Conditions: Schizophrenia Schizoaffective Disorder Schizophreniform Disorder Bipolar Disorder Severe Major Depression With Psychotic Features
Keywords: antipsychotic severe mental illness weight loss
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
This study is designed to look at the effects of naltrexone on weight loss in individuals treated with antipsychotic medications. Naltrexone is an FDA approved medication for the management of alcohol dependence and drug dependence, but has not been fully evaluated for its effect on weight loss in individuals with severe mental illness (i.e. schizophrenia, schizoaffective disorder, bipolar disorder etc.) The purpose of this study is to find out how effective two different doses of oral naltrexone is on reducing body weight when compared to placebo (an inactive substance or "sugar pill").

Detailed description:
Persons with severe mental illness (SMI) die, on average, 25 years earlier than the general population1. Most of this early mortality can be attributed to cardiovascular disease (CVD) and diabetes mellitus (DM), which are directly related to obesity. Obesity is a leading cause of preventable death in the United States, second only to smoking. The physical health of patients has become a major focus of schizophrenia care, as recent decades have seen immense gains in symptom control and community integration. There is an urgent need for the development of interventions that address the obesity crisis in schizophrenia.

Patients treated with antipsychotic medications have been shown to have a preference for diets high in fat and sugar. Patients with schizophrenia typically seek behaviors that increase dopamine mediated reward in the brain such as smoking and substance use, both of which occur more often in this group than the general population. The system might require intact dopamine and opioid function.

Naltrexone is an oral agent that competitively antagonizes all known opioid receptors in the brain. Human studies with naltrexone were completed in individuals with different illnesses, including schizophrenia, and have been shown to be a safe and easy agent to use. It is shown to decrease craving in alcoholics and is approved by the FDA for the treatment of alcohol dependence. Naltrexone is reported to decrease craving for other substances of abuse, like nicotine. Furthermore, it has been shown to prevent secondary weight gain due to cessation of cigarette smoking at low (25mg and 50 mg), but not higher doses. Naltrexone has been tested in human feeding studies, and has been shown to reduce both the quantity of food eaten and the choice of palatable foods.

Subjects will be randomized to either 25, 50 or 0mg of Naltrexone and will take the study medication daily for 52 weeks. Subjects will be seen weekly for the first 4 weeks of the study, thereafter they will be seen on a bi-weekly (every other week) basis to be assessed (i.e. weight, side effect check, paper questionnaires) throughout the remaining 48 weeks of treatment.

The purpose of this study is to determine the efficacy of two doses of naltrexone (25mg \& 50mg) versus placebo for weight and health risk reduction in 144 obese individuals with severe mental illness treated with an antipsychotic medication.

Arms:
arm 1: Oral Naltrexone 50mg capsule taken once daily for 52 weeks arm 2: Oral placebo capsule taken once daily for 52 weeks arm 3: Oral Naltrexone 25mg capsule taken once daily for 52 weeks

Interventions: intervention 1: Naltrexone intervention 2: Placebo
Intervention descriptions: intervention 1: 25 or 50mg (randomized) oral capsule taken once daily for 52 weeks to establish optimal dose for weight loss over the course of the study. intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 37 
YALE UNIVERSITY 
 HUMAN INVESTIGATION COMMITTEE 
Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2011-6) 
SECTION I: ADMINISTRATIVE INFORMATION 
Title of Research Project: Naltrexone for Anti-psychotic Induced Weight Gain in Severe Mental Illness 
Principal Investigator:  Cenk Tek, MD 
Yale Academic Appointment: Associate Professor 
Campus Address: 34 Park Street, 267E  New Haven, CT 06519 
Campus Phone: 974-7484 
Fax: 974-7691 
Pager: N/A 
E-mail: cenk.tek@yale.edu 
Protocol Correspondent Name & Address (if different than PI): 
 Erin Reutenauer Sullivan 34 Park Street, 10  New Haven, CT 06519 
Campus Phone: 974-7317 
Fax: 974-7691 
E-mail: erin.sullivan@yale.edu 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):  N/A 
Campus Phone: 
Fax: 
E-mail: 
Investigator Interests: 
Does the principal investigator, co-investigator, or any other responsible research team member, or any of 
their family members (spouse, child, domestic partner) have an incentive or interest, financial or otherwise, 
that may be viewed as affecting the protection of the human subjects involved in this project, the scientific 
objectivity of the research or its integrity? See Disclosures and Management of Personal Interests in Human 
Research http://www.yale.edu/hrpp/policies/index.html#COI  
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)
 NA 
Yale Academic Appointment: 
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
DATE STAMPED-RECEIVED 
PROTOCOL NUMBER 
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html  
Submit the original application and two (2) copies 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.   
HIC OFFICE USE ONLY 
Protocol Date: 8/16/2017
ID: 1207010507


Page 2 of 37 
 
  Yes  
X  No  
 
 
If yes, list names of the investigator or responsible person: 
 
The Yale University Principal Investigator and all Yale University and Yale New Haven Hospital 
individuals who are listed as co-investigators on a protocol with a Yale University Principal 
Investigator must have a current financial disclosure form on file with the University’s Conflict 
of Interest Office. If this has not been done, the individual(s) should follow this link to the COI 
Office Website to complete the form:  http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center  
 
 Yale University PET Center 
     (MR-TAC)    
 
 
 
 
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Clinical Trials Office (CTO)     
 YCCI/Hospital Research Unit (HRU) 
 Yale Cancer Center/Smilow 
 
 
 
 YCCI/Keck Laboratories 
 Yale-New Haven Hospital  
 
 
 Cancer Data Repository/Tumor Registry 
 Specify Other Yale Location: 
 
 
 
 
 
b. External Location[s]: 
 APT Foundation, Inc. 
 
 
 
 Haskins Laboratories 
 Connecticut Mental Health Center 
 
 John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven 
 
 Other Locations, Specify: 
 International Research Site  
 
 
 
(Specify location(s)): 
 
 
c. Additional Required Documents (check all that apply): 
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)  
Approval Date:  
*Pediatric Protocol Review Committee (PPRC) 
 
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC) 
 
Approval Date: 
 
*Dept. of Veterans Affairs, West Haven VA HSS 
 
Approval Date:  
*Radioactive Drug Research Committee (RDRC) 
 
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC) 
 
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) 
Approval Date:  
 YSM/YNHH Cancer Data Repository (CaDR)  
 
Approval Date:  


Page 3 of 37 
 
 Dept. of Lab Medicine request for services or specimens form 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  
 
5 years (2012-2017) 
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
   
 Single Center Study 
   
 Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes 
 
No 
 
  
 Coordinating Center/Data Management 
  
 Other:  
 
 
b. Study Phase 
 N/A 
    
 Pilot  
 Phase I 
 Phase II 
 Phase III 
 Phase IV 
    
 Other (Specify)  
 
 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c: 
 Clinical Research: Patient-Oriented 
   
 
 Clinical Research: Outcomes and  
 Clinical Research: Epidemiologic and Behavioral  
                 Health Services 
 Translational Research #1 (“Bench-to-Bedside”)      
 Interdisciplinary Research 
 Translational Research #2 (“Bedside-to-Community”)  
 Community-Based Research 
 
 
5.   Is this study a clinical trial? Yes 
 
No 
 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events” 
  
If yes, where is it registered? 
  
 
Clinical Trials.gov registry 
 
  
 
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 


Page 4 of 37 
 
  
 
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used. 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx  or 
 contact YCCI at 203.785.3482) 
 
6. Will this study have a billable service as defined by the Billable Service Definition? 
Yes 
 No
 
If you answered "yes", this study will need to be set up in Patient Protocol Manager (PPM) 
http://medicine.yale.edu/ymg/systems/ppm/index.aspx  
 
7. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No __X_  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? 
  
c. Will a novel approach using existing equipment be applied? 
  
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol. 
 
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.  
 
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed. 
 


Page 5 of 37 
 
SECTION IV: 
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As the principal investigator of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 I assume full responsibility for the protection of human subjects and the proper conduct of the 
      research. 
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
      rights and welfare. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 All members of the research team will be kept apprised of research goals. 
 I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
      study or any change and I will obtain continuing approval of this study prior to the expiration date      
      of any approval period. 
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
      participants. 
 I am in compliance with the requirements set by the University and qualify to serve as the 
      principal investigator of this project or have acquired the appropriate approval from the  
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
      Yale-New Haven Hospital, or have a faculty advisor. 
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
 
_____ 
 
 
 
 
 
 
 
 
 
 
 
 
  
PI Name (PRINT) and Signature 
 
 
 
 
Date 
As the faculty advisor of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 This project has scientific value and merit and that the student or trainee investigator has the  
      necessary resources to complete the project and achieve the aims. 
 I will train the student investigator in matters of appropriate research compliance, protection of 
      human subjects and proper conduct of research. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 The student investigator will obtain approval for this research study and any subsequent revisions 
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
      of any approval period. 
 The student investigator will report to the HIC any serious injuries and/or other unanticipated  
      problems involving risk to participants.  
 I am in compliance with the requirements set forth by the University and qualify to serve as 
      the faculty advisor of this project. 
 
