at the West Los Angeles Veterans Administration Medical Center (WLAVA), in collaboration with colleagues at UCLA provides an ideal infrastructure for this training. He will be mentored by renowned experts in these areas, Drs. Arthur Brody, and Edythe London. The mentors have several NIH and VA grant-funded ongoing studies in alcohol and other addictive disorders research with strong ties to the VA PET research infrastructure. As part of training, the nominee will attend several courses and workshops at UCLA in foundational neuroimaging topics with relevance to PET (statistics, neuroimaging, neuroanatomy), as well as courses in the neurobiological bases of addiction. He will also attend annual conferences in Alcohol Dependence (Research Society on Alcoholism annual meeting) and neuroimaging (e.g., Society for Nuclear Medicine annual meeting), and meet with mentors regularly. The nominee plans to submit an NIH R01 and/or VA Merit Review grant toward the end of the award period. Long term, he plans to found an independent research career studying neuropharmacological approaches to treating and understanding substance use disorders, focusing primarily on alcohol.

D. Project Design and Methods: This project proposes to study 20 individuals in each of 3 groups (Type A alcohol dependence, Type B alcohol dependence, and healthy control subjects) for a double-blinded, placebo-controlled, within-subjects, outpatient study with iv citalopram (40 mg and saline, in counter-balanced order) and \[18F\]fallypride PET scanning. Participants should be in good physical health, have no history of complicated alcohol withdrawal symptoms (e.g., seizures, delirium tremens), be 21-55 years of age, and taking no psychoactive medications. Typology among alcohol-dependent subjects will be assessed after Kampman et al. (2007). The project aims: 1) To determine whether iv citalopram (40 mg) affects measures of craving for alcohol compared to a blinded saline iv control infusion; 2) to determine the change in striatal dopamine receptor D2/3 receptor availability (measured as binding potential for the radiotracer) with iv citalopram (40 mg) as compared to iv saline by \[18F\]fallypride PET scanning; and 3) to assess whether changes in striatal D2/3 receptor availability with iv citalopram (40 mg, compared to iv saline control) is related to measures of craving for alcohol among subjects.

E. Description of Intervention(s)/Treatment(s): Through Internet advertising, interested participants will be invited to call a phone number for anonymous phone screening, and individuals who pass phone screening will be invited to the WLAVA for a screening visit. Potential subjects will meet criteria for alcohol dependence (via SCID; except for control subjects), will have no current psychotropic medication use, will be in good physical health (as assessed by clinical history and physical examination and laboratory assay), and have no current dependence on other substances of abuse (SCID; aside from nicotine). After screening, qualified participants will be invited to participate in a structural magnetic resonance imaging (sMRI scan) for PET scan registration purposes, and two day-long experimental sessions at WLAVA, where they will undergo infusions with iv citalopram (40 mg and saline, double blinded); at least one week will separate infusion days to allow for participants to return to baseline functioning between sessions. After each infusion, participants will undergo \~30 min of paper- and computer-based questionnaires designed to assess measures of mood and other psychiatric symptoms, and \~15 min of assessment of both baseline and cue-induced craving for alcohol. Subsequently, participants will undergo \[18F\]fallypride PET scanning (\~2h) to assess striatal D2/3 receptor availability. After completion of both infusions and PET scans, participants will be discharged from the study. Participants will be compensated for their participation according to VA research guidelines.

Arms: arm 1: Intravenous saline control, in a double-blind, crossover study, with infusion days at least 2 weeks apart. arm 2: 40 mg citalopram in 250 ml saline infused over 1 hour, in a double-blind, crossover study, with infusion days at least 2 weeks apart.
Interventions: intervention 1: citalopram
Intervention descriptions: intervention 1: citalopram, 40 mg IV, vs. saline control, each to be administered in a double-blinded, within-subjects design.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Research Protocol: Citalopram Effects on Craving and Striatal Dopamine 
Availability in Alcohol Dependence 
Todd Zorick MD PhD 
April 27, 2012 


 
 
Research Protocol: Citalopram Effects on Craving and Striatal Dopamine 
Availability in Alcohol Dependence 
A. 
Introduction 
Alcohol abuse and dependence represent a spectrum of maladaptive behaviors with 
enormous public health impact, especially for the U.S. veteran population (Calhoun et al, 2008). 
Depressive symptoms are frequently comorbid with alcohol use disorders, and the use of 
serotonin reuptake inhibitors (SSRIs) to treat these symptoms is common in clinical practice 
(Nunes and Levin, 2004).  Clinical trials with SSRIs for alcohol use disorders, however, have 
yielded mixed results concerning their impact on drinking behavior (Nunes and Levin, 2004; 
Kenna, 2010).  
The characterization of alcohol-dependent subjects on the basis of demographic 
variables, severity of addiction, and psychiatric symptomatology has revealed a divergence in 
response to treatment with SSRIs among different subtypes of alcoholics (less severe “Type A” 
vs. more severe “Type B” alcohol dependence; Kampman et al., 2007). Type A alcoholics 
exhibit a trend toward decreased drinking behavior in clinical trials with SSRIs, whereas type B 
alcoholics show a trend in the opposite direction (Kampman et al., 2007). The literature does not 
offer an explanation for this divergence, and therefore, it is not clear how these research 
findings can be applied clinically.   
Citalopram is an SSRI that is commonly used as a first-line medication for the treatment 
of depression (Bezchlibnyk-Butler et al., 2000).  Intravenous (iv) citalopram infusion (40 mg) 
bypasses hepatic metabolism, and a single infusion is well tolerated and produces a clinically 
relevant concentration of the medication in the human brain (Smith et al., 2009). A single 
infusion reduces striatal dopamine (DA) receptor availability (presumably through an action to 
increase intrasynaptic dopamine) by a magnitude comparable to the effect of chronic oral 
citalopram treatment, as measured by positron emission tomography (PET) (Smith et al., 2009). 
The subjective experience of craving for alcohol in alcohol-dependent individuals has been 
associated with decreased dopamine receptor availability in the striatum, as demonstrated with 
PET imaging (Heinz et al., 2004).  
In the proposed project, we will examine the effect of the SSRI citalopram on 
intrasynaptic DA concentration using PET in participants with alcohol dependence.  Specifically, 
20 research volunteers in each of 3 groups (Type A alcohol dependence, Type B alcohol 
dependence, and healthy control subjects) will be recruited for a double-blinded, placebo-
controlled, within-subjects, outpatient study with iv citalopram (40 mg and saline, in counter-
balanced order) and [18F]fallypride PET scanning. Typology among alcohol-dependent subjects 
will be assessed post hoc as in Pettinati et al. (2000).  
The goal of the project is to assess whether SSRI effects on drinking behavior in 
alcoholic subtypes is mediated by altering the level of craving for alcohol and/or via changes in 
intrasynaptic dopamine in the striatum. Results of this study will have clinical importance in the 
treatment of alcohol dependence, by providing an increased understanding of the 
neuropsychopharmacology of practical treatment options for this condition in Veteran clinical 
populations. 
B. 
Methods 
B.1. Summary of experimental design. This project proposes to study 20 completing 
individuals in each of 3 groups (Type A alcohol dependence, Type B alcohol dependence, and 
healthy control subjects) for a double-blinded, placebo-controlled, within-subjects, outpatient 
study with iv citalopram (40 mg and saline, in counter-balanced order) and [18F]fallypride PET 
scanning. Participants will be non-treatment seeking. Participants will be in good physical 


 
health, have no history of complicated alcohol withdrawal symptoms (e.g., seizures, delirium 
tremens), be 21-55 years of age, and taking no psychoactive medications. Typology among 
alcohol-dependent subjects will be assessed as per Pettinati et al. (2000). U.S. Veterans will be 
encouraged to participate in the study, and are expected to be highly represented in the enrolled 
participants, given that alcohol dependence is more common among Veterans than in the U.S. 
civilian population. 
After screening, qualified participants will be undergo a structural MRI (sMRI) scan at the 
Greater Los Angeles VA Medical Center, which will be used for co-registration of subsequently 
obtained PET images. Participants will then have two separate procedure days on which they 
will receive a double-blinded iv infusion of one of the two test compounds (citalopram 40 mg or 
saline control, counter balanced). Participants will be randomly assigned to either condition on 
the first procedure day. After each infusion, participants will undergo ~15 min of assessment of 
both baseline and cue-induced craving for alcohol, followed by ~45 min of paper- and computer-
based questionnaires designed to assess measures of mood and other psychiatric symptoms. 
Subsequently, participants will undergo [18F]fallypride PET scanning (~90min) to assess striatal 
D2/3 receptor availability. After PET scanning on the first procedure day, participants will be sent 
home, with at least one week separating procedure days to allow for washout of first test 
compound and radiotracer. Participants will then return to the VA for the second procedure day, 
with the second test compound infusion (citalopram 40 mg or saline control, opposite of first 
procedure day) and PET scan. After completion of both infusions and PET scans, participants 
will be discharged from the study. 
B.2. Participants 
Note: To comply with VA-funded research guidelines, potential study participants will be 
restricted to U.S. Veterans. 
B.2.1. Selection criteria for alcohol dependent subjects. Initial selection criteria for 
alcohol-dependent subjects will be consistent with Kampman et al. (2007).  
Inclusion criteria are: (1) age between 21 and 55; (2) meeting DSM-IV diagnostic criteria 
for alcohol dependence; (3) report drinking at least 48 standard drinks in a 30-day period, during 
the 90 days before enrollment, and must have had at least 2 days of heavy drinking (at least 5 
drinks/day for men, 4 drinks/day for women) in the last 30 days.  
Exclusion criteria are: (1) current treatment for alcohol problems or a history of treatment 
in the 30 days before enrollment or are treatment seeking; (2) a current (last 12 months) DSM-
IV diagnosis of dependence on any psychoactive substances other than alcohol and nicotine. 
B.2.2. Initial Screening criteria for typology in alcohol dependent subjects. In order to 
provide for approximately equal numbers of participants in the Type A and B groups a priori, 
alcohol dependent participants will be enrolled in the study following the criteria of Kampman et 
al. (2007). However, final typological classification for all alcohol dependent participants will be 
conducted post hoc with K-means clustering of clinical and demographic variables for potential 
participants following an updated protocol based upon the original classification of Babor et al. 
(1992; Pettinati et al., 2000). Type B alcohol dependence will be conditionally classified as those 
who: drink more than 12 drinks per day on average for males, 10 for females over the last 90 
days prior to study, and have at least one of the following: 1. Age of onset of alcohol 
dependence prior to age 25; 2. A HAM-D score of greater than or equal to 14 at study entry; 3. 
Meeting three or more childhood criteria for Antisocial Personality Disorder. Alcohol dependent 
participants during screening and recruitment who are not provisionally classified as Type B will 
be provisionally classified as Type A (Kampman et al., 2007), again pending final post hoc 
typological clustering, at which time all participants will be assigned to their correct typological 
grouping (Babor et al., 1992; Pettinati et al., 2000).  


