Metabolic and Behavioural Effects of CONTRAVE as Potential Mechanisms of Weight Loss in Adults With Obesity

Detailed Description This study is a two-arm, randomized, double-blind, placebo-controlled design, wherein N=40 adults aged 18-64 years with obesity (body mass index \[BMI\] \> 30) and who meet all inclusion criteria (outlined below) will be randomized to one of two groups: Diet + CONTRAVE® (CONTRAVE®, N=20) or diet + Placebo (Placebo, N=20). Participants will be randomized 1:1 per condition using a randomization program (computer-program). Each participant will be assigned a unique identifier code. Master codes containing the link between the identification code and name of the individual will be stored on a password-protected master file (excel) that will be saved on hospital servers (password-protected) in the Clinical EEG \& Neuroimaging Laboratory (Co-PI: N. Jaworska). All hard-copies of confidential information (e.g., screening documents, consent forms) will be housed in secured cabinets within the Clinical EEG Laboratory. Recruitment for this study will occur from Dr. J. Shiau's LEAF Weight Management Clinic. Following initial assessment of needs, a staff member of the LEAF clinic will mention this study and ask interested individuals to complete an online form as initial registration in the study. These potential participants will be contacted by research staff who are not affiliated with the LEAF clinic (i.e., research assistant or trainees who are part of the research team); the research personnel will then phone interested participants to explain the study and associated risks and benefits of participating. Participants who do not wish to participate in the research study after details are provided, will continue with the normal intake process at the LEAF clinic. Participants who wish to participate will complete a telephone screening questionnaire with the research staff. Eligible participants will be booked for an in-person screening session at The Royal Ottawa Mental Health Centre. Screening and Testing Sessions Overview: Participants will have 5 in-person laboratory visits (Clinical EEG \& Neuroimaging Laboratory, under the direction of Dr. Natalia Jaworska, at The Royal/IMHR; and, Behavioural and Metabolic Research Laboratory, under the direction of Dr. Eric Doucet, at the University of Ottawa). Specifically, * Visit 1: in-person screening and test dose visit at the Clinical EEG \& Neuroimaging Lab, at The Royal; * Visit 2: baseline metabolics/cognition/food craving assessment at the Behavioural and Metabolic Research Laboratory, University of Ottawa; * Visit 3: baseline EEG/MRI imaging at the Clinical EEG and Neuroimaging Laboratory at The Royal; * Visit 4: 4-week post-intervention metabolics/cognition/food craving assessment at the Behavioural and Metabolic Research Laboratory, University of Ottawa; * Visit 5: 4-week post-intervention EEG/MRI imaging at the Clinical EEG and Neuroimaging Laboratory at The Royal. Phone Screening: Participants will be recruited from the LEAF clinic. Those who are interested in participating complete an online registration form. They will then be contacted by research study personnel and screened over the phone, regarding basic inclusion criteria. The study will also be explained. Following successful phone screening, an in-person screening visit and test dose (administered by The Royal pharmacy and overseen by Dr. Pierre Blier) visit will be scheduled at the IMHR (Dr. Jaworska's laboratory). Only participants who have been cleared medically by the LEAF clinic/Dr. Judy Shiau will be referred to this study. In Person Screening: This will occur at The Royal. The informed consent will be carried out, and any questions will be addressed and documented directly on the consent form. Second, a brief clinical assessment (to ensure that outstanding inclusion and exclusion criteria are met), using modules from the MINI (Mini International Neuropsychological Inventory) including the mood module, substance use module, psychotic disorders module, and eating disorders module (approximately 30min). Heart rate and blood pressure will then be measured reviewed by Dr. Pierre Blier. Test Dose Administration (as part of In Person Screening Session): Subsequently (during the in-person screening), The Royal's pharmacy would issue one test dose of the drug placebo or CONTRAVE® based on the participant drug randomization. This pill would be given to the participant. The test dose will be 1 tablet of placebo or CONTAVE® (8mg Naltrex/90 mg Buproprion). The participant and study doctor and research staff will be blind to treatment (they will not know whether they will be given CONTRAVE® or placebo). Only research personnel from the laboratory -not directly related to this study- and the pharmacy team will know what the randomization is (i.e., what participant is receiving what drug). The participant would take the pill along with crackers/light snack in Dr. Blier's laboratory (as CONTRAVE® should be taken with food) and watch a movie and/or read a book or work (participant preference) for 3 hours in one of the examination chambers in the Mood Disorders Unit. After 3 hours of ingesting the test dose, and -at that time- exhibiting no/minimal adverse symptoms (i.e., most common adverse events symptoms include nausea, vomiting, constipation, stomach pain, headache, dizziness, trouble sleeping, increased sweating, flushing, and dry mouth or strange taste in the mouth), participants will be free to go home. If any concerning, unexpected or severe adverse events linger, the clinician will be responsible for managing the participant, in accordance with standard medical procedures (Dr. Blier). Based on tolerability to the test dose, in consultation with the participant and the clinician, the participant will be invited to continue (or not) with the remainder of the study. A week after the test dose, eligible participants (i.e., those who tolerate the test dose, and wish to proceed) will be booked for their baseline session. Those participants