 
 
 
___________  
______ 
 
 
 
_____ 
    Advisor Name (PRINT) and Signature 
 
 
 
 
Date 


Page 6 of 37 
 
 
 
 
 
 
 
 
 
Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
 No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
   ____________________________  
 
 
 
 
 
 
   Chair Name (PRINT) and Signature   
     
 
 
 Date 
 
   _________________________________ 
   Department 
 
 
 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
 I have read a copy of the protocol and approve it being conducted at YNHH. 
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
 The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
 
  ______________________________________ 
 
 
 
 
 
 
 
 
    YNHH HSPA Name (PRINT) and Signature         
 
 
Date 
 


Page 7 of 37 
 
 
 
 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.  
 
The purpose of this study is to determine the efficacy of two doses of naltrexone (25mg & 
50mg) versus placebo for weight and health risk reduction in 200 obese individuals with severe 
mental illness treated with an antipsychotic medication.   
 
Hypothesis 1: Subjects receiving naltrexone 25mg and 50mg for one year will reduce weight, 
and improve body mass index (BMI) and waist circumference, at a greater level than the 
subjects who receive placebo. 
 
Hypothesis 2: Both naltrexone arms will improve health risk markers: serum lipid profile, 
fasting glucose, and glycosylated hemoglobin (HbA1c) better than placebo. 
 
Exploratory Aim: To determine the optimum effective dose of naltrexone to counteract 
antipsychotic induced weight gain. 
 
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data. 
 
 
Persons with severe mental illness (SMI) die, on average, 25 years earlier than the general population1-
3.Most of this early mortality can be attributed to cardiovascular disease (CVD) and diabetes mellitus 
(DM), which are directly related to obesity4,5. Obesity is a leading cause of preventable death in the 
United States, second only to smoking. The physical health of patients has become a major focus of 
schizophrenia care, as recent decades have seen immense gains in symptom control and community 
integration. There is an urgent need for the development of interventions that address the obesity crisis 
in schizophrenia6. 
Obesity rates in psychiatric populations are much higher than the general population. Several studies 
demonstrate an alarming increased prevalence of obesity among patients with SMI. Allison et. al. found 
that 42% of a group of individuals with schizophrenia had a BMI of 27 or greater, compared to 27% of 
the general population7. In the Northern Finland 1966 birth cohort study, rates of obesity in patients 
with schizophrenia were 42% compared to 13% for rest of the cohort. Keck et. al. reviewed 45 studies of 
patients with bipolar disorder and found that the overall prevalence of overweight and obesity was 
higher in these patients than in control populations5. Studies of obesity risk need to carefully examine 
socioeconomic and geographic differences. Figure 1 shows our (unpublished) analysis of obesity and DM 
rates in a large schizophrenia cohort, compared with a socioeconomically- and geographically-matched 


Page 8 of 37 
 
population sample. Both obesity and DM rates are about three times higher among patients with long 
standing schizophrenia than the general population. Obesity is associated with significantly increased 
outpatient medical costs (25%)8-9. Both SMI and obesity are associated with significant stigma, and 
discrimination at work or in society10,11. Obesity in SMI has 
been associated with additional decline in quality of life12 and 
improvement has been shown with weight loss13,14. We have 
recently completed an analysis comparing cardiovascular risk 
of obese schizophrenia patients to similarly obese matched 
population controls (submitted). It appears that not only do 
schizophrenia patients suffer from higher rates of obesity, but 
the impact of obesity is also more dramatic. Obese individuals 
with schizophrenia had a mean vascular age that was 14.1 
years older than their mean actual age compared to a 6.7 year 
difference for 
socio-
demographic and BMI matched population controls; 
these obese patients also had significantly higher 
cardiovascular event risk (Figure 2). This finding 
underscores the higher impact of obesity, and urgency of 
the problem in this vulnerable population.  Increased 
obesity rates in schizophrenia is an iatrogenic problem. 
Fig. 1 also depicts our first episode psychosis cohort, 
which did not have increased rates of obesity, or diabetes 
at the onset of their schizophrenia treatment. Indeed, we 
have shown that the age adjusted cardiovascular risk for 
first episode patients is similar to population controls during initial assessment 15. On the other hand, 
after one year of treatment, mean BMI increased by 9% in first episode schizophrenia patients (n=79) vs. 
1% in age matched population controls (N=156). During this period, Framingham 10 year CV risk score 
disproportionately and significantly increased  from 0.7 to 1.22 for first episode patients, whereas it 
remained similar (0.74 to 0.79) in population controls). Both results were highly significant (manuscript 
in preparation). These findings from our group provide preliminary evidence that obesity is not a direct 
result of schizophrenia. Indeed, several lines of evidence support this notion. First, pre-antipsychotic era 
historical data typically points to lower than population average body weight, even after the 
development of specialized nutrition programs to bring patients up to population weight norms16,17. 
Second, historical data also suggest normal fasting sugar and oral glucose tolerance tests among 
schizophrenia patients18. Third, untreated chronic schizophrenia patients, as can be found and studied in 
India, appear to have lower body weight and metabolic profiles that are similar to those of historical 
cohorts19. Fourth, first reports of excessive increases in body weight initially appeared following the 
introduction of first-generation antipsychotic medications20,21. Combined with the short and long term 
weight gain observed with antipsychotic use in various patient groups, the evidence indicates that 
increased obesity in schizophrenia is largely an iatrogenic problem22. In ours and other’s analyses of risk 
factors for obesity, it is clear that obesity rates are closely associated with the appetite-increasing side 
effects of antipsychotic medications23. Patients on antipsychotic medications consume more total fat 
and sugar than comparable populations (in press)23. They also perform significantly less moderate 
physical activity, and have less nutritional knowledge than matched general population samples (in 
press). 
Antipsychotics significantly contribute to the increased rates of obesity, and related medical 


Page 9 of 37 
 
morbidity. Anti-psychotic medications have been associated with weight gain since their introduction in 
the 1950’s22. In a landmark study, Allison et al reviewed available research data and found that patients 
on average gain weight after 10 weeks of treatment with any antipsychotic medication, but that there 
were differences across medications: patients taking clozapine had a mean weight gain of 3.99 kg, 
followed by a mean weight gain of 3.51 kg for olanzapine treated patients, 2.10 kg for chlorpromazine, 
2.00 kg for risperidone, 0.48 kg for haloperidol, 0.43 kg for fluphenazine, and 0.04 kg for ziprasidone22. 
Results from a different study reported mean weight gains of 0.71 kg for Aripiprazole and 2 kg for 
quetiapine 6. In the CATIE trial, >7% of baseline weight gain occurred in 30% of patients taking 
olanzapine over 18 months, but only 7% to 16% of patients taking other antipsychotics had this clinically 
significant weight gain 24. Although some agents appear to have better weight gain profiles than others 
in the above mentioned studies, these results are somewhat misleading, since the data is obtained from 
patients already taking antipsychotics. Even aripiprazole and ziprasidone, with their more favorable 
weight gain profiles, produce over 7% total body weight gain in approximately 10% of clinical trial 
subjects (PDR). In a large study of first episode psychosis patients, participants gained an average of 16 
kg on olanzapine and 7.5 kg on haloperidol25. Figure 3 presents weight gain observed with various 
antipsychotic agents published from first episode psychosis studies. Both first generation agents, as well 
as second generation agents with seemingly more favorable weight gain profiles, produced significant 
weight gain for these relatively young and more active patients. The mechanism of weight gain 
associated with the novel antipsychotics has not been fully 
elucidated, but may be related to blockade of histamine 
(H1), serotonin 2C (5HT2c) and alpha 1- adrenergic 
receptors on hypothalamic neurons, resulting in distortion 
of signals from the gastrointestinal tract to the brain. Such 
distortion may in turn lead to excessive appetite and 
impaired satiety signals26,27. H1 receptor blockade is well 
known to increase appetite, and affinity for this receptor is 
clearly the best predictor of weight gain liability28. Similarly, 
5HT2c  receptors play a role in energy regulation, and 
agonism of this receptor reduces appetite and weight28,29. 
While these two receptors may explain the excess weight gain that is observed with newer agents, they 
fail to explain the weight gain produced by agents, like haloperidol, which have no affinity to these 
receptors. In fact, the sole effect of haloperidol is to block D2 receptors, an action which is shared to a 
varying degree by all approved antipsychotic agents. Thus, D2 receptor blockade appears to play an 
additional role in weight gain. D2 receptors are not directly involved with energy regulation; however, 
they do play an important role in the brain's food reward system. Food is one of the primary substrates 
of the reward system in higher living organisms. Highly storable energy sources, such as fats and sugars, 
are extremely enjoyable through the actions of opiate receptors, which are partly mediated by D2 
receptors30. Blockade of D2 receptors may make the whole system less sensitive to stimuli, and thereby 
push the organism to eat more in order to achieve similar levels of enjoyment. 
Table 1. Summary of Prospective Behavioral Weight 
Management Studies for Psychotic Outpatients 
 
Intervention 
N 
Interventi
on weight 
change 
(weighted 
mean) 
Control 
N 
Control 
weight 
change 
(weighted 
mean) 
Prevention 
of weight 
gain (RCT) 
79 
+2.1kg 
76 
+7.1kg 