 
B.2.3. Post hoc final typological classification. Given that the diagnostic criteria for Type 
A vs. Type B classification used in screening may have some level of diagnostic uncertainty with 
regard to the original definition based upon statistical clustering, post hoc K-means clustering 
will be performed on all alcohol dependent subjects after study completion, utilizing a 
streamlined version of the typological procedure to ensure accuracy of typological classification 
(Pettinati et al., 2000). This updated procedure has shown to produce identical results to the 
method of Babor et al. (1992), while utilizing only validated rating scales as input measures 
(Pettinati et al., 2000). Specifically, information from thirteen separate intake assessment data 
sources will be standardized to a common metric range, and then K-means cluster analysis will 
be performed on these data from all randomized participants, using SAS software, (Babor et al., 
1992; Brown et al., 1994; Pettinati et al., 2000). The assessments utilized will be (after Pettinati 
et al., 2000):  
(1) Addiction Severity Index (ASI; McClellan et al., 1992), number of first degree 
relatives with current or past alcohol problems;  
(2) Number of childhood conduct disorder problems as determined by the SCID-II 
Antisocial Personality Disorder module;  
(3) Life Change Index score for “life crisis level” based on lifetime psychosocial stressors 
(Holmes, 1967);  
(4) ASI Alcohol Composite score;  
(5) ASI Drug Composite score;  
(6) Obsessive-Compulsive Drinking Scale score (Anton et al., 1996);  
(7) Average number of drinks per drinking day, last 90 days by Time Line Follow Back 
(TLFB; Sobell, 1992);  
(8) Short Michigan Alcohol Screening Test score (MAST; Selzer et al., 1975);  
(9) Medical ASI Composite score;  
(10) Legal ASI Composite score;  
(11) Family ASI Composite Score;  
(12) Psychiatric ASI Composite score;  
(13) 24-item baseline HAM-D score. 
B.2.4. Selection criteria for healthy control subjects:  
(1) age between 21 and 55;  
(2) no Axis I DSM-IV diagnosis (except for nicotine dependence);  
(3) report drinking less than 10 drinks weekly over the past 90 days prior to study entry 
by TLFB.  
Exclusion criteria are:  
(1) Any history of treatment for alcohol or other substance use disorders;  
(2) any history of DSM-IV diagnosis of dependence on any psychoactive substances 
other than nicotine;  
(3) any history of DSM-IV diagnosis of Axis I mental illness.  
B.2.5. Exclusion criteria for all subjects:  
(1) a current (last 12 months) DSM-IV diagnosis of schizophrenia, bipolar disorder, other 
psychotic disorder, eating disorder, panic disorder with or without agoraphobia;  
(2) current use of psychoactive drugs, other than occasional marijuana use (< 3 uses per 
week), as determined by a positive urine screen for narcotics, amphetamines, or sedative 
hypnotics;  
(3) serious alcohol withdrawal symptoms as indicated by a score > 10 on the Clinical 
Institute Withdrawal Assessment for Alcohol-Revised (CIWA);  
(4) clinically significant physical abnormalities as indicated by physical examination, 
hematological laboratory assay, or urinalysis, defined as: hematology and chemistry laboratory 
tests that are within normal (+/- 10%) limits with the following exceptions:  a) liver function tests 


 
(total bilirubin, ALT, AST, and alkaline phosphatase) < 3 x the upper limit of normal, and b) 
kidney function tests (creatinine and BUN) < 2 x the upper limit of normal; 
(5) A screening ECG that demonstrates anything other than normal sinus rhythm, normal 
conduction, and no clinically significant arrhythmias; 
(6) history of epilepsy, seizures, or severe head trauma;  
(7) history of alcohol intoxication delirium, alcohol withdrawal delirium or seizure, 
alcohol-induced persisting dementia, or alcohol-induced psychosis;  
(8) treatment with any of the following medications within the last 30 days prior to 
randomization: antidepressants, anti-convulsants, hypnotics, antipsychotics, psychomotor 
stimulants,  anti-anxiety agents, or cimetidine;  
(9) previous treatment with citalopram discontinued due to an adverse event;  
(10) pregnancy, nursing, or refusal to use reliable barrier method of birth control, if 
female;  
(11) the presence of metal fragments, pacemaker, or other ferromagnetic material which 
would prevent safe completion of an MRI scan;  
(12) Recent history of radiation exposure which would make exposure to radiation from 
serial PET scans contraindicated;  
(13) Non-zero breath-alcohol level on screening. We will exclude participants who 
present to study appointments intoxicated, as active alcohol intoxication may interact 
unpredictably with citalopram and produce unreliable results in assessments of mood or alcohol 
craving (e.g. Ray and Hutchison, 2007; Ray et al., 2011; see preliminary data C.2. above); 
(14) Resting vital signs on any study visit outside of acceptable parameters:  Pulse of 
50-105 bpm, Blood pressures of 90-160 mm Hg systolic, 55-100 mm Hg diastolic; 
(15) Any indication of suicidal ideation (i.e. as assessed by question 9 on the BDI-II), or 
elevated index of depressive symptoms, as evidenced by BDI-II score of ≥20; 
(16) Presence in the body of a metal device (e.g., pacemaker, infusion pump, aneurysm 
clip, metal prosthesis or plate) that could either interfere with the acquisition of the MRI scan of 
the brain or for whom the MRI scan would pose a potential risk will be excluded. 
(16)Radiation exposure:  Participation in any other research study involving exposure to 
ionizing radiation in the past year if the total cumulative exposure from the past research studies 
and the current research study would exceed the limits described by the FDA in 21 CFR 361.1.  
Specifically, the total cumulative dose to the whole body, active blood-forming organs, lens of 
the eye, and gonads must remain below 5 rems, and the cumulated dose to all other organs 
must remain below 15 rems over the last year.   
(17)Baseline QT prolongation (QTc> 455 ms): Given that citalopram has been found to 
be associated with a dose-dependent risk of ECG QT interval prolongation, in order to avoid the 
potential risk of causing ventricular arrhythmias including Torsades de Pointes, we will exclude 
participants from the study who exhibit baseline QTc prolongation. 
B.2.6. Criteria for Discontinuation Following Initiation 
1. Positive urine drug screen or breath test indicating use of cocaine, methamphetamine, 
alcohol, opiates, or other abused drugs on any study day; 
2. Inability to comply with study procedures; 
3. Meet discontinuation criteria due to severe side effects from citalopram infusion; 
4. BDI-II score of 20 or greater and/or indicating any suicidal thoughts. 
5. Vital signs outside of acceptable range: SBP <90 or >160 mm Hg, DBP <55 or >100 mm Hg, or 
P <50 or >105 bpm. 
6. CIWA score of >10 on any testing day. 
B.2.7. Gender, minority, and child representations. Both men and women of all ethnic 
backgrounds will be recruited for this project. Generally, about 70% of alcohol dependent 
individuals are men. Research shows no gender differences in cue reactivity for alcohol 