who are deemed to be intolerant to the test-dose will be counted screen failures. Body measures (e.g., weight, height, approximately 5min) will be collected and the neurocognitive battery (NIH Toolbox; approximately 30min); The neurocognitive battery, which assesses various cognitive domains (e.g., spatial memory, verbal memory, attention, inhibition) will be used to characterize the sample, and explore whether CONTRAVE® changes cognitive profiles. Participants will also undergo a session in the mock scanner situated at the BIC to ensure that they can fit into the bore of the magnet and are comfortable with neuroimaging (approximately 15min). For participants who are not comfortable with scanning/cannot fit into the scanner, they will be invited to participate in all the other elements of the proposed work (outlined below), apart from the neuroimaging. Baseline Session (uOttawa): Participants will complete a baseline assessment in the Behavioural and Metabolic Research Laboratory, University of Ottawa under Dr. Doucet's supervision. In his laboratory, they measure the following: * Body Composition * Resting and Post-Prandial Energy Expenditure * Food palatability and appetite ratings * Food Craving * Food Reinforcement * Changes in eating behavior traits/styles (Restrained, Emotional and External eating) * Taste sensitivity/olfaction to a variety of flavors (e.g., sweet, salty, bitter etc) * Lunch will be served and participants will be asked to self-select foods from a food menu. They will be instructed to eat as much as they desire of these foods. Energy intake and food preferences will then be assessed from the weight of the different foods consumed. Baseline Session (The Royal): The baseline session will take place in the Clinical EEG \& Neuroimaging Lab under the supervision of Dr. Jaworska. The following measures will be collected: A) Electroencephalographic (EEG) \& Autonomic Nervous System (ANS) assessments: EEG \& ANS assessments involve using a 64 or 32-channel EEG system along with additional electrodes for ANS indices like HRV and SCR. Setup by experienced personnel takes 20-30min. Data collection includes: * 5-min eyes closed EEG and ANS recordings for baseline neural features. * EEG and ERPs during a food impulsivity task, evaluating impulsivity for various food and non-food stimuli. * A reward task assessing effort for rewards, with specific ERPs reflecting reward and error processing. * Measurement of HRV and SCR during each task. B) Neuroimaging: Participants qualifying for neuroimaging will undergo a 30min brain scan at the Brain Imaging Centre using a 3T PET-MR Siemen's scanner. Scans include: * Resting-state fMRI focusing on connectivity and activity in appetitive, reward, and cognitive regions. * Task-based fMRI comparing responses to high-caloric vs. low-caloric vs. neutral images * High-resolution structural imaging (MEMPRAGE) to assess anatomical features in obesity, compared with healthy-weight data. * If time permits, magnetic resonance spectroscopy (MRS) to assess neurochemical composition in the ventral striatum/nucleus accumbens, primarily related to reward processing. C) Clinical measures include self-report depression and anxiety questionnaires. D) Sleep and activity data will be collected via daily logs and accelerometry. Intervention: Following the completion of the baseline sessions (TheRoyal/uOttawa), participants will begin their interventions, which will include starting their medication (placebo or CONTRAVE®, based on randomization) and LEAF diet program. Participants will obtain their 4-week prescriptions from The Royal pharmacy after their in-person screening visit at The Royal. However, they will be told not to commence their treatment until they complete both baseline testing sessions and are instructed to start the medication (i.e., start of intervention week 1). The prescription for the CONTRAVE® and placebo will be filled out by the responsible physician, Dr. Judy Shiau; this will be faxed/send directly to the The Royals' pharmacy prior to the participants' arrival for their in-person screening visit. The diet intervention will commence the same day as the start of the placebo/CONTRAVE® administration. Diet adherence and food intake will be measured daily using our online data capture system (REDCap) (approximately 1min) (carried out the same time as the sleep and adverse events questionnaire). Food journaling will be carried out through the Eat.Love platform as part of the diet coaching that will be guided by the LEAF clinic. Monitoring: Daily monitoring of side effects/adverse events will be conducted by a devoted research team member in Dr. Jaworska's laboratory using our REDCap during the first week of use, and weekly thereafter (i.e., mid of week 2, week 3 and week 4). A copy of all adverse events ratings for all active participants will be shared with Dr. Shiau on a weekly basis for clinical review and assessment, which Dr. Shiau will then sign, date and return to the research team. If participants experience moderate adverse events, the research personnel will inform Dr. Shiau immediately, and she can recommend dose adjustments. Participants who experience unexpected/severe adverse events will be instructed to contact the LEAF clinic to report this immediately (as per LEAF protocols). Severe adverse events will be handled as per regulated standards of care. If Dr. Shiau (responsible physician) deems that the adverse events are severe, she might advise the participant to discontinue the drug. This will be communicated to the research team (a member of the research team will thus break the blind to determine whether the drug was placebo or CONTRAVE®). Discontinuation due to adverse symptoms will be documented in the participant file. Post-Intervention Assessment: Following the completion of the 4-weeks of medication and diet program, participants will complete the exact same testing sessions as during the baseline sessions. The sessions will be carried out as close as possible to the end of the 4-weeks.