Page 10 of 37 
 
Behavioral interventions for 
antipsychotic induced weight gain are 
necessary but not sufficient. 
There have been several non-
randomized, prospective, clinical intervention trials31-45 using a variety of 
behavioral methods for obesity management in patients with SMI; these methods include nutritional 
education, commercial programs and lifestyle interventions. These studies can be categorized into two 
classes: those aimed at preventing weight gain and those aimed at promoting weight loss. These studies 
are small and heterogeneous, but for the sake of brevity, in Table 1, we summarize the results for the 15 
studies that have been published to date31-45. Regardless of the method used, most studies arrested 
weight gain, and/or provided modest weight reductions (Table 1). Only 6 of these trials were 
randomized, controlled studies (RCT) of weight loss for obese patients with schizophrenia, 3 of these 
studies used lifestyle modification32,37,45, and 3 studies utilized CBT31,31,38. The weighted average reported 
in these studies for intervention groups is 2.7 kg weight loss (range 2.0-4.0 kg) over an average 
intervention of 15 weeks compared to a 0.4 kg weight gain for control groups. As can be seen in Table 1, 
behavioral weight loss programs provided limited benefit for patients with schizophrenia, especially 
compared to the long term weight gain produced by antipsychotics. 
Preliminary Study: SIMPLE Weight Loss Program (Simplified Intervention to Modify Physical 
activity, Lifestyle, and Eating behavior):  
We have recently completed the largest randomized weight loss trial in schizophrenia patients using our 
SIMPLE program. This is an intensive 16 week lifestyle intervention that adjusts for the cognitive 
impairment of schizophrenia, integrates social cognitive theory, and utilizes other components of 
successful lifestyle programs. First, the concepts and language implemented in the program are 
simplified, the information is imparted at a slow pace initially then builds progressively, and knowledge 
is reinforced with repetition. This simplified approach is crucial for retaining study subjects because 
lower perceived rule complexity is associated with lower attrition. Second, we used an innovative food 
reimbursement program. This program provides financial reimbursement for healthy foods purchased. 
The reimbursement is not contingent on weight loss; instead, it serves as a behavioral reinforcement 
and learning tool. Financial reimbursement addresses the disparity in income, since the higher cost of 
healthy foods represents a barrier to dietary change for low SES individuals. Lastly, our intervention 
includes supermarket visits to teach how to shop for healthy foods while on a budget and how to 
negotiate large, crowded stores. This trip also reinforces nutrition label reading. Additionally, 
participants are given bus tokens and given guidance about which markets to shop at. 
Pharmacological weight loss interventions: First, the obesity problem in schizophrenia is not purely 
behavioral, given the substantial contribution of antipsychotic medications. As seen in our large RCT, 
patients are able to implement lifestyle changes, arrest weight gain, and improve serum risk markers; 
however, these gains are limited. Greater weight loss might be achieved by simply stopping the 
antipsychotic medication; many patients do, and the results of stopping medication can be catastrophic. 
Second, persons with schizophrenia often have significant attention and learning problems, which 
complicates the delivery of behavioral programs to this population more than the general population. 
Even in a specialized program, such as SIMPLE, these obstacles may not be completely offset. Finally, 
there is limited support by health care systems and funding agencies for implementing behavioral 
programs to treat obesity because the magnitude of weight loss achieved in clinical studies is one sixth 
to one-third of the average weight gain induced by antipsychotic medication. 
Opiate antagonists may be useful for antipsychotic induced weight gain: 
Reward system, opioid receptors and appetite: The biology of feeding and regulating body weight is 
extremely complicated, not exactly elucidated, and a full presentation is beyond the scope of this 
application. Many neuropeptides, hormones, and neurotransmitters, both in the brain and the GI tract, 
Weight loss 
(RCT ) 
141 
-2.7kg 
121 
+0.4kg 
All 
Published 
544 
- 2.0kg 
217 
+ 2.7kg 


Page 11 of 37 
 
are involved. Like any non-automatic function that is essential for survival, mammalian feeding behavior 
is closely modulated by the reward circuits in the brain. Endogenous opioids play an important role in 
these reward circuits46. Opioid derivatives have been used in human medicine for more than a 
millennium, and their appetite increasing effects are well known. Following the discovery of endogenous 
opioids, it was discovered that opioid receptor antagonists (ORA) decrease self-feeding in food deprived 
rats47. Since then, the animal literature has expanded significantly, and this finding has been replicated 
in non-food deprived rats and many other mammalian species (reviewed by Bodnar47). It is now fairly 
clear that ORAs have little effect on initiation of feeding, but rather attenuates preference for “palatable 
diets” and eating behavior48. Injecting animals with opioids increases the preference for high 
carbohydrate, and even more so, on high fat diets, an effect readily blocked by ORAs. There is no 
evidence that ORAs actually block the taste sensation in animals or humans47. Human studies revealed 
intact taste, but a decrease in the pleasantness of sweets, after administering the ORA naltrexone46. 
Since ORAs block the preference for saccharin solutions in rats, it appears that the macronutrient or 
caloric content of food does not activate opioid pathways 49. 
Dopamine connection: Other findings show that palatable foods result in endogenous opiate release, 
related mRNA expression, and opioid receptor occupation in sites of the brain that are critical for both 
feeding and overall reward circuits, most strikingly in nucleus accumbens and hypothalamus46. 
Rewarding effects of opioids are exerted mainly through dopamine41. Obese human subjects are shown 
to have significant increases in their circulating β-endorphin levels than non-obese controls82. Also, more 
palatable foods are shown to induce higher circulating β-endorphin levels in normal weight human 
subjects83. Increased extracellular dopamine levels occur in the nucleus accumbens and striatum in 
response to rewarding food stimuli. Of note, obese subjects have been shown to have lower striatal D2 
receptor availability, at a rate that is inversely proportional to the level of obesity. A mechanism for 
obesity in this population has been proposed in which overeating occurs in an attempt to stimulate the 
dopamine system. 
A working hypothesis of antipsychotic induced weight gain: Patients with schizophrenia treated using 
antipsychotic medications have been shown to have a preference for diets high in fat and sugar. Patients 
with schizophrenia typically seek behaviors that increase dopamine mediated reward in the brain such 
as smoking and substance use, both of which occur more often in this group than the general 
population. The system might require intact dopamine and opioid function. We propose a model where 
patients with schizophrenia increase their intake of foods high in sugar and fat in order to increase their 
low dopaminergic tone,which results from dopamine receptor blockade, via endogenous opioid release. 
The finding that medicated obese women with schizophrenia have been shown to possess higher 
circulating β-endorphin levels than matched controls provides partial support for this hypothesis52. 
Medications with additional H1 receptor blockage impair satiety signaling from GI tract to the 
hypothalamus; thus, there is no “stop” signal to reward eating, which in turn causes further weight gain.  
Clinical trials with the opioid receptor antagonist naltrexone for obesity: 
Naltrexone is an oral agent that competitively antagonizes all known opioid receptors in the brain. 
Human studies with naltrexone were completed in individuals with different illnesses, including 
schizophrenia, and have been shown to be a safe and easy agent to use. It is shown to decrease craving 
in alcoholics and is approved by the FDA for the treatment of alcohol dependence53. Naltrexone is 
reported to decrease craving for other substances of abuse, like nicotine. Furthermore, it has been 
shown to prevent secondary weight gain due to cessation of cigarette smoking at low (25mg and 50 mg), 
but not higher doses54. Naltrexone has been tested in human feeding studies, and has been shown to 
reduce both the quantity of food eaten and the choice of palatable foods46. A study that was conducted 
for antidepressant- and lithium-induced weight gain in bipolar women reported weight loss during 
naltrexone treatment; however, weight on average returned to baseline after cessation of active 