 
(Rubonis et al., 1994; Ray and Hutchison, 2004). However, studies of gender differences on 
alcohol-related variables in response to iv citalopram have not been reported. Thus, we will 
conduct analysis of gender differences.  We will encourage participation of all ethnicities and 
racial minorities, and anticipate a diverse participant population (See section E, Human Subjects 
for more details). Children will not be studied because the safety of citalopram for alcohol use in 
children/adolescents has not been demonstrated, and alcohol is illegal for individuals under the 
age of 21 in the state of California. 
B.3. Procedures 
B.3.1. Recruitment and informed consent procedures. Participants will be recruited from 
the community through advertisements, such as flyers and advertisements on the internet (e.g., 
Craigslist). These procedures have been used successfully to recruit alcohol dependent 
individuals in previous studies with heavy alcohol drinkers by the consultant, Dr. Lara Ray (Ray 
and Hutchison, 2007; Ray et al., 2007; Ray et al., 2011). The ads will target non-treatment 
seeking alcohol-dependent and healthy control men and women.    
People who call about the study will receive an individual telephone screen for self-
reported inclusion and exclusion criteria and the nature of the study will be further explained. 
Treatment-seeking individuals will be provided an appropriate referral. Those who appear 
eligible will be scheduled for an appointment with our staff for an in-person screening session in 
which we will obtain a medical history and physical exam, administer a battery of individual 
differences measures, and complete a psychiatric diagnostic interview. A separate consent form 
will be used for the medical screening. If, after completing the medical history and diagnostic 
interviews the potential participant still appears eligible, the study will be fully explained 
including all aspects of procedures, potential side effects, and those who continue to be 
interested will have blood drawn and a urine sample collected for the laboratory tests outlined 
for medical eligibility. The P.I. will review each participant’s screening results and if those 
preclude participation, the individual will be telephoned and the reason why the participant 
cannot continue in the study will be explained.  
B.3.2. Incentives for participation. Per VA research guidelines, participants will be 
compensated for their participation. Recruits will receive $50 for participating in the initial 
screening interview, since it requires approximately four hours plus blood and urine samples. 
Participants will be paid $40 for the sMRI scan, $50 for each of the laboratory infusion sessions 
(i.e., citalopram or saline infusion followed by mood and cue-reactivity assessment), up to $30 
each for computer tasks to be done after infusions, $100 for each PET scan, plus a $50 bonus 
for completing the entire study. Therefore, completing participants may receive up to $500. 
B.4. Citalopram Infusions. 
B.4.1. General procedures. Participants will be blinded for infusions (citalopram and 
saline). Infusions will occur in the VA West Los Angeles CRC, on the 3rd floor of the hospital. VA 
pharmacy staff will provide double-blind study compound on infusion days. An intravenous line 
will be placed using sterile technique by CRC nursing staff, and citalopram (40 mg or saline 
control in 250 ml saline) will be infused via perfusion pump over 1h, after Smith et al. (2009). 
The P.I., a board-certified psychiatrist, will be present during all infusions to monitor for any 
physical or psychiatric side effects.  
B.4.2. Medical monitoring.  All infusions will be monitored by the P.I. Participants will be 
given a 24-hour telephone number for calling the P.I. to discuss side effects which may arise 
subsequent to infusion days, and office hours will be available as needed. All participants will 
meet with the P.I. on infusion days to review side effects, discuss ways to manage possible side 
effects, and to assess for possible complications.  
B.5. Assessments: Interviews and Questionnaires 


 
B.5.1. Screening measures. The following will be used to screen for inclusion and 
exclusion criteria: 
(1) Alcohol dependence and other psychiatric diagnoses will be assessed 
using the Structured Clinical Interview for DSM-IV (SCID-IV; First et al., 1995) in 
order to determine inclusion based on diagnostic criteria. Additionally, age of onset of 
alcohol dependence and additional axis I DSM-IV diagnoses will be recorded. 
Research Assistants (RAs, with at least bachelor-level education) will receive formal 
training on the sensitivity and specificity of psychiatric diagnoses and the SCID 
algorithm by rating 10 video interviews (www.scid4.com). To ensure inter-rater 
reliability, ratings will be compared against expert or "Gold Standard" ratings and an 
overall kappa of .85 across the 10 videos must be achieved prior to participating in 
SCID administration.  RAs will be observed annually by the P.I., and together they 
will co-rate a live interview to avoid rater drift. Every diagnostic evaluation will be 
discussed in a weekly meeting led by the P.I. 
(2) A medical history form to screen for medical conditions that contraindicate 
taking citalopram. The P.I. will review each participant’s history along with laboratory 
tests. 
(3) Physical examination form conducted by the P.I. includes a 
comprehensive physical exam, vital signs, weight, and review of medical systems. 
(4) Blood and urine samples will be collected to assess: (a) blood LFTs, (b) 
urine drug screen, (c) blood chemistry screen (including assays for potassium and 
magnesium) (e) urine pregnancy screen (females only). All tests will be conducted by 
the hospital laboratory. A urine pregnancy test will also be conducted immediately 
prior to each procedure day.  
(5) ECG: a clinical electrocardiogram will be performed as part of the intake 
physical exam (see exclusion criteria above). 
(6) To ensure that participants are not seeking treatment, they will be asked 
whether they want to receive any treatment now or have received any treatment for 
alcohol problems (including formal treatment and/or use of self-help groups) in the 
past 30 days, and will be excluded for positive answers. 
(7) Screening questions about quantity and frequency of drinking will be 
assessed using the 90-day Time Line Follow Back (TLFB), (Sobell and Brown, 
1996). 
(8) Depression: the Hamilton Rating Scale for Depression (HAM-D 17) is a 
17-item measure of depressive symptoms, previously used in studies of 
pharmacotherapies for alcoholism (e.g., Kampman et al., 2007; Pettinati et al., 2000);  
(9) MRI Safety Screen: A 1 page questionnaire to screen for any potential 
risk factors for MRI, including metal implants, fragments, pacemaker, etc. 
B.5.2.  Measures of baseline alcohol and drug use at Screening 
(1) The 90-day TLFB interview (Sobell et al., 1980) is a calendar-assisted 
self-report method with high reliability and validity that will be used to obtain a 
detailed baseline of quantity and frequency of drinking.  
(2) The Alcohol Dependence Scale (ADS; Skinner and Allen, 1982) will be 
used to assess severity of alcohol dependence at baseline. This 25-item scale 
measures alcohol dependence symptoms over the past 12-months and has been 
shown to contain items that are relevant for alcohol dependent drinkers (Kahler et al., 
2003).   
(3) Addiction Severity Index (ASI-lite): The ASI-lite is the interviewer's 
estimate of the severity of the subject's status in seven areas (medical, 
employment, drug use, alcohol use, legal, family/social, and psychological).  


 
The Lite version is a shorter version of the ASI that retains all questions used 
to calculate the ASI composite scores.  
(4) Obsessive-Compulsive Alcohol Disorder scale (Anton et al., 1996). 
Information from this validated instrument will be used to determine post hoc Type 
A/B cluster membership for alcohol dependent participants. 
(5) Short Michigan Alcohol Screening Test (Selzer et al., 1975). Information 
from this validated instrument will be used to determine post hoc Type A/B cluster 
membership for alcohol dependent participants. 
B.5.3. Other individual differences measures at screening 
(1) Demographic information will be collected, including age, gender, 
ethnicity, education level, and employment. 
(2) Current smoking will be assessed by asking (a) number of cigarettes per 
day and use of any other form of tobacco, and (b) the Fagerstrom Test for Nicotine 
Dependence (FTND; Heatherton et al., 1991). Although not directly related to any 
aim, this measure will be investigated for possible interaction with the effects of 
citalopram, and as dependent measures in their own right given findings that 
medication affecting drinking behavior and urge to drink often also affects tobacco 
use and nicotine craving (e.g., Ray et al., 2007). 
(3) Conduct disorder symptoms and adult antisocial personality disorder 
symptoms will be assessed using the Antisocial Personality Disorder Module of the 
Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II; First et al., 
1997). 
(4) The Cognitive Reflection Test (Frederick et al, 2005) is a 3-item 
questionnaire designed to assess the degree to which a participant relies on 
impulsive cognitive styles for routine tasks, which has been shown to be largely 
uncorrelated to measured IQ or scholastic achievement testing. 
(5) Barratt Impulsivity Scale (BIS-II; Patton et al, 1995): This is a 30-item 
questionnaire that is self-administered during screening. The questionnaire assesses 
trait measures of impulsivity, broken up into attentional, motor, and non-planning 
domains. 
(6) Delay Discounting Task (~5-8 min): Subjects are given a number of 
choices between smaller, immediate rewards, and larger, delayed rewards. The 
results provide an estimate of how steeply individuals discount the future value of 
money compared to their estimation of the present value. Rates of delay discounting 
(DD) have been demonstrated to be independent of measured IQ. An increased rate 
of DD (signifying a steeper discounting of the future value of money) has been 
observed in alcoholics, heroin addicts, cocaine addicts, smokers, and pathological 
gamblers; 
(7) Satisficing/Maximizing Behavior Assessment: (Schwartz et al., 2003) A 
survey measuring the extent to which participants explore different options while 
making decisions. 
(8) Life Change Index score for “life crisis level” based on lifetime psychosocial 
stressors (Holmes, 1967), which will be used to determine alcohol dependence 
typology in alcohol-dependent participants. 
B.5.4.  Baseline and repeated assessments. The following measures will be 
administered at baseline and then prior to procedures on every procedure day. 
(1) Breath Alcohol assessment via breathalyzer, and urine drug screen (with 
urine pregnancy test for female participants). 


 
(2) Drinking behavior: the TLFB (Sobell et al., 1980) will be the primary 
measure of prior drinking behavior in the study.  
(3)  Beck Depression Inventory, Revised (BDI-II) is a 22-item measure of 
depressive symptomatology, widely used in psychological research and practice.   
(4) Brief Symptom Inventory (BSI) is a 53-item measure of global psychiatric 
symptomatology, used in psychiatric research to assess for psychiatric symptoms. 
(5) Alcohol craving: the Penn Alcohol Craving Scale (PACS) is a 5-item, self-
report measure of craving for alcohol during the previous week (Flannery et al., 
1999). 
(6) Clinical Institute for Withdrawal from Alcohol scale (CIWA): This is a 10-
item rater-administered scale which assesses for common signs and symptoms of 
alcohol withdrawal. Participants who score ≥10 on any study day will be excluded 
from the study and referred immediately for medical treatment (See exclusion 
criteria, above). 
(7) Adverse Events:  An adverse event (AE) is defined as any reaction, side 
effect, or untoward event that occurs during the course of the clinical trial, whether or 
not the event is considered related to the study medications.  For this study, AEs will 
include events reported by the subject, as well as clinically significant abnormal 
findings on physical examination or laboratory evaluations.  Clinically significant blood 
pressure elevations and changes in psychiatric symptomatology (including suicidal 
ideation) will be classified as AEs.  If an AE is reported to study personnel that requires 
medical attention, it will be reported to a study physician immediately.  Study 
physicians will assess subjects for any medical or psychiatric side effects.  All AEs will 
be recorded on an adverse event case record form that is updated at least weekly. 
Unresolved AEs will be assessed daily by study personnel starting as soon as subjects 
give informed consent.   
B.5.5. Magnetic Resonance Imaging Protocol   
An MRI scan of the brain will be obtained prior to infusion procedures, on a 1.5-T 
scanner (Signa; GE Medical Systems, Milwaukee, WI) in the same building as the 
CRC and PET scanner, in order to aid in localization of regions on the PET scans.  
The MRI will have the following specifications: three-dimensional Fourier-transform 
(3DFT) spoiled-gradient-recalled acquisition with TR=30ms, TE=7ms, 30 degree 
angle, 2 acquisitions, 256 x 192 view matrix.  The MRI scanning procedure typically 
lasts ~ 30 minutes.  The acquired volume will be reconstructed as roughly 90 
contiguous 1.5-mm thick transaxial slices. 
B.5.6. Infusion assessments.  
(1) Profile of Mood States (POMS), short version. A self-report questionnaire 
that measures dimensions of affect or mood.  It consists of 65 adjectives to which the 
client responds according to a 5-point scale ranging from ‘not at all’ to ‘extremely’. 
The POMS will assess changes in mood states from pre- to post- infusion (McNair et 
al., 1971).  
(2) Alcohol Urge Questionnaire (AUQ). The AUQ is an 8-item scale where 
subjects rate their craving for alcohol at the present moment. Participants will be 
asked to use a 7-point Likert scale expressing agreement with statements such as “I 
crave a drink right now.” The AUQ is appropriate for use in laboratory investigations 
examining state levels of urge to drink (Bohn et al., 1995; Mackillop, 2006). 
(3) Heart rate and blood pressure will be measured prior to infusion, and 1 
hour after infusion, to ensure that vital signs remain within safety parameters (see 
B.2.5. above.)    