Page 12 of 37 
 
treatment. Patients reported decrease in food cravings while they received naltrexone, but not while 
taking placebo in this study55. There is also a well studied bupropion/naltrexone combination 
currently in FDA review for obesity treatment. Only one of these large studies provided lifestyle 
intervention to both groups: the placebo group lost 5.1% of TBW and the active group lost 9.3% over a 
56 week period56. Although, the kg difference between the two groups is not published, we calculated it 
as about 4kg from the information provided in the paper. In another study by the same company, 
naltrexone alone at a 48mg dose provided 1.2 kg (1.7kg completers) average weight loss over 24 weeks, 
which was slightly better than placebo (0.8kg), but only half of the bupropion/naltrexone combination 
(about 5kg at all doses)57. The rationale for combining bupropion/naltrexone is based on the anorexia 
reported with both medications. While admitting possible effect through mesolimbic dopamine reward 
pathways, the investigators speculate that the actual effect is due to bupropion blocking dopamine 
reuptake, which results in increased α-melanocyte stimulatinghormone (MSH) levels leading to 
decreased appetite. β-endorphin in turn produces feedback inhibition for MSH secretion. Thus, by 
blocking naltrexone's feedback inhibition, they believe the bupropion effect is enhanced. This 
hypothesis provides a related but separate pathway on why naltrexone may be useful for antipsychotic 
induced weight gain. Since MSH release is possibly mediated by D2 and D1 receptors which are 
partially blocked by antipsychotic use, the MSH release may be decreased and further inhibited by high 
β-endorphin levels due to overeating. In this case, the addition of bupropion would not be useful, but 
naltrexone might block the feedback inhibition and reduce appetite through MSH activity. Among 
several bupropion studies for smoking cessation in schizophrenia concomitant to antipsychotic use, only 
one –from our center reported weight effects. In this study, both bupropion and placebo groups gained 
similar levels of weight regardless of their quit status58. 
PROOF OF CONCEPT: Pilot Study of Low Dose Naltrexone To Arrest and Reduce Antipsychotic 
Induced Weight Gain (clinicaltrials.gov identifier NCT00793780 ): 
Based on our working hypothesis that opioid receptor blockade might arrest antipsychotic induced 
weight gain, we have conducted a pilot 8 week randomized, double blind, placebo controlled, parallel, 
fixed dose clinical study of naltrexone (25mg) for treatment of weight gain in schizophrenia. The study 
was supported by Women’s Health Research at Yale and only obese women with clinically stable 
schizophrenia who had gained over 2% of their TBW in the previous year were recruited. Substance 
abuse and pregnancy were the major exclusion criteria. Over a period of one year, 29 volunteers were 
screened, and 24 subjects were randomized to 25 mg oral naltrexone or matching placebo for a period 
of 8 weeks. No diet advice or behavioral weight loss intervention was provided. No subjects reported 
joining an outside program at the end of the study. One subject in the placebo arm dropped out at the 
fourth week due to personal reasons, all remaining subjects completed the 8 week trial. No serious 
adverse effects were reported and study medicines were well tolerated. At the end of the study, 
subjects who were randomized to active naltrexone arrested the weight gain, with a further average 
reduction of 2.45 kg as opposed to subjects who were randomized to placebo, who continued to gain 
weight at an average of 0.47kg (Figure 3). The difference between two groups closely approached 
significance at p=0.051, and produced a power of d=0.59. Baseline weight was not correlated with 
weight change in the study. On the other hand, exploratory analyses revealed that diabetes was a 
confounding factor, and only non-diabetic subjects on naltrexone lost significant weight compared to 
placebo subjects (non-DM -4.98kg (±3.03) vs. DM - .27 (±3.05),Figure 3). It was also discovered that the 
intensity of craving for sweets as measured by the Questionnaire of Cravings for Sweet and Rich Foods 
(QCSRF) was significantly reduced for the NTX group and unchanged for the placebo. Unfortunately the 
study was underpowered, as expected from a pilot study, and provides no information on naltrexone 
effects on males. In spite of these limitations, our study provides important information. Given that 
obese patients with chronic schizophrenia typically continue to gain weight at a clinically significant 
level, this pilot is unique among other studies, and its results must be interpreted within this 


Page 13 of 37 
 
clinical context. The current study will focus on non-diabetics which constitutes about 80% of the SMI 
population59. 
RATIONALE AND SIGNIFICANCE: In summary, obesity interventions in severe mental illness are urgently 
needed. Unfortunately, behavioral programs are not sufficient to counter the antipsychotic induced 
weight gain due to the magnitude of the problem and the ongoing need for antipsychotic medications in 
schizophrenia. Pharmacological strategies to augment the behavioral programs need to be developed. 
Currently available medications for this purpose are limited and have not been effective in this 
population. Antipsychotic medication actions on H1 and 5HT2 receptors only partly explain why they 
cause weight gain. We developed a working hypothesis that D2 receptor blockade might be partly 
responsible for weight gain by interacting with the dopamine-opioid system. In a proof of concept study, 
we have shown that an already FDA approved, widely available, and inexpensive generic oral opioid 
antagonist, naltrexone, was able to arrest antipsychotic induced weight gain and provide significant 
weight loss in a relatively short time period. FDA obesity intervention guidelines necessitate adequately 
powered, longer duration studies. Thus, in this application we are proposing a fully powered, 
randomized, double blind, placebo controlled study of two different doses of naltrexone for adequate 
duration to counteract antipsychotic induced weight gain. 
 
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3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. 
 
Subjects will be randomized to active Naltrexone 25mg, Naltrexone 50mg, and placebo groups in a 1:1:1 
ratio using a computer randomization procedure at the CMHC research pharmacy, blind to both 
research team and subjects. Separate randomization schedules will be applied based on gender, and 
antipsychotic agent to yield an equal number of male and female subjects in each arm. This is to control 
for possible differential gender and racial/ethnicity specific effects of Naltrexone on weight as well as 
differences brought on by higher and lower weight liability medications.   
 
Subjects will take the study medication daily for 52 weeks.  Subjects will be seen weekly for the first 4 
weeks of the study, thereafter they will be seen on a bi-weekly (every other week) basis to be assessed 
(i.e. weight, side effect check, paper questionnaires) throughout the remaining 48 weeks of treatment.  
Compliance will be monitored by pill counts as well as 25mg riboflavin added to the capsules which 
provides florescence to urine under Wood’s lamp (UV or black light).  Subjects will be given a study 
identification card listing the fact that they may be taking naltrexone and this card will include the study 
emergency cell phone number which will be available 24 hours a day, 7 days per week in case of an 
emergency. 
 
The study is planned to be run at the Connecticut Mental Health Center (CMHC) and its affiliated 
satellite clinics throughout the greater New Haven area. 
 
All participants will be carefully assessed with physical examination and laboratory findings, any medical 
problems that need immediate attention will be referred to each participant’s own primary care 
physician.  All potential subjects will meet with study staff for intake and evaluation sessions to 
determine eligibility prior to enrollment.  
 
A description of assessments is given below: 
1) Intake interview including demographics, clinical history, Structured Clinical Interview for DSM-IV 
(SCID) to ascertain diagnosis. 2) Urine toxicology (Utox) screen to rule out substance use.  The initial 
sample will also be sent to the lab to confirm opiate results for safety purposes and a follow-up sample 
will be taken immediately before randomization to study medication to ensure it is negative for opiates; 
continued random testing will occur at the discretion of the study physician throughout the trial along 


Page 17 of 37 
 
with medication compliance procedures; and pregnancy tests for female subjects as it may not be 
advisable for pregnant women to lose weight. 3) Weight (Wt) measurement to the nearest 0.5kg and 
height (ht) will be measured to calculate BMI. Waist circumference (WC) will be measured with a tape 
measure placed on the midpoint between iliac crest and lowest rib rounded to the nearest 5 mm. 
Resting blood pressure (bp) and pulse will be measured. Our lab has established procedures for 
calibrating scales (National institutes of Standards and Technology Certified weights) and waist 
measurement. The lab conducts reliability exercises for waist measurements for study stuff (ICC= 0.97, 
TEM=2.4%) 4) Standard Laboratory Testing (Lab) 5) Brief Psychiatric Rating Scale (BPRS) is the gold-
standard overall measure of schizophrenia symptoms which will be utilized to demonstrate that the 
Naltrexone and/or SIMPLE intervention does not cause worsening of the illness symptoms apart from 
the usual fluctuations of the natural course. 6) Beck Depression Inventory (BDI) 21-item version is a 
psychometrically sound, widely used measure of the features and symptoms of depression. The BDI taps 
a broad range of negative affect – not just depression – and is a highly efficient measure for detecting 
fluctuations in broad psychopathology and distress. 7) Three Factor Eating Questionnaire (TFEQ) also 
known as the Eating Inventory is a measure of eating behaviors with three factors: dietary (cognitive) 
restraint, disinhibition, and hunger. The TFEQ has received psychometric support and is a frequently 
used measure in obesity trials. 8) The Questionnaire on Craving for Sweet or Rich Foods (QCSRF) The 
QCSRF is a two factor, nine item scale assessing the presence of cravings for rich and sweet foods and 
has been found to have good psychometric properties. 10) The Yale Physical Activity Survey (YPAS) is an 
interview-administered questionnaire that assesses activity participation in number of hours/week in 
different categories (i.e. work, recreation, exercise) and takes about 20 minutes to complete.  11) 
Resting Metabolic Rate (RMR) is calculated through a mathematical formula not indirect calorimetry. No 
special procedure is utilized that would be bothersome to subjects. 12) Quality of Life Enjoyment and 
Satisfaction Questionnaire (Q-LES-Q) is specifically designed to use with schizophrenia patients and 
focuses on patient’s subjective perception of various aspects of their life. 13) SF-36 Health related 
Quality of Life Questionnaire; a 36-item short-form (SF-36) was constructed to survey health status in 
the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health 
policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that 
assesses eight health concepts: 1. limitations in physical activities because of health problems; 2. 
limitations in social activities because of physical or emotional problems; 3. limitations in usual role 
activities because of physical health problems; 4. bodily pain; 5. general mental health (psychological 
distress and wellbeing); 6. limitations in usual role activities because of emotional problems; 7. vitality 
(energy and fatigue); and 8. general health perceptions. SF-36 can be administered as a self-rating scale 
or by interviewer. In this study, trained rates will administer the SF-36. 14) UKU Side Effect Checklist 
(UKU) This is a comprehensive rating scale developed for psychotropic drugs and a cross-sectional study 
of side effects in neuroleptic-treated patients. Common adverse events related to naltrexone will be 
added to this scale, as needed. 15) Columbia-Suicide Severity Rating Scale (C-SSRS126) is a scale 
developed for use in clinical trials of psychoactive agents and recommended by the FDA to be used for 
safety tracking of medications for suicidality. 16) Cognitive Battery. Tests from the Measurement and 
Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery 
(MCCB): Given the cognitive impairment of schizophrenia, careful assessment of cognition is necessary 
for feasibility of any medication use in schizophrenia. This is a cognitive battery developed on NIMH 
initiative by experts from academia, pharmaceutical industry, and US government for the specific 
purpose of use in clinical trials in schizophrenia. Validity, reliability, sensitivity to change, and normative 
data is established. 
 


Page 18 of 37 
 
 
 
4. Genetic Testing    N/A 
 
A. Describe 
i. the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned 
ii. the plan for the collection of material or the conditions under which material will 
be received 
iii. the types of information about the donor/individual contributors that will be 
entered into a database 
iv. the methods to uphold confidentiality 
 
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects? 
C. Is widespread sharing of materials planned? 
D. When and under what conditions will materials be stripped of all identifiers? 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials? 
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? 
 
F. Describe the provisions for protection of participant privacy 
G. Describe the methods for the security of storage and sharing of materials  
 
 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study. 
 
200 patients with severe mental illness 
 
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
Assessment Schedule 
SCID, Demographics, Physical exam  
Week 0  
Urine toxicology, pregnancy test for female subjects  
Fluorescence check in urine for compliance  
Week 0 and every 4 weeks subsequently + as needed 
determined by study physician  
Fasting Glucose, Insulin, HbA1c, Lipid Profile, Liver function tests  Week 0, 16, 32, 52  
Serum leptin, ghrelin, peptide YY, adiponectin, high sensitivity 
CRP, interleukin 6  
Week 0, 16, 52  
Framingham Score  
Calculated same time with blood draws.  
Vitals (Blood Pressure, pulse)  
Weekly for first 4 weeks, then every two weeks  
Weight, BMI  
Weekly for first 4 weeks, then every two weeks  
RMR, Waist Circumference (WC), 24hr Food Recall, TFEQ, YPAS, 
BPRS, BDI, QCSRF, QLS, SF-36, C-SSRS.  
Week 0 and every 4 weeks  
UKU side effects  
Weekly for first 4 weeks, then every two weeks  
Cognitive Battery  
Week 0, Week 16, Week 52  


Page 19 of 37 
 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement. 
 
 Children 
 
 
 Healthy  
 
Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners  
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees  
 Pregnant women and/or fetuses 
 Yale Students  
 
Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements) 
 
Subjects must pass the following quiz (80% correct) in order to be eligible to consent for the study. 
 
1. I will take study medication for 52 weeks/1 year in this study. 
 
 
T_X_  
F____ 
2. This study aims to help me lose weight.  
 
 
 
 
T_X_    F ____ 
3. I have to be in the study, even if I don’t want to.  
 
 
 
T____   F _X_ 
4. I will have blood drawn in this study. 
 
 
 
 
 
T_X_  
 F ____ 
5. I should report to the study doctor if I have any side effects 
 
 
T_X_    F ____ 
6. I will be paid for study assessments. 
 
 
 
 
 
T_X_    F ____ 
7. The study doctor and research team will know which medication  
 
T____   F _X_ 
      I’m taking during the study. 
 
8. Please circle the names of the study medication that you may receive in this study. 
 
Haldol  
 
Prolixin  
Mellaril 
 
Naltrexone 
 
Paxil 
 
 
Placebo 
 
9. I can stop being in the study any time that I want. 
 
 
 
T_X_    F ____ 
 
10. One of the possible side effects of the study medication in nausea. 
 
T_X_     F____ 
 
 
11. If I take the study medication while taking an opiate (see list on last 
T_X___ F ____ 
page) I may experience withdrawal symptoms, such as nausea, vomiting 
diarrhea, muscle aches, abdominal cramping, anxiety, and sweating. 
 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion? 
 
Inclusion Criteria 
1) Age 18 to 75 
2) Meet DSM-IV criteria for schizophrenia, schizoaffective disorder, bipolar disorder, major 
depression, or another psychotic disorder based on SCID interview 
3) Body Mass Index (BMI) of 28 and over 
4) On a stable dose of antipsychotic medication; i.e. at least one month with no dose change, 
and three months from an antipsychotic switch 
5) Deemed to be symptomatically stable by the clinical staff in the last two months 


Page 20 of 37 
 
6) Over 7% total body weight increase on antipsychotics for subjects within first year of illness 
Exclusion Criteria 
1) Meet criteria for current opiate abuse or dependence (confirmed by positive urine drug 
screen for opiates or, if suspected by study doctor via patient history and or suspicion of 
occult opiate use, a naloxone challenge will be performed.) 
2) Current history of dementia, mental retardation 
3) Not capable of giving informed consent for participation in the study 
4) Women who are pregnant or breast-feeding 
5) Physical conditions affecting body weight (e.g. Cushing’s disease, polycystic ovary syndrome) 
6) Diabetes Mellitus (defined as prescribed an anti-diabetic medication for diabetes or a 
hemoglobin A1c level > 7 confirmed by primary care physician at screening) 
7) Severe liver dysfunction, (serum aminotransferases greater than three times normal), acute 
infectious hepatitis, liver failure. 
 
 
 
 
8. How will eligibility be determined, and by whom?  
 
Eligibility will be determined through participant report, chart review, and communication with 
CMHC clinician/psychiatrist, and this will be completed by the PI and research coordinator. 
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.  
 
Naltrexone 25mg/50mg/Placebo 
Hepatotoxicity: Liver functions reported to be effected in terms of increased liver transaminase levels at 
doses of naltrexone 10 to12 times the study dose. No hepatotoxicity reported at or twice the study 
dose.  
Opioid Withdrawal: Naltrexone may cause acute withdrawal on subjects who had used opioids as far as 
seven days before the drug administration. Symptoms commonly associated with opiate withdrawal 
include severe nausea, abdominal cramping, diarrhea, vomiting, muscle aches, anxiety, and sweating. 
Reduced efficacy of opioid medications with naltrexone: Patients taking naltrexone may not benefit from 
opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and 
opioid analgesics. In an emergency situation when opioid analgesia must be administered to a patient 
taking naltrexone, the amount of opioid required may be greater than usual, and the resulting 
respiratory depression may be deeper and more prolonged. Study participants will carry an information 
card to be used in case of an emergency. 
Small increased risk of depression, suicidal ideation, and suicide: Based on data from placebo controlled 
trials in patients with alcohol and/or opiate dependence there was observed an infrequent however 
small increased incidence of depression, suicidal ideation, attempts, and completed suicides in the 
naltrexone treated group compared to the placebo group. 
Other Side Effects: In an open label safety study with approximately 570 individuals with alcoholism 
receiving naltrexone, the following new-onset adverse reactions occurred in 2% or more of the patients: 
nausea (10%), headache (7%), dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting 
(3%), anxiety (2%) and somnolence (2%). 


Page 21 of 37 
 
Exposure to Naltrexone during Pregnancy: Naltrexone is a pregnancy Category C medication meaning 
the drug should be given to patients only if the potential benefit justifies the potential risk to the fetus. 
There is no data on the use of naltrexone or other opioid antagonists in pregnant women. The effects, if 
any, on the developing fetus are unknown. We will require that female patients of child bearing age use 
contraception to prevent pregnancy during participation in the study and will not enroll participants 
who are pregnant or who are trying to get pregnant. 
 
Urine collection 
Urine specimens are collected for research assessments and should pose no appreciable risks, and will 
be done using established procedures already in place at CMHC. 
 
Blood collection 
Subjects participating in these studies will have multiple blood draws using established procedures in 
the CMHC. The blood draw has the risk of producing a bruise at the venipuncture site, and rarely 
development of a small infection. 
 
Cognitive Assessments, Rating Scales and Questionnaires 
These are all non-invasive, should add no risk, and have been used without difficulty in previous studies 
with these populations. The disadvantage is that they are time consuming to complete. Our experience 
in the past with these measures is that they are acceptable to subjects, and careful efforts will be made 
to ensure confidentiality of this data, including coding of the research assessments by study subject 
numbers, which are kept in locking filing cabinets or in password protected computers, with access only 
to key research staff. 
 
Suicide Risk 
Due to the small increased incidence of depression, suicidal ideation, attempts, and completed suicides 
in people having taken Naltrexone, we will monitor this risk using the Columbia Suicide Severity Rating 
Scale.  If, during screening or throughout the trial, a patient indicated suicidal thoughts or plans, they 
will be further assessed by a clinical team member or the study doctor, who will then refer the patient 
to their regular clinician, CMHC acute services or the YNHH emergency room, as indicated.   
 
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
Described above 
 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24. 
 
a.  
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?  Moderate Risk 
b. 
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  N/A 
c. 
Data Safety Monitoring Plan 
 
This is a moderate risk study.  Although the naltrexone dosages we use are at and below the FDA 
approved dose and this drug has been safely used in this particular population in the literature, the 


Page 22 of 37 
 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since 
it is not possible to predict with certainty the absolute risk in any given individual.  Therefore, we 
provide a plan for monitoring the data and safety of the proposed study as follows. 
 