 
B 5.7.  Cue reactivity assessment (CR) 
CR Procedures. (~15 min total time) In this trial, the CR will follow each of the 
intravenous infusions (i.e., citalopram 40 mg or saline control). Specifically, participants will 
receive standardized instructions about the assessment while becoming acclimated to the 
laboratory and psychophysiological monitors. Sessions will begin with a 3-minute relaxation 
period, in which participants are asked to sit quietly and do nothing. Participants will then hold 
and smell a glass of water for 3 minutes as a standard procedure to control for the effects of 
simple exposure to any potable liquid, followed by another 3-minute relaxation period. Next, the 
participant will hold and smell a glass of a preferred alcoholic beverage for three 3-minute trials. 
During each trial, the participant will be asked to sniff the beverage for 5 seconds each time a 
tone sounds: 13 tones sound during each 3-minute block of time with variable intervals to 
ensure that all receive the same olfactory exposure. Order is not counterbalanced because of 
carryover effects that are known to occur (Monti et al., 1987) and that would interfere with 
determination of CR. The water trial provides a baseline that controls for all aspects of stimuli 
and movement except the nature of the beverage.  
CR Measures. After every 3 minutes of exposure, each participant will rate his/her urge 
to drink alcohol level on an 7-point Likert scale via the AUQ, from “no urge at all” to “extremely 
strong urge.” The term urge to drink is explained to the participant as “want, desire, craving, 
thirst for, or wish to drink.” Urges ratings will be the primary outcome variable for Specific Aim 2.   
B.5.8. Post-Infusion Assessment of Mood, Personality, and Decision-Making 
These assessments will occur over approximately 45 min, immediately after the CR 
measures described above. The following assessments will be administered by the RA: 
(1) Delay Discounting Task (~5-8 min): Subjects are given a number of choices between 
smaller, immediate rewards, and larger, delayed rewards. The results provide an estimate of 
how steeply individuals discount the future value of money compared to their estimation of the 
present value. Rates of delay discounting (DD) have been demonstrated to be independent of 
measured IQ. An increased rate of DD (signifying a steeper discounting of the future value of 
money) has been observed in alcoholics, heroin addicts, cocaine addicts, smokers, and 
pathological gamblers. 
(2) Simple Reversal Learning Task (SRLT, ~10 min): Participants perform a simple 
categorization task with reversal stages. Participants learn to make one of two key-press 
responses to a set of abstract visual patterns on the basis of trial-by-trial feedback. Participants 
are trained on stimuli that have varying numbers of trials before reversal, and reversals occur 
throughout most of the training sessions, but not all, in order to make them unpredictable. 
Subjects view the stimuli (which are novel visual patterns) and must make a key press.  
Immediately after the response, feedback will appear on the screen: “correct”, “incorrect”, or a 
“no response recorded” message if no response is made within the response window. In order 
to minimize the effect of practice on performance, we will use different sets of stimuli in each 
test run. Performance on RLTs has been shown to be sensitive to serotonergic pharmacology. 
(3) Loss Aversion Gambling task (LAG, ~10 min): Participants will first be presented with 
a possible gamble (i.e., “Would you choose $10 for sure or a 50% chance to win $25?”) and asked 
to judge whether they would accept the gamble by pressing one of two keys.  Participants will 
receive one of several stipend types, plus an incentive-compatible payment depending upon their 
choices during the decision making task and the outcome of relevant chance gambles.  Although 
some gambles will entail the possibility of monetary loss, no participant will ever experience actual 
monetary loss during the task. The total money that a participant could win in this task is $15. 
(4) Balloon Analogue Risk Task (BART, ~10-12 min): The BART is a computer based 
assessment of risk taking behavior. A subject uses a computer mouse to click a balloon pump 
that inflates a balloon on the screen. Subjects are informed that the objective of the task is to 
get the largest amount of money possible while avoiding balloon explosions. Participants are not 


 
given any detailed information about the probability of the balloon exploding. Each pump of the 
balloon without an explosion places money into a money reserve. Should the subject pop their 
balloon they lose all money and another balloon appears. At any time during a trial the subject 
can click "collect money" and transfer all money from a temporary bank account to a permanent 
account where a new total is updated. Participants may earn up to $15 based upon their 
performance in this task. 
B.7. PET Scan Acquisition and Analysis 
After the collection of the measures of mood state and decision-making on infusion days, 
participants will be escorted to the basement of the hospital where the PET scan is located.  
CR-induced craving for alcohol quickly subsides after a peak ~6 min into the CR procedure 
(Monti et al., 1993). Given that > 45 min will have elapsed between the end of the cue-induced 
craving session and the beginning of the PET scanning procedures (which includes ~30 min of 
mood state assessments), CR procedures will not affect the results of subsequent PET 
scanning (~90 min duration); indeed, alcohol CR-induced craving in alcohol dependent subjects 
has previously been shown to produce no change in subsequent PET scan signals, compared 
to a non-CR baseline (Lingford-Hughes et al., 2006).  [18F]fallypride will be synthesized in the 
Cyclotron Facility of the VA by procedures currently in use for ongoing studies. [18F]fallypride will 
be synthesized via nucleophilic substitution of tosyl-fallypride with [18F]fluoride ion, supported by 
Investigational New Drug (IND) Application no.78,226 to Dr. London. Each batch of radiotracer 
will be tested for quality control including (radiochemical purity, specific activity, apyrogenicity). 
After placement in the PET scanner, participants will be given a bolus injection of 
[18F]fallypride (~5 mCi in 30 sec). PET scans will be obtained on a Philips GEMINI TruFlight 
Positron Emission Tomography and Computed Tomography (CT) system (Philips Medical 
Systems, Eindhoven, Netherlands), with CT scans being acquired for attenuation correction.  
Scans will be acquired in the 3-dimensional mode, with the scanner having a diameter of 90 cm 
and an axial field of view set to 18 cm.  The transverse and axial resolutions of this scanner are 
4.8 mm at the center.  Scans will be acquired as series of 8 10-min frames with a short break for 
participant comfort (~90 minutes total time).   
[18F]fallypride will be prepared and administered by an established method (Mukherjee 
et al., 1995), as in previous and ongoing studies by Dr. London (e.g., Lee et al., 2009; see 
preliminary data C.5.). 
PET analysis will be performed using ROIs drawn on MRIs by a trained research 
assistants using a Macintosh-based software program (PACE) that has been used in many 
clinical studies (e.g., Brody et al., 2010). ROIs will be reviewed in team meetings with the 
mentors, Dr. Brody and Dr. London.  Based on prior reports and our preliminary studies, ROIs 
will include the dorsal and ventral caudate (Cd) and dorsal and ventral putamen, with the 
cerebellum being drawn as a reference region (Lee et al., 2009; Brody et al., 2010).  The dorsal 
and ventral halves of both Cd and putamen will be drawn in approximately 6 planes.  
Cerebellum will be drawn in approximately 14 planes.  ROIs transferred onto PET from MRI will 
be visually inspected to ensure no gross misalignments of the co-registered images.  Hand 
drawn ROIs have been shown to have consistent findings between those drawn on MRI and 
transferred to PET and those drawn directly on [18F]fallypride PET images (Lee et al, 2009; 
Brody et al., 2010). 
B.8. Statistical Methodology 
The distributions of raw and change scores (for clinical rating scales and ROI measures) 
will be examined for suitability for parametric analyses.  Analysis of PET data will be performed 
for binding potential (BP) in the two primary ROIs, where BP = CROI/Ccerebellum – 1 with C = mean 
counts, and the two primary ROIs are the ventral Cd and putamen.  The same calculations will 
also be performed for the dorsal Cd and putamen, which are easily visible on [18F]fallypride 


 
scans.  Statistical calculations will be performed using the software package SAS (v. 9.2; SAS 
Institute Inc., 2008). 
B.9. Sample Size Power Calculation.  
The group sample sizes for this study (n=20 each of Type A, Type B, and healthy 
controls) were chosen based upon the following statistical considerations, in order to have an 
adequately sized sample to be able to detect a group difference given expected experimental 
differences in the context of expected variance in the data. Power analyses were conducted to 
determine the sample size needed to achieve a power of 0.80 at a two-tailed alpha level of 0.05, 
utilizing Java Applets for Power and Sample Size software (Lenth, 2009).  
B.9.1. Aim 1. Decreased dopamine D2/3 receptor availability with citalopram in Type B 
alcoholics compared to healthy control subjects. Based upon data from Smith et al. (2009), a 
single dose of iv citalopram (40 mg) resulted in a decrease in striatal dopamine receptor 
availability from 3.81+/-0.29 to 3.64+/-0.27 (mean +/- s.d.) compared to placebo. Given that the 
difference to be observed between groups would be of a comparable magnitude, with a similar 
variance, adequate power to detect a group difference is achieved with sample sizes of n=16. 
B.9.2. Aim 2. Craving with citalopram will be increased in Type B alcoholics compared to 
healthy control subjects. Based on data from section C.1. (Zorick et al., 2011b) from 
methamphetamine-dependent individuals who had a poor response to the SSRI sertraline, we 
expect increased craving for alcohol in Type B alcoholics taking who receive an SSRI compared 
to those who receive placebo. Given the magnitude of the 1st week difference in craving in the 
methamphetamine study, and the sample variances of the levels of craving for the population 
(4.2±1.5 vs. 3.1±2.1 for worse-sertraline vs. placebo; Visual Analogue Scale craving score (0-10 
range) ± s.d.), adequate power to detect a similarly sized group difference with similarly sized 
variances is achieved with sample sizes of n=14 each.  
B.9.3. Aim 3. Striatal dopamine D2/3 receptor availability in Type B alcoholics will be 
correlated to measures of craving for alcohol after citalopram infusion. Based upon data from 
Heinz et al. (2004), for the correlation of striatal dopamine receptor availability and craving for 
alcohol in alcohol-dependent individuals of -0.9, adequate power to detect a correlation at least 
as strong as that observed is achieved with a sample size of n=12.   
B.10. Data Analysis Plan 
In order to examine the study hypotheses of group differences and treatment effects, 
statistical analyses will be conducted using SAS software. K-means clustering for final group 
membership of all study participants will be performed on the 13 individual data sources 
discussed in B.2.3 above. Briefly, scores from all instruments will be normalized to a common 
metric range to avoid overrepresentation of any individual score, and then data on all 13 
instruments will be utilized in a K-means clustering algorithm (Babor et al., 1992; Pettinati et al., 
2000).  
Aim 1: To determine change in striatal dopamine receptor D2/3 receptor availability 
(measured with the radiotracer [18F]fallypride and PET scanning) from before to after iv 
citalopram (40 mg, compared to iv saline control) among different subject groups. Similar to 
prior research (see sections C3-5, preliminary data), dopamine D2/3 receptor availability from 
hand-drawn ROIs will be extracted from striatal regions using the cerebellum as a reference 
tissue. For group comparisons, a mixed linear procedure will be utilized that represents a 
generalization of the standard linear model (GLM) procedure, such that the data are allowed to 
exhibit correlation and non-constant variability. The mixed linear model permits the modeling not 
only the means of the data, but their variances and covariances as well. This approach is 
consistent with that of Kampman et al. (2007) and with our previous work in pharmacotherapy 
studies for addictive disorders (e.g., Zorick et al., 2009). Demographic variables which differ 
between groups (e.g., age, gender, smoking status, lifetime drinking history) will be utilized as 
covariates.  


 
Aim 2: To test the effect of citalopram (40 mg iv vs. saline iv control) on measures of 
alcohol craving and mood among different subject groups. A MANOVA will be performed, using 
changes in craving and mood assessments as dependent variables, and group membership 
(Type A/B or control) as an independent variable.  Demographic and laboratory variables (such 
as age, smoking status, gender, lifetime drinking history) will be compared between groups, and 
will be used as nuisance covariates, if there are group differences in these variables.  Post-hoc 
t-tests will be used to determine which independent variables account for significant findings.   
Aim 3: To assess whether changes in striatal D2/3 receptor availability with iv citalopram 
(40 mg, compared to iv saline control) are related to measures of craving for alcohol. For 
correlations, Pearson’s moment correlation will be performed using SAS with adjustment for 
covariates that may differ between study groups (such as age, smoking status, gender, lifetime 
drinking history). Region-specific dopamine D2/3 receptor availability in each participant in each 
study condition will be correlated with the VAS measure of cue-induced alcohol craving. 
B.11. Timeline of Proposed Activities 
Based upon prior experience with recruitment of subjects for studies of addictive 
behaviors, we anticipate that we will have a 60% drop out rate for alcohol-dependent 
participants, and about a 50% drop out rate for healthy control subjects. This estimated rate of 
study non-completion includes those recruited individuals who pass phone screening who either 
fail the medical safety screen (for active medical issues, e.g.), who drop out for procedural 
reasons (i.e. illicit drug use during the study), who voluntarily withdraw their participation for 
personal reasons, or any other reason. Therefore, to achieve the final goal of 40 completed 
alcohol-dependent participants (20 each Type A and Type B), we anticipate screening 100 
participants, and to achieve the final goal of 20 completed healthy control participants, we 
anticipate screening 40.  
 
Table B.11. Timeline for Study Activities. Abbreviations: Alcohol-Dependent Participants: 
AD; Healthy Control Participants: HC.  
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5  
Totals 
Screened 
10AD/4HC 
20AD/8HC 
32AD/16HC 
16AD/4HC 
8AD/4HC 
100AD/ 
40HC 
Completed 
4AD/2HC 
8AD/4HC 
16AD/8HC 
8AD/4HC 
4AD/2HC 
40AD/ 
20HC 
Ongoing 
Activities 
IRB 
Approval/ 
Education 
and Training 
first 6 
months 
Data 
fidelity 
checks and 
preliminary 
analyses 
Data fidelity 
checks and 
presentation 
of 
preliminary 
findings at 
conferences 
Data 
analysis 
and 
manuscript 
preparation 
Manuscript 
submission 
and future 
grant 
writing, last 
6 months 
 
 
 
 


 
C. Human Subjects Participation 
C.1.1. Subject Participation Overview: 20 completing subjects will be recruited in each of 3 
subject groups (20 Type A and 20 Type B alcohol dependent subjects, along with 20 healthy 
control subjects) for this 5-year study.  Recruitment will be accomplished by using flyers, print 
ads, and radio advertisements. These media will direct potential participants to call a phone 
number for additional information if they are interested in participating. 
Those who call the toll-free number will be informed about the general requirements of the 
study.  Appointments for face-to-face screening interviews will be scheduled for those who 
maintain interest. During these screening interviews, participants will read the informed consent 
document and discuss any questions or concerns they have with research staff, including the 
P.I. Participants who remain interested in taking part will sign the consent document. At several 
times during this screening process, participants will be informed that treatment is available and 
referrals will be provided if desired. Enrolled participants who meet the inclusion criteria will be 
scheduled for a session of structural MRI scanning (~1 h; see Table C.1.).  
C.1.2. Procedures (see Table C.1.): Research subjects will enter the study upon 
completion of an interview and questionnaires on drug use history and a screening evaluation, 
which will include a comprehensive medical history, physical examination, EKG testing, and 
laboratory blood and urine screening.  They must provide urine samples negative for any illicit 
substance and report no current or prior drug dependence (other than nicotine dependence). 
We will collect a urine sample for drug testing, and test for alcohol breath level in each 
participant immediately after we receive informed consent.  Urine samples will also be collected 
on procedure days for all subjects to screen for cocaine, amphetamine, MA, opiates, 
cannabinoids, and benzodiazepines.   
We will also assess for evidence of possible psychiatric disorders, status of 
neuropsychological functioning, and current use of medications.  During the study, they will be 
required to refrain from illicit and prescription drug use; compliance will be confirmed with urine 
drug screen and breath alcohol level testing on all procedure days. Prior to each procedure day 
subjects will be asked to remain abstinent from alcohol and other illicit substances. 
On infusion days, participants will be escorted to the VA WLA Clinical Research Center 
(CRC) for infusions and assessment of mood and craving. On each infusion day, each subject 
will participate in a study arm with citalopram 40 mg iv or matched saline control infusion, 
double-blinded. The second infusion day will occur at least 1 week after completion of the first 
infusion. After infusion of each test compound (citalopram 40 mg or saline, iv), subjects will self-
rate alcohol craving, followed by a 15 min session to elicit measures of alcohol cue-induced 
craving. Next, participants will answer a series of paper- and computer-based questionnaires 
about their mood state that will last about 30 min. Subsequently, participants will be escorted to 
the VA PET facility (in the basement of the same building as the CRC) for PET scanning with 
[18F]fallypride (~90 min). 
 