The principal investigator is responsible for monitoring the data, assuring protocol compliance. The 
safety officer is responsible for conducting the safety reviews bi-annually. During the review process, the  
safety officer will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment. Either the principal investigator, the safety 
officer, the Human Investigation Committee (HIC) or Human Subjects Committee (HSC) have the 
authority to stop or suspend the study or require modifications.  
 
This protocol presents moderate risks to the subjects and adverse events or other problems are not 
anticipated. In the unlikely event that such events occur, serious and unanticipated and related adverse 
events or unanticipated problems involving risks to subjects or others will be reported in writing within 
48 hours to the HIC or HSC (using the appropriate forms from the website) and any appropriate funding 
and regulatory agencies (NIH). The investigator will apprise fellow investigators and study personnel of 
all adverse events that occur during the conduct of this research project In accordance with Federal and 
Institutional regulations, the Data and Safety Monitoring Board (DSMB) for this study will conduct bi-
annual reviews of aggregated study outcome data and adverse events via a set of tables updated by the 
study coordinator, per our DSMP with NIH. The chairman of the DSMB and designated safety officer will 
be Dr. Eda Cengiz, Assistant Professor of Pediatric Endocrinology. The DSMB committee will be 
composed of Tyrone Cannon, Ph.D., a Professor of Psychology and a foremost leader in the field of 
clinical neuroscience.  His work focuses on schizophrenia and related disorders, in particular on 
identifying the neurocognitive, neuroanatomical, and neurochemical changes associated with genetic 
liability to schizophrenia; Bingqing (Teresa) Zhou, Ph.D. an Assistant Professor in the departments of 
Biostatistics and Public Health.  Her current work involves regression modeling and focuses on design 
and analysis of clinical trials; and James I Hudson, M.D., Sc.D., a professor of Psychiatry at Harvard 
Medical School. He also serves as the director of the Biological Psychiatry Laboratory and the director of 
the Psychiatric Epidemiology Research Program at McLean Hospital.   The committee will be presented 
aggregated data on study outcomes and adverse events on a bi-annual basis in a blinded manner. 
 
Attribution of Adverse Events: 
 
Adverse events will be monitored for each subject participating in the study and attributed to 
the study procedures/design by the principal investigator according to the following categories: 
 
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e.) Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
 
The following scale will be used in grading the severity of adverse events noted during 
the study: 


Page 23 of 37 
 
 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe 
 
In addition to grading the adverse event, the PI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered 
serious if it: 
 
1. is life-threatening 
2. results in in-patient hospitalization or prolongation of existing hospitalization 
3. results in persistent or significant disability or incapacity 
4. results in a congenital anomaly or birth defect OR 
5. results in death 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition, or 
7. adversely affects the risk/benefit ratio of the study 
 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event. Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE. 
 
Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse 
events occurring at a greater frequency than expected, and other unanticipated problems 
involving risks to subjects or others to the HIC or HSC: 
 
The investigator will report the following types of adverse events to the HIC(IRB), DSMB and the 
FDA (as appropriate): a) serious AND unanticipated AND possibly, probably or definitely related 
events; b) anticipated adverse events occurring with a greater frequency than expected; and c) 
other unanticipated problems involving risks to subjects or others. These adverse events or 
unanticipated problems involving risks to subjects or others will be reported to the HIC (IRB), 
DSMB and the FDA (as appropriate) within 48 hours of it becoming known to the investigator, 
using the appropriate forms found on the website. 
 
We plan to report adverse events to co-investigators on the study, DSMB members (listed 
above), funding and regulatory agencies and regulatory and decision-making bodies.  
Specifically, for the current study: National Institutes of Health (NIH)/National Institutes of 
Mental Health (NIMH). 
 
The safety officer (Eda Cengiz M.D.) will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 


Page 24 of 37 
 
severity of the adverse events and determine if modifications to the protocol or consent form 
are required at that time. 
 
The Safety officer will be completely independent of the DSMB and information will be 
provided to the DSMB in the form of tables, narrative summaries etc.  Data on the potential 
side effects of Naltrexone will also be reported to the DSMB members via these tables. The 
study coordinator will provide these tables etc as blinded data reports to the DSMB on a bi-
annual basis.   
 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A 
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? 
ii. What provisions are in place for management of interim results? 
iii. What will the multi-site process be for protocol modifications? 
 
12. Statistical Considerations: Describe the statistical analyses that support the study design.  
 
Data will be electronically scanned into databases and will be double checked by hand. Hard copy 
documents will be examined to verify questionable observations. Missing data will be examined for 
each variable. Histograms, normal probability plots, and numerical summaries (skewness, kurtosis) will 
be used to examine distributional assumptions required for the mixed model analysis described below. 
Transformations such as the logarithm, square root, and reciprocal will be considered in the event the 
normality assumption is inadequate. Residual analysis will also be performed to evaluate distributional 
variance and linearity assumptions. Data analysis will be conducted in collaboration with Brian Pittman, 
statistician in the department of Psychiatry and Dr. Ralitza Gueorguieva faculty member of the 
Department of Biostatistics at Yale University School of Public Health.  For all analyses, an alpha 
threshold of 5% (two-sided) will be used to test for statistical significance and will be performed using 
SAS v9.3 (SAS Institute, Cary, NC).  
 
Analyses will be performed according to the intent-to-treat (ITT) principle where data from any 
randomized subjects will be analyzed. We will calculate descriptive statistics for participants at baseline, 
and compare naltrexone to placebo participants using analysis of variance (ANOVA) for normally 
distributed covariates and chi-square tests for categorical covariates. The impact of baseline variables 
that demonstrate clinically relevant group differences will be assessed in supportive analyses using 
covariate adjustment.  
 
Approach to Missing Data: The primary analysis method will use a likelihood-based mixed model, which 
accommodates incomplete observations and operates under the assumption that the missing data is 
missing at random (MAR). Missing data patterns, time to withdrawal and reasons for dropout will be 
compared between the two naltrexone and placebo groups. T-tests, cross-tabulations, and logistic 
regression will be used to evaluate whether withdrawal is dependent on any observed variables. Finally, 
should missing data patterns and reasons for missing data suggest a bias or confounding, we will 
conduct sensitivity analyses using pattern mixture models to examine the influence that dropout bias 
(informative missingness) may have on treatment differences.  Multiple imputation (MI) will also be 
used in the case of data not MAR.  Sensitvity analyses will be performed secondarily among study 
completers.  


Page 25 of 37 
 
 
Hypothesis Testing: The primary goal of this study is to compare the weight changes resulting from two 
different doses of naltrexone compared to placebo.   The primary ITTanalysis will employ a linear mixed 
effects model (LMM) to determine the effect of treatment status (between-subjects for: naltrexone 
25/50mg vs. placebo) on the trajectory of weight change over time (within-subjects for: study time 
points).  The interaction between treatment and time will be modeled and interpreted using graphical 
displays and post-hoc contrasts on least square means.   The latter will include estimation of group 
contrasts at each time point and polynomial (linear, etc.) contrasts for time within each group.  
However, the primary contrasts will be each dose compared with control at 52 weeks. Because the 
outcome data are correlated (i.e., weight assessed from the same subject at different time points), 
weight over time will be modeled through the inclusion of random subject effects and/or structured 
variance-covariance matrices, with the best-fitting structure determined by Bayesian-Schwartz 
Information criteria (BIC). Supportive analyses will also include covariate adjustment for clinically 
significant variables (as determined from baseline evaluations and also other treatment variables, such 
as sessions attended). The above model will be fit using SAS PROC MIXED (Cary, NC), using restricted 
maximum likelihood (REML). The effect of treatment assignment on the secondary outcomes, such as 
BMI, waist circumference, serum lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c) will 
be evaluated using the linear mixed modeling approach described above. The proportion of subjects 
achieving 3, 4, or 5% weight loss will be compared between the treatment groups with the Fisher’s Exact 
test.  Type 1 error for secondary outcomes will be adjusted using the Bonferroni correction, basing the 
adjustment on the number of conceptually related statistical tests. 
 
Other Outcomes: Schizophrenia symptoms (BPRS), depression (BDI), dietary consumption (TFEQ), 
exercise ( YPAS), quality of life (Q-LES-Q and SF-36), cognition (MATRICS) and metabolism/inflammation 
markers will be obtained as presented in table 3. Summary statistics (frequencies, percents, means and 
standard deviations, and medians and interquartile ranges) will be calculated for naltrexone vs. placebo 
at each time point. Appropriate parametric (for normally distributed data) and non-parametric 
(deviation from normality in data distribution) approaches will be used to ascertain clinically meaningful 
group differences at each time point. Depending upon the distribution of these outcomes, the effect of 
naltrexone vs. placebo on change over time in each outcome will also be examined with GLMM, making 
appropriate model selections for either binary or continuous outcomes. 
Using UKU Side Effect Checklist and C-SSRS we will list and summarize side effects and suicidal 
tendencies reported in each treatment group. Medication changes that could not be avoided during the 
study will be examined in three groups: no change, change from a higher weight liability to a lower 
weight liability medication, and vice versa. Weight liability rankings of antipsychotics will be based on 
Allison and Newcomer. Distributions of all variables will be evaluated for normality. Alternative 
statistical approaches such as transformations or non-parametric tests will be used, as required. 
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES 
 
 
 
A.  DRUGS, BIOLOGICS and RADIOTRACERS 
 
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s)  
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s).  


Page 26 of 37 
 
 
Naltrexone is an FDA approved medication with the indication of alcohol dependence. 
 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:   
a. What is the Investigational New Drug (IND) number assigned by the FDA? N/A 
b. Who holds the IND?  
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________ 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________ 
 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step) 
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.      
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
 an exemption is being sought, review the following categories and complete the category that applies 
 (and delete the inapplicable categories): 
 
Exempt Category 1 
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes: 
 
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
     of a new indication for use or to be used to support any other significant change in the labeling for 
     the drug.  
 Yes  
 No 
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
      the intention of the investigation is NOT to support a significant change in the advertising for the 
      product. 
 Yes  
 No 
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations 
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)    
      associated with the use of the drug product. 
 Yes  
 No 
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)    
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). 
 Yes  
 No 
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No 
 
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption) 
 
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply): 
 Blood grouping serum 


Page 27 of 37 
 
 Reagent red blood cells  
 Anti-human globulin 
 
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and 
 
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160. 
 
Exempt Category 3 
 
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60 
 
Exempt Category 4 
 
 A clinical investigation involving use of a placebo if the investigation does not otherwise require 
submission of an IND. 
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
Pharmacodynamic Actions: Naltrexone is a pure opioid antagonist. It markedly attenuates or completely 
blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered 
with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and 
other opioids. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. 
However, it does produce some pupillary constriction, by an unknown mechanism. 
The administration of naltrexone is not associated with the development of tolerance or dependence. In 
subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology. 
Clinical studies indicate that 50 mg of naltrexone hydrochloride will block the pharmacologic effects of 
25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that 
doubling the dose of naltrexone hydrochloride provides blockade for 48 hours, and tripling the dose of 
naltrexone hydrochloride provides blockade for about 72 hours. 
Naltrexone blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition 
of enzymes) at opioid receptors. This makes the blockade produced potentially surmountable, but 
overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in 
excessive symptoms of histamine release in experimental subjects. 
The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the 
endogenous opioid system is suggested by preclinical data. Naltrexone, an opioid receptor antagonist, 
competitively binds to such receptors and may block the effects of endogenous opioids. Opioid 
antagonists have been shown to reduce alcohol consumption by animals, and naltrexone has been 
shown to reduce alcohol consumption in clinical studies. 


Page 28 of 37 
 
Naltrexone is not aversive therapy and does not cause a disulfiram-like reaction either as a result of 
opiate use or ethanol ingestion. 
Clinical Trials:  Alcoholism: The efficacy of naltrexone as an aid to the treatment of alcoholism was 
tested in placebo-controlled, outpatient, double blind trials. These studies used a dose of naltrexone 
hydrochloride 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods 
when given under conditions that enhanced patient compliance. Patients with psychosis, dementia, and 
secondary psychiatric diagnoses were excluded from these studies. 
In one of these studies, 104 alcohol-dependent patients were randomized to receive either naltrexone 
hydrochloride 50 mg once daily or placebo. In this study, naltrexone proved superior to placebo in 
measures of drinking including abstention rates (51% vs. 23%), number of drinking days, and relapse 
(31% vs. 60%). In a second study with 82 alcohol-dependent patients, the group of patients receiving 
naltrexone were shown to have lower relapse rates (21% vs. 41%), less alcohol craving, and fewer 
drinking days compared with patients who received placebo, but these results depended on the specific 
analysis used. 
The clinical use of naltrexone as adjunctive pharmacotherapy for the treatment of alcoholism was also 
evaluated in a multicenter safety study. This study of 865 individuals with alcoholism included patients 
with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. 
Results of this study demonstrated that the side effect profile of naltrexone appears to be similar in both 
alcoholic and opioid dependent populations, and that serious side effects are uncommon. 
In the clinical studies, treatment with naltrexone supported abstinence, prevented relapse and 
decreased alcohol consumption. In the uncontrolled study, the patterns of abstinence and relapse were 
similar to those observed in the controlled studies. Naltrexone was not uniformly helpful to all patients, 
and the expected effect of the drug is a modest improvement in the outcome of conventional 
treatment. 
Treatment of Opioid Addiction: Naltrexone has been shown to produce complete blockade of the 
euphoric effects of opioids in both volunteer and addict populations. When administered by means that 
enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the 
use of cocaine or other non-opioid drugs of abuse. 
There are no data that demonstrate an unequivocally beneficial effect of naltrexone on rates of 
recidivism among detoxified, formerly opioid-dependent individuals who self-administer the drug. The 
failure of the drug in this setting appears to be due to poor medication compliance. 
The drug is reported to be of greatest use in good prognosis opioid addicts who take the drug as part of 
a comprehensive occupational rehabilitative program, behavioral contract, or other compliance-
enhancing protocol. Naltrexone, unlike methadone or LAAM (levo-alpha-acetyl-methadol), does not 
reinforce medication compliance and is expected to have a therapeutic effect only when given under 
external conditions that support continued use of the medication. 
Dosage: Treatment of Alcoholism:   The placebo-controlled studies that demonstrated the efficacy of 
naltrexone as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 


Page 29 of 37 
 
50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not studied in 
these trials. 
Physicians are advised that 5% to 15% of patients taking naltrexone for alcoholism will complain of non-
specific side effects, chiefly gastrointestinal upset. Prescribing physicians have tried using an initial 25 
mg dose, splitting the daily dose, and adjusting the time of dosing with limited success. No dose or 
pattern of dosing has been shown to be more effective than any other in reducing these complaints for 
all patients. 
Treatment of Opioid Dependence: Once the patient has been started on naltrexone hydrochloride, 50 
mg once a day will produce adequate clinical blockade of the actions of parenterally administered 
opioids. As with many non-agonist treatments for addiction, naltrexone is of proven value only when 
given as part of a comprehensive plan of management that includes some measure to ensure the 
patient takes the medication. 
A flexible approach to a dosing regimen may be employed to enhance compliance. Thus, patients may 
receive 50 mg of naltrexone hydrochloride every weekday with a 100 mg dose on Saturday or patients 
may receive 100 mg every other day, or 150 mg every third day. Several of the clinical studies reported 
in the literature have employed the following dosing regimen: 100 mg on Monday, 100 mg on 
Wednesday, and 150 mg on Friday. This dosing schedule appeared to be acceptable to many naltrexone 
patients successfully maintaining their opioid-free state. 
Experience with the supervised administration of a number of potentially hepatotoxic agents suggests 
that supervised administration and single doses of naltrexone hydrochloride higher than 50 mg may 
have an associated increased risk of hepatocellular injury, even though three-times a week dosing has 
been well tolerated in the addict population and in initial clinical trials in alcoholism. Clinics using this 
approach should balance the possible risks against the probable benefits and may wish to maintain a 
higher index of suspicion for drug-associated hepatitis and ensure patients are advised of the need to 
report non-specific abdominal complaints. 
CONTRAINDICATIONS 
Naltrexone is contraindicated in: 
1. Patients receiving opioid analgesics. 
2. Patients currently dependent on opioids, including those currently maintained on opiate 
agonists [e.g., methadone or LAAM (levo-alpha-acetyl-methadol)]. 
3. Patients in acute opioid withdrawal  
4. Any individual who has failed the naloxone challenge test or who has a positive urine screen for 
opioids. 
5. Any individual with a history of sensitivity to naltrexone or any other components of this 
product. 
6. Any individual with acute hepatitis or liver failure. 
WARNINGS 
Hepatotoxicity: 


Page 30 of 37 
 
Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.  
Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver 
disease must be carefully considered in light of its hepatotoxic effects.  
The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic 
injury appears to be only five-fold or less. Naltrexone does not appear to be a hepatotoxin at the 
recommended doses.  
Patients will be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek 
medical attention if they experience symptoms of acute hepatitis. 
3.  Source:  a) Identify the source of the drug or biologic to be used.  
 
 
  
CMHC Research Pharmacy 
 
  
 
 
  
b) Is the drug provided free of charge to subjects? 
 Yes  
 No 
 
  
    If yes, by whom?  NIH grant funding 
 
4.  Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.  
 
Check applicable Investigational Drug Service utilized: 
     
   YNHH IDS                                                                      
   Yale Cancer Center  
     
   CMHC Pharmacy                                                          
  West Haven VA 
     
   PET Center                                                       
    None       
     
    Other:  
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
   
 
5.  Use of Placebo: 
 Not applicable to this research project 
 
If use of a placebo is planned, provide a justification which addresses the following: 
a. Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this. 
No other medications are approved or proven to be efficacious for antipsychotic weight gain. 
b. State the maximum total length of time a participant may receive placebo while on the study.  
52 weeks 
 
c.   Address the greatest potential harm that may come to a participant as a result of receiving     
       placebo.  
 