Table C.1. Timeline for Study Procedures 
Study Day 
 
Procedures 
Intake  
Consent, eligibility, SCID, Medical History and Physical (~4 h) 
Participants released to the community 
sMRI Scanning 
Structural MRI scanning (~1 h). 
Participants released to community 
Infusion day 1 (40 mg citalopram or saline, iv) 
Test compound 1 
IV infusion over 1 h. 
Craving Assessment 
      
Baseline and cue-induced craving for alcohol assessment 
(~15 min)  


 
 
Participants released to community >1 week 
Infusion day 2 (40 mg citalopram or saline, iv), opposite of test compound 1 
Test compound 2 
IV infusion over 1 h. 
Craving Assessment 
      
Baseline and cue-induced craving for alcohol assessment 
(~15 min)  
Mood, Personality, Decision-Making 
State Testing 
Paper and computer-based questionnaires and tasks (~45 
min) 
[18F]fallypride PET Scan 2 
~90 min 
  Participants will be discharged from the study after completion of Infusion day 2  
 
Nausea, headache, fatigue, and tachycardia may be side effects of citalopram. High doses 
of citalopram have been associated with a risk of ECG QTc prolongation, and concomitant risk 
of ventricular arrthymias, including Torsades de Pointes. To minimize the risk associated with 
citalopram administration, the study procedures include a plan for careful participant 
assessment and monitoring.  A medical screening will be conducted that consists of a history 
and physical, baseline ECG, as well as blood tests including hematology, chemistry, renal and 
hepatic function tests.  In order to qualify for the study, participants must have vital signs that fall 
within the acceptable range, must have a normal ECG and baseline QTc<455 ms, and 
participants must continue to meet inclusion criteria to remain in the study (see section B.2.5. 
above for vital signs criteria).  
Participants will also have blood samples taken for RPR, HIV and Hepatitis C testing, and 
will also have a PPD placed during medical screening, to be read by CRC nursing staff in 48-72 
h. If subjects are PPD positive, a chest x-ray will be performed to rule out active pulmonary 
lesions indicative of active tuberculosis  
Participants will be required to refrain from illicit and prescription drug use for the duration 
of the study and this will be confirmed with urine toxicology testing on testing days.  Participants 
will be required to refrain from drinking on testing/procedure days during the study, and this will 
be confirmed by breath alcohol testing on testing days. 
Caffeine will be restricted on study days for least 2 h prior to infusion days and MRI scan 
day. Participants will be permitted to drink their normal daily intake of caffeine, given the caveat 
above. Cigarette smoking will be permitted during the study.  The incorporation of smoke breaks 
during testing days assures that acute nicotine withdrawal does not negatively impact 
performance on cognitive tests or neuroimaging. 
C.2. Characteristics of Subjects 
C.2.1. Number of subjects: Over the course of the project, a total of 100 alcohol-dependent 
subjects and 40 healthy control subjects will be recruited as potential participants, with the final 
sample (with complete data) to be 20 subjects in each group (Type A and B alcohol-dependent, 
and healthy control subjects). We estimate that about 60% of the alcohol-dependent participants 
we enroll will either voluntarily leave the study, wash out, or be lost to follow up during the study; 
and, that roughly 50% of the healthy control participants enrolled will go on to complete the 
study. Based upon the study’s location at the West Los Angeles VA, Veterans will be recruited 
as participants, and will be expected to be highly represented in the study population. 
C.2.2. Gender and ethnicity: Alcohol dependence is more common among men than 
women, but we intend to recruit a representative sample of the population for the study. Minority 
subjects are expected to be represented at about 40% based upon prior studies with substance 
using populations in the West LA area.  
Mood, Personality, Decision-Making 
State Testing 
Paper and computer-based questionnaires and tasks (~45 
min) 
[18F]fallypride PET Scan 1 
~90 min 


 
C.2.3. Age range: Subjects will be between the ages of 21 and 55 years old, as the target 
population is adults with histories of alcohol dependence, and to avoid age- and alcohol-related 
cognitive changes in older individuals. 
C.2.4. Health status: Potential subjects will be those individuals who are in adequate 
health to permit their participation in study procedures without likelihood of experiencing undue 
harms or risks (see Inclusion Criteria, Exclusion Criteria and Criteria for Discontinuation above). 
C.3. Sources of Research Material Obtained from Human Subjects 
C.3.1. Specimens and safety measurements: Blood and urine will be taken for laboratory 
tests, and blood pressure, heart rate, and oral temperature will be measured upon admission 
and on each procedure day.  Blood samples and urine samples for laboratory examination will 
be disposed of in standard fashion.   
c.3.2. Mood and craving state assessment: Participants will complete several pen and 
paper and computer-based questionnaires to assess their current mood state and levels of 
craving for alcohol on procedure days. Computerized data will be stored on a laptop computer 
and backed up to a main database in the Brody lab.  Other behavioral measurements and paper 
questionnaires will be stored for entry into the Brody lab computer database using double entry 
for accuracy.  
C.3.3. Structural Magnetic Resonance Imaging:  Participants will complete an sMRI scan 
for use in PET scan co-registration. Electronic images from the scan will be transferred to the 
Brody lab imaging database. 
C.3.4. Positron Emission Tomography: Participants will undergo PET scanning with 
[18F]fallypride as a radiotracer. Electronic images of the time evolution of radiotracer binding will 
be transferred to the Brody lab imaging database for storage. 
C.3.5. Medical records and data: Clinical features that characterize each subject’s alcohol 
use history and details of their personal history will be recorded. These data will be obtained 
through the SCID to determine diagnoses, and the Time Line Follow Back (Sobell et al., 1996). 
Demographic data (age, ethnicity, gender) and general medical data (other medical diagnoses, 
non-psychotropic medications, etc.) will also be recorded. Subjects will complete at intake and 
on infusion days the Beck Depression Inventory (BDI-II), a 21-item self-report inventory that 
focuses on subjective feelings of depression.  
C.3.6. Maintenance and security of research material: The research material obtained will 
be data in the form of digital images and coded files, which will be used for further analysis.  
Risks to confidentiality from the proposed research will be minimized by using a coding system 
for all data collected, with personal identifying information kept in a secure area accessible only 
to the investigators.  Results of measurements and tests will be stored as data that are 
associated with a unique subject identification number; one CD will be retained on-site in a 
locked office accessible to the P.I. (Dr. Zorick), and mentor (Dr. Brody) and the other is kept in a 
secure, off-site location for backup, accessible to the P.I. and the co-investigators. After 
processing, all data are exported into spreadsheets. All clinical data are scored, transferred to a 
summary sheet, and then entered into a database system on a local area network keyed to the 
same unique identification number, and to be used specifically for research purposes per 
authorization of the P.I. exclusively.   
C.4. Recruitment of Subjects and Consent Procedures 
C.4.1. Recruitment, Screening and Enrollment: We will recruit non-treatment-seeking 
subjects from the greater Los Angeles area by newspaper, Internet, and radio advertisements 
and flyers. In telephone interviews, we will describe the study and obtain information about 
subject eligibility.  Veterans will be particularly encouraged to enroll, and are expected to be 
highly represented in the subject population. Volunteers who meet initial criteria will be invited to 
read the consent form and if willing to participate, give informed consent, as approved by the VA 


 
Institutional Review Board (IRB).  After providing informed consent, subjects will undergo an 
evaluation that will include physical examination and medical history, psychiatric diagnostic 
interview, self-report questionnaires, and urine and blood tests.   
C.4.2. Consent procedures:  The consent form, outlining procedures, potential risks and 
anticipated benefits, right to withdraw, and confidentiality, will be read to each participant, 
allowing time for questions. During the recruitment and consent process, participants will be told 
about a Certificate of Confidentiality obtained from NIDA under PL 94-255, which limits the 
collected data from being used in any criminal or legal proceedings. If the subject agrees to 
participate, two consent forms will be signed by both the study participant and the principal 
investigator, indicating a mutual understanding of the purpose of the study and confidentiality 
precautions. The study participant will be provided with a signed copy of the consent form, 
which will contain contact addresses and telephone numbers for the investigators and the VA 
IRB. 
C.4.3. IRB approval:  All procedures proposed in this study will be approved by the VA 
IRB. The equipment and methods to be utilized have been employed in several VA- and NIDA-
supported projects. All participants will receive a copy of the Subject’s Bill of Rights prior to 
giving consent to participate. 
C.5. Potential Risks to Subjects 
C.5.1. Risk of blood sampling during screening:  When having blood drawn participants 
may experience some discomfort as a result of the needle prick in the arm. Some bruising or 
slight bleeding may occur. Although infection is possible, it is extremely rare, because the 
needle is sterile and disposable. Occasionally, people feel lightheaded or faint when blood is 
drawn, but the volume taken will be small (around 10 ml per blood draw). 
C.5.2. Risk of abstinence from alcohol:  Initiating acute abstinence from alcohol in alcohol-
dependent individuals can cause serious withdrawal symptoms, which may include behavioral 
agitation, hypertension, lowered seizure threshold, and in severe cases, delirium tremens.  
Therefore, we will exclude subjects with a history of severe alcohol withdrawal symptoms, or 
active severe alcohol withdrawal symptoms (see exclusion criteria above).  
C.5.3. Risks of intravenous saline infusions: When having an intravenous line placed, 
some discomfort, bruising, or bleeding may occur. With intravenous saline infusions, infiltration 
of the intravenous line site is possible, which can result in swelling, pain, inflammation, and 
localized cellulitis or superficial thrombophebitis.   
C.5.4. Risks of citalopram administration: Based upon randomized controlled trials, the 
following side effects have been to occur more frequently in individuals taking citalopram than in 
placebo-treated individuals (in order of declining frequency): nausea, dry mouth, somnolence, 
insomnia, dizziness, diarrhea, tremor, and sexual side effects (including ejaculatory delay, 
decreased libido, and impotence). Postmarketing surveillance of pooled analyses of short-term 
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs 
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and 
young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric 
disorders. As a result, the FDA has included the following “black box” warning in the package 
insert of all serotonergic antidepressants prescribed to patients in the US: 
Suicidality and Antidepressant Drugs 
Antidepressants increased the risk compared to placebo of suicidal 
thinking and behavior (suicidality) in children, adolescents, and young 
adults in short-term studies of major depressive disorder (MDD) and other 
psychiatric disorders. Anyone considering the use of citalopram or any 
other antidepressant in a child, adolescent, or young adult must balance 
this risk with the clinical need. Short-term studies did not show an increase 


 
in the risk of suicidality with antidepressants compared to placebo in adults 
beyond age 24; there was a reduction in risk with antidepressants 
compared to placebo in adults aged 65 and older. Depression and certain 
other psychiatric disorders are themselves associated with increases in the 
risk of suicide. Patients of all ages who are started on antidepressant 
therapy should be monitored appropriately and observed closely for clinical 
worsening, suicidality, or unusual changes in behavior. Families and 
caregivers should be advised of the need for close observation and 
communication with the prescriber. Citalopram is not approved for use in 
pediatric patients.  
 