    Placebo, in this case, is equal to treatment as usual. 
 
d.   Describe the procedures that are in place to safeguard participants receiving placebo.  
Weekly (for the first 4 weeks) and every other week for the remainder – MD check ins/safety 
visits 
 
6. Use of Controlled Substances: 


Page 31 of 37 
 
 
Will this research project involve the use of controlled substances in human subjects? 
 
 Yes  
 No  See HIC Application Instructions to view controlled substance listings.  
 
 
If yes, is the use of the controlled substance considered: 
 
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant. 
 
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information. 
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project 
 
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.  
 
 
 
 No    If no, explain why this is acceptable.  Patients may not continue taking the study medication 
after their participation in the study has ended, however, if they are free to discuss taking naltrexone in an 
un-blinded manner with their primary physician, who should make the decision as to whether this is 
appropriate to do. 
 
  
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES  
1. 
Targeted Enrollment: Give the number of subjects: 
a.  targeted for enrollment at Yale for this protocol_200__ 
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites_N/A__  
 
2. 
Indicate recruitment methods below.  Attach copies of any recruitment materials that will 
be used. 
 
 Flyers 
 
 
 
 
 Internet/Web Postings 
 
 
 Radio 
 Posters  
 
 
 
 Mass E-mail Solicitation  
 
 Telephone 
 Letter 
 
 
 
  
 Departmental/Center Website 
 
 Television 
 Medical Record Review  
 
 Departmental/Center Research Boards 
 Newspaper 
 Departmental/Center Newsletters 
 Web-Based Clinical Trial Registries 
 
  YCCI Recruitment database 
 
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe): Clinician Referrals 
 
3. 
 Recruitment Procedures:  
a. Describe how potential subjects will be identified. 
Potential subjects will either self-identify by seeing a flyer and contacting us with their 
interest, or their clinician may identify them as potentially eligible and give them our contact 
information.  Familiar patients who have done multiple studies with us or who are patients of 
Dr. Tek may be identified by research staff as potentially eligible. 


Page 32 of 37 
 
b. Describe how potential subjects are contacted.  
Potential subjects will contact research staff in order to complete a telephone screening 
procedure that will determine eligibility.  At that point, we will get permission from the 
patient to contact them further about the study, via telephone or through their clinician.  If a 
potential subject has been in one of our studies in the past and has given permission to be 
contacted about future studies, research staff will call them to see if they are interested.  
c. Who is recruiting potential subjects?  
Cenk Tek, Vinod Srihari, Erin Reutenauer, Ismail Sinan Guloksuz, Suat Kucukgoncu, Katherine 
Lucas 
 
4. 
Screening Procedures 
a. Will email or telephone correspondence be used to screen potential subjects for eligibility 
prior to the potential subject coming to the research office? 
 Yes  
 No 
b. If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.  
 
HEALTH INFORMATION TO BE COLLECTED: 
 
 
HIPAA identifiers:  
 Names  
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits 
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 
20,000 or fewer people is changed to 000.  
  Telephone numbers 
 Fax numbers  
 E-mail addresses 
 Social Security numbers  
 Medical record numbers 
 Health plan beneficiary numbers  
 Account numbers  
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older  
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers  
 Device identifiers and serial numbers  
 Web Universal Resource Locators (URLs)  
 Internet Protocol (IP) address numbers  
 Biometric identifiers, including finger and voice prints  
 Full face photographic images and any comparable images  
 Any other unique identifying numbers, characteristics, or codes  
 
 
5. 
Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  
 Yes, all subjects 


Page 33 of 37 
 
 Yes, some of the subjects 
 No 
 
If yes, describe the nature of this relationship. 
 Subjects are clinically stable outpatients with SMI who are followed up in the PI’s clinic 
within CMHC. 
 
6. 
Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only.  Note: if you are collecting 
PHI as part of a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
 
Choose one: For entire study: ______ For recruitment purposes only: ___X___ 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; 
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data; 
It would be impractical to obtain a subject’s authorization, as the initial PHI we 
collect from them is obtained over the phone.  This information is kept in a locked, 
secure filing cabinet and is not shared with anyone outside of the study.  
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
 
  
 Compound Consent and Authorization form 
 
  
 HIPAA Research Authorization Form 
 
 
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  
 
Tek, Srihari, Reutenauer, Guloksuz, Kucukgoncu, Lucas 
 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.  


Page 34 of 37 
 
 
The procedures, risks and benefits of the study will be discussed in detail during a face to face 
interview with the subject. Subjects will be given the consent for to review.  Consent staff will 
be available in person to answer all questions at that time. 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.  
Subjects with limited decision making capacity will not be enrolled. 
 
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.  
 
Adult compound consent form for patient volunteers will be employed. 
 
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.  
 
Non-English speaking subjects will not be enrolled 
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.   
 
 Not Requesting a consent waiver  
 
 Requesting a waiver of signed consent 
       
 Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity   
 No  
AND 


Page 35 of 37 
 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
    Confidentiality & Security of Data: 
a.    What protected health information (medical information along with the HIPAA 
identifiers) about subjects will be collected and used for the research?   
 
PHI that will be collected includes name, date of birth, and other demographic variables.  Access to 
existing CMHC clinical charts will be authorized by release of information.  This information will be 
used solely for access to diagnosis and medication information and not for research data collection 
purposes. 
Some PHI will become part of a separate CMHC medical record. If a participant does not already have 
a medical record at CMHC, one will be created. The information that will be entered into the medical 
record will include the following: a copy of your signed informed consent and a Research Tracking for 
CMHC Patients Form which states information about the patient’s participation in this study for chart 
records including the title of the research study, duration of their participation, and if the study 
involves taking a medication/placebo.  No information regarding the results of drug testing will be 
included in the CMHC medical record. 
        
b.    How will the research data be collected, recorded and stored?  
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard    
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
the identifiable study data and the storage media indicated above during and after the 
subject’s participation in the study? 
 
All data will be kept in locked confidential files in locked offices at the Connecticut Mental Health 
Center or on the secure Yale or CMHC server. Computerized data will be password protected and 
only researchers involved in the study will have access to it.  For purposes of data analysis and 
publication, only identification numbers will identify subjects. In all records of this study, 
participants will be identified by a number, and their name will be known only to the researchers. 
The principal investigator will keep a link that identifies the participant and their coded information, 
but this link (key) will be kept secure and available only to the PI or selected members of the 
research team and will be kept in a different physical location than the coded data.  At the end of 
the study, any personal identifying information will be destroyed. 
 
Do all portable devices contain encryption software? 
 Yes   
 No 
         If no, see http://hipaa.yale.edu/guidance/policy.html 
  
e. What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. 
If no, describe how the data and/or identifiers will be secured. 
 


Page 36 of 37 
 
At the end of the study, any personal identifying information will be destroyed.  We will utilize the 
expertise of the Yale ITS to perform approved degaussing procedures in order to fully destroy any 
electronic and physical data remaining at the end of the study. 
 
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)  
     National Institutes of Health (NIH), Tek, Srihari, Reutenauer, Guloksuz, Kucukgoncu, Lucas 
 
g.   If appropriate, has a Certificate of Confidentiality been obtained?  
 
      An application was submitted to NIDDK for a certificate of confidentiality.  The Coc was 
granted on April 8, 2013 and is set to expire February 28, 2018. 
 
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? No (e.g. HIV testing – reporting of communicable diseases; parent interview -
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to 
be reported. N/A 
SECTION IX: POTENTIAL BENEFITS 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)  
 
Obesity is an important health risk. Modest decreases of body weight (4% total body weight) in 
overweight individuals decrease risk for development of diabetes and cardiovascular disease as much as 
fifty percent. Prevention of development of these illnesses will increase subjects’ quality of life, decrease 
morbidity and mortality as well as decrease health care expenditures for the overall society. 
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
 
Subjects can enroll in available weight loss and exercise programs at CMHC, community, and through 
their primary care providers. 
 
2.  
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  
 
 
Subjects will be paid in cash at each in person appointment.  The baseline procedures will span 3 
appointments, for which they will receive $15 each time ($45 total).  Following enrollment, subjects will 
be seen weekly for the first 4 weeks.  They will be paid $5 each for weeks 1-3.   After the first 4 weeks, 
subjects will attend appointments every other week.  They will be paid $10 for these appointments and 


Page 37 of 37 
 
on an escalating payment for each monthly milestone ($15, $20, $25, $30, $35…$70).  The total amount 
a subject can earn for completing the entire study is $700. 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.      
 
 
There is no cost to the subject. 
 
4. 
In Case of Injury: This section is required for any research involving more than minimal risk. 
 
a.     Will medical treatment be available if research-related injury occurs?  
 
Yes, medical care will be provided for physical injury or illness that occurs as a direct 
result of subject participation in this study. 
b. Where and from whom may treatment be obtained?  
The PI is responsible to make the necessary referrals to Yale University/YNHH clinics or 
patient’s own primary care physician. 
c. Are there any limits to the treatment being provided?  
 
No 
d. Who will pay for this treatment? 
There are no funds available for compensation of care.  The patient and/or their 
insurance will be responsible for treatment for any study related injury.  
e. How will the medical treatment be accessed by subjects?  
 
Referral by the PI.