The SCID-IV will be used on all subjects to exclude those with any active Axis I clinical 
disorder (except alcohol and nicotine dependence), in order to reduce the possibility that 
participants with active mood disorders will receive study procedures. Also, all participants will 
be screened with the BDI-II on screening and all procedure days, and those individuals with 
suicidal thoughts and/or elevated depression scores will be excluded from further study 
participation (see exclusion criteria above).   
Based upon evidence from post-marketing surveillance, the FDA found that citalopram is 
associated with a dose-dependent prolongation of the ECG QTc interval, which increases the 
risk for ventricular arrhythmias, including Torsade de Pointes. As a result, they released the 
following additional “black box” warning for healthcare professionals, originally on 8/24/11, and 
subsequently modified on 3/27/12: 
• 
Citalopram causes dose-dependent QT interval prolongation. Citalopram should no 
longer be prescribed at doses greater than 40 mg per day.  
• 
Citalopram should not be used in patients with congenital long QT syndrome.  
• 
Patients with congestive heart failure, bradyarrhythmias, or predisposition to 
hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher 
risk of developing Torsade de Pointes.  
• 
Hypokalemia and hypomagnesemia should be corrected before administering 
citalopram. Electrolytes should be monitored as clinically indicated.  
• 
Consider more frequent electrocardiogram (ECG) monitoring in patients with congestive 
heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the 
QT interval.  
• 
20 mg per day is the maximum recommended dose for patients with hepatic impairment, 
who are greater than 60 years of age, who are CYP 2C19 poor metabolizers, or who are 
taking concomitant cimetidine (Tagamet®), because these factors lead to increased 
blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de 
Pointes.  
• 
No dose adjustment is necessary for patients with mild or moderate renal impairment.  
• 
Advise patients to contact a healthcare professional immediately if they experience signs 
and symptoms of an abnormal heart rate or rhythm while taking citalopram.  
• 
Report adverse events involving citalopram to the FDA MedWatch program, using the 
information in the "Contact Us" box at the bottom of the page. 
 
In order to minimize the cardiac risk to participants, we will utilize only a single 40 mg dose 
of citalopram, and only to healthy participants between 21 and 55 years of age. All study 
participants will undergo an extensive medical screening procedure, which will include a full 
history and physical examination, including baseline ECG and laboratory studies, which will 
include assays for potassium and magnesium. Participants with any history of cardiac disease, 


 
arrhythmia, abnormal laboratory values, or abnormal screening ECG will be excluded from the 
study. Participants taking cimetidine will be excluded from the study. Participants with baseline 
QTc prolongation (QTc > 455 ms) will also be excluded from the study to minimize the risk of 
citalopram administration. 
C.5.5. Risk of MRI:  There are no known risks associated with the MRI scanning 
procedures; however, the magnetism of the machine does attract certain metals.  Therefore, if a 
subject would fail to make the investigator aware of the presence of such a device (e.g., cardiac 
pacemaker, artificial heart valve, implanted infusion pump, cochlear implant, spinal cord 
stimulator) in his or her body and were to be scanned, the magnetism could affect or stop the 
device from working properly. 
C.5.6. Risk of PET: The PET scan entails exposure to a small amount of radiation.  The 
maximum total amount of radiation per scan is 606 mrem.  The maximum radiation dose for the 
entire study (two PET scans) is 24% of the annual limit for those people who work with radiation 
(e.g., x-ray technicians, radiologists etc.).  The legal radiation limit for these people is 5000 
mrem/year.  The radiation dose received in this study is well below the levels that are thought to 
result in significant risk of harmful effects.  The radioactivity disappears very quickly; half of the 
radiation will disappear within 2 hours and the remainder will disappear within 24 hours.  
C.5.7. Psychological Risk:  The interview instruments request information of a personal 
nature; some respondents might experience embarrassment and unease because of items 
about medical conditions, health-related behaviors, or stigmatized behaviors such as alcohol or 
drug use. Subjects are forewarned of this remote possibility and notified that discomfort with 
questions may be dealt with by discussing the resultant discomfort with the P.I. to help resolve 
the issue or, in some cases, by declining to answer particularly troubling questions. 
During the MRI or PET scans, subjects may experience some anxiety or claustrophobia 
associated with confinement in the scan apparatus.  Both the MRI and PET scanning procedure 
requires that the subject be confined in a small, partially enclosed space. The sound of the MRI 
scanner can be loud, but will be reduced by special earplugs. The scan procedures may be 
boring or difficult.  All efforts will be made to assist the subject in remaining calm and as 
comfortable as possible. 
Testing in the CRC and the administration of rating scales are procedures with minimal 
risk to subjects. Typical risks associated with these procedures involve fatigue, boredom, and 
frustration. Subjects will be counseled to be prepared for the experience and encouraged to 
bring reading materials or other items that will help them pass the time.  
Participants may experience some symptoms from brief alcohol abstinence. These may 
include restlessness, anxiety, depressed mood, irritability, or difficulty concentrating. 
C.5.7. Risk Classification: Based on the procedures described, the overall risk of this 
research is classified as "more than minimal risk".  Based on the HHS/FDA Regulations (45 
CFR 46), a classification of "minimal risk" is given when the probability and magnitude of harm 
or discomfort anticipated in the research are not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of routine physical or psychological 
exams or tests. 
 
C.6. Procedures for Protecting against or Minimizing Potential Risks 
C.6.1. Safety Procedure Overview: Subjects will be fully informed of potential risks 
(described above), which has been considered and addressed in extensive previous human 
research. Attempts will be made to make the subject as comfortable as possible during his or 
her participation in the study. Attempts will be made to make the subject as physically 
comfortable as possible while undergoing laboratory and physical assessments and tests.  For 
example, a pillow and blanket will be provided when possible, as will refreshments following 


 
blood draws or before and after lengthy procedures.  Subjects will be told that they can request 
breaks when needed during assessments that can be interrupted without compromising results.   
To minimize the potential risk of exposure to a magnetic field, subjects will be queried as 
to whether they have any metals or devices (see above) implanted, and if so, will be excluded 
from participation.  Safety screening forms based on guidelines distributed by the International 
Society for Magnetic Resonance in Medicine will be used.  Subjects will also be informed of the 
consequences that could result in undergoing an MRI scan with such an implanted device 
present.  To minimize any potential for exposure of a fetus to low levels of magnetic activity, 
pregnant women will be excluded and fertile women will be required to use acceptable birth 
control methods as described above. 
To minimize the potential risk of exposure to the small amount of radiation from the PET 
scans, subjects will be queried as to their recent history (over the last year) of radiation 
exposure. Any individual indicating that they have received exposure to more than 5 rems of 
radiation over the last year will be excluded from the study. 
Risks associated with citalopram treatment will be minimized through careful assessment 
and monitoring.   Psychiatric screening will consist of a diagnostic interview with the SCID, and 
screening for depressive symptoms and suicidality with the BDI-II. Medical screening will consist 
of a history and physical exam, including ECG, and blood tests including hematology, chemistry, 
renal and hepatic function tests.  Subjects will be seen by P.I. on every infusion day to assess 
for possible side effects during the study. The duration of treatment with citalopram is extremely 
brief (only 1 dose of active compound, iv).   
The dose of citalopram chosen for the study (40 mg iv) is a standard therapeutic dose for a 
~75 kg human subject (Smith et al., 2009). Vital signs will be monitored on each procedure day 
for participants; participants with persistently elevated vital signs (>5 min. duration; see section 
C.6.2. below for criteria) will be withdrawn from the study.  
C.6.2. Safety Procedures: All trials conducted by both the Brody and London laboratories 
use a set of safety procedures to ensure safe participation during the research trial.  The P.I. 
assumes primary medical responsibility for each participant and personally evaluates any 
significant complaints, clinical adverse events, and abnormal laboratory findings. Weekly rounds 
are held with the full study team and the status of each participant is reviewed to assess 
medical and psychiatric safety, and data completion. Consistent monitoring of participant 
progress provides one level of safety procedures.  Another level of safety procedures involves 
evaluation of data collected (especially item 9 of the BDI-II that assesses suicidal intentions) 
and of verbal reports of suicidal and/or homicidal intent to staff members. Participants assessed 
by the P.I. at any point to be a danger to self or others or who are judged to be in grave danger 
due to extreme psychiatric problems will be discontinued from the study and connected with an 
appropriate treatment facility.  All staff receive training in identifying suicide/homicide risks 
and/or signs of intoxication and in following the steps needed to appropriately respond to these 
signs. Vital signs including heart rate and blood pressure will be checked on infusion day visits 
during the study. Any vital sign abnormalities during study visits meeting the criteria for high-risk 
cardiovascular status (see section B.2.5. above) will prompt immediate notification of the study 
physician who will assess the patient and take appropriate clinical action.  
C.6.3. Provisions for addressing risks and possible adverse effects: In addition to those 
measures to protect subjects noted above, careful clinical procedures will be followed to avoid 
any potential harm to subjects from possible adverse medical reactions or from study conditions 
such as infusion procedures in the CRC.  Subjects will be monitored closely by the medical staff 
upon induction into and throughout the study.  They will be withdrawn from participation if they 
show signs of serious adverse reactions that pose a threat to their physical or psychological 
health. In the unlikely event that a subject experiences a medical emergency, the VA CRC is 
fully prepared to respond to any situation that may arise. It is located on the third floor of the 
West Los Angeles VA Medical Center and is fully staffed with physicians and nurses.  The 


 
general and psychiatric emergency rooms are located two minutes away on the 1st floor of the 
hospital.  There is a 24-h medical Emergency Code team in the hospital. Physicians and nurses 
in the CRC are fully trained to respond to all types of medical and psychiatric emergencies. A 
fully equipped crash cart is located on the unit.  All potential risks will be thoroughly discussed 
with each subject during the pre-enrollment interview. 
C.6.4. Protection of Confidentiality: All patient information and identifying materials will 
remain confidential and will kept in locked storage locations and will be accessible only to 
authorized study personnel.  An HHS certificate of confidentiality will be obtained from NIDA 
which will further reduce the possibility of violations of patient confidentiality.  All of the staff 
have received required training in research ethics, including risks associated with breaches in 
confidentiality.  In addition, all staff members have received HIPAA training, further enhancing 
this aspect of patient protection. Patients are informed during the informed consent interview of 
the exceptions to confidentiality mandated by California state law, which include a study 
participant being deemed imminently suicidal or homicidal, or making statements alluding to 
their involvement in the perpetration of child or elder abuse.      
C.6.5. Reporting of Serious Adverse Events: The intervention being studied poses 
minimal-moderate safety risks to study participants, and there is a low probability of adverse 
events occurring given the careful assessments incorporated in the study design. The 
investigator will classify all adverse events as serious or non-serious and appropriate reporting 
procedures followed.  Serious Adverse Events (SAEs) are defined as any fatal event, any 
immediately life-threatening event, any permanent or substantially disabling event, any event 
that requires or prolongs inpatient hospitalization, or any congenital anomaly.  This category 
also includes any other important medical event that a study investigator judges to be serious 
because it may jeopardize the subject or require intervention to prevent one of the above 
reportable outcomes, or which would suggest a significant hazard, contraindication, side effect, 
or precaution. 
All investigators in this study will promptly report all SAEs to the VA Institutional Review 
Board. Expedited reporting of Serious Adverse Events to the VA IRB will adhere to the 
appropriate guidelines. 
C.6.6. Safety-Potential Risks for Participants: Overall, the risk in this study is “more than 
minimal.” This will be addressed in all consent/assent forms and IRB applications. During the 
consent process, clients are informed that they have the right to refuse to answer any question 
or to stop their participation in the study at any time.  Some client interviewees may experience 
anxiety or embarrassment when answering sensitive questions about alcohol and drug use 
history, treatment history, and related behaviors. The study staff will be trained to respond 
appropriately to subject safety issues. All research personnel will be able to provide local hotline 
and referral phone numbers where immediate help is available. 
C.6.7. HIPAA- Confidentiality/Privacy: Participants’ medical information obtained during the 
study is confidential, and disclosure to third parties is prohibited. Research personnel will 
complete HIPAA training, as well as training on the “Protection of Human Research Subjects” in 
order to ensure understanding and compliance with HIPAA and confidentiality requirements. All 
study personnel will be required to sign a confidentiality agreement, and certificate of 
confidentiality will be obtained from the Department of Health and Human Services. No medical 
information will be provided to any other person or agency except as required by law. Research 
records may be reviewed by Dr. Zorick and pertinent study personnel, the Veterans 
Administration and its contracted agents, and monitors or auditors or other agencies, such as 
the Department of Health and Human Services (DHHS).  Data from this study that are sent by 
mail and electronically to data repositories will be coded with initials and/or a number, and not 
the participants' names.  No identifying participant information, including names, will be 


 
disclosed in reports, publications or presentations. At the participant's request, medical 
information may be given to his/her personal physician.                                                                       
C.6.8. Data monitoring to ensure subject safety and confidentiality: None of the data 
collection procedures will present significant physical or psychological risks to the subjects. Data 
files on the medical histories of subjects will be kept in a locked file cabinet in the P.I.’s offices, 
accessible only to Todd Zorick, M.D., Ph.D. as needed. Electronic media (i.e., computer-stored 
data, and data stored on CDs) will be password-protected via encrypted code key known only to 
the senior study personnel. Furthermore, all subject information will be coded with a unique 
numerical identifier. Protections of privacy of subjects’ medical information will be described to 
the prospective subjects as part of the enrollment interview and the informed consent 
procedures. 
C.7. Possible Risks in Relation to Anticipated Benefits 
C.7.1 Benefits to subjects: This project is not a treatment study, and there are no 
anticipated physical, medical or psychological benefits associated with study participation. It is 
possible, however, that some subjects may experience some benefit from education about the 
effect of alcohol on their body while they are enrolled in the study.  It is also possible that 
subjects may, in some instances, benefit from the knowledge of their psychological, medical, 
and/or laboratory test results (i.e., medical disorder previously unknown to subject, detected 
through study participation).  
C.7.2. Potential risks: The major medical risks are those associated with abstinence from 
alcohol, exposure to citalopram, exposure to radioactivity as part of [18F]fallypride PET 
scanning, and strong magnetic fields as part of MRI scanning.  These risks are described 
above; substantial precautions will be taken to reduce these risks as much as possible. 
C.7.3. Benefits to society and to the knowledge base: Alcohol dependence is an enormous 
global public health problem.  The potential benefit to society, particularly to the component of 
society with alcohol dependence, from which some study participants will be drawn, is a better 
understanding of the response to pharmacological treatment seen in alcohol dependence and of 
the neurobiological bases for this disorder.  The results from this study may significantly improve 
our ability to identify and develop more effective treatments. As such, the benefits outweigh the 
risks. 
C.8. Data and Safety Monitoring Plan 
C.8.1. Responsibility for Data and Safety Monitoring: Over the past several years, research 
oversight bodies at all levels have expressed concern that the safety of subjects be an 
aggressive process conducted by the research team locally and by the sponsors of the research 
(typically a pharmaceutical company and/or NIH). The safety monitoring process at the WLA VA 
begins with the initial review of the protocol during the study development process. This review 
is conducted at multiple levels, including the FDA, VA research infrastructure, and the local IRB. 
Once the trial is initiated, the first and most aggressive action to monitor subject safety involves 
an initial medical evaluation and review of data forms (e.g., BDI) by research staff. The Principal 
Investigator and the mentors review these reports regularly and make recommendations about 
the safe participation of subjects while they are in the trial. Of course, if serious or unexpected 
adverse events occur during the trial, the Principal Investigator reports these occurrences within 
the specified time frames to the IRB, VA, and FDA as required.  
C.8.2. Frequency of Data Safety Monitoring: At least annually, the PI (Dr. Zorick) and 
primary mentor (Dr. Brody) will prepare the summary of all Adverse Events.  As the Principal 
Investigator, Dr. Zorick will be ultimately responsible of monitoring the safety and efficacy of this 
trial, executing the DSM plan, and complying with reporting requirements. 


 
C.8.3. Conflict of Interest: Neither the mentors nor Dr. Zorick have any financial 
relationships with any organization or corporation related to the study medication.  Additionally, 
Dr. Zorick will not be primarily responsible for the health care of the patients beyond ensuring 
adherence to the protocol and requirements of the study. At any time during the research, 
patients may ask for a second opinion about their care from another doctor who is in no way 
associated with the study.   
C.8.4. Safety monitoring activities for SAEs:  For the purpose of reporting to the VA IRB, 
serious adverse events include all adverse events meeting the FDA definition of serious, plus 
drug overdoses (from the pharmacological investigation under evaluation) that require medical 
intervention (regardless of severity), instances of suicidal ideation requiring therapeutic 
intervention, and illegal activity resulting in arrest, incarceration or harm to others.  In the 
assessment of serious adverse events, the local IRB, FDA, and VA administration will receive 
detailed descriptions that summarize all available information about each case.    
C.8.6. Communication plan to IRB, VA, and FDA (if applicable): As stipulated above, all 
reports of SAEs will be provided to the VA IRB, and the FDA (in applicable situations specific to 
effects of citalopram, or other study procedures).   
C.9. Inclusion of Women and Minorities: We will recruit women aggressively and plan to 
over-sample women in order to compensate for poor inclusion of women in research. Generally 
about 25% to 36% of alcohol dependent persons in the community are women, and that about 
33% of participants who enroll in studies similar to the ones proposed are women, so we expect 
about 33% women representation in the proposed study. 
Volunteers will be recruited without regard to race or ethnicity.  Racial and ethnic group 
participant will be based on the characteristics of the study population in the general Los 
Angeles area, which is highly diverse. Based upon similar types of studies conducted in West 
Los Angeles, we anticipate that ~60% of the participants will be Caucasian, ~25% will be African 
American, ~10% will be Asian/Pacific Islander, ~5% other racial groups (including Native 
American), with about ~30% of participants reporting Hispanic ethnicity. 
C.10. Inclusion of Children 
 
Children under the age of 21 will be excluded because drinking below that age is illegal 
in the state of California. 
 
        C.11. Study Timeline for Gender Recruitment 
First 6 months  
 
Prepare study manual; train staff and implement procedures 
Month 6 to Year 4 Month 6 
Enroll participants into the study and prepare preliminary results 
for conference presentations 
Last 6 months  
 
Complete data management, analyze data, and publish results 
 
 


 
 
 
Enrollment Table C.11. Projected Completed Participant Study Flow, Males/Females (Total) 
Year 
0-3 mo. 
3-6 mo. 
6-9 mo. 
9-12 mo. 
Yearly Total 
 
1 
00/00 (00)* 
00/00 (00)* 
02/01 (03) 
02/01 (03) 
04/02 (06) 
 
2 
02/01 (03) 
02/01 (03) 
02/01 (03) 
02/01 (03) 
08/04 (12) 
 
3 
04/02 (06) 
04/02 (06) 
04/02 (06) 
04/02 (06) 
16/08 (24) 
 
4 
02/01 (03) 
02/01 (03) 
02/01 (03) 
02/01 (03) 
08/04 (12) 
 
5 
02/01 (06) 
02/01 (03) 
00/00 (00) 
00/00 (00) 
04/02 (06) 
 
*Reflects start-up time. 
 
 
 
         Grant Total: 40/20 (60) 
 
 


 
 
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