The goal of this clinical study with research procedures is to learn how stopping and restarting tirzepatide (a medication that helps regulate blood sugar and appetite) affects brain activity, behavior, and health in adults ages 18-70 who are currently taking tirzepatide. Specifically, the study aims to examine how a short pause in tirzepatide affects hunger, mood, sleep, and daily functioning; how stopping and restarting tirzepatide alters brain chemistry and brain responses to food-related images; and how these changes relate to health measures such as quality of life and emotional well-being. There is no comparison group; instead, researchers will assess changes within each participant across three time points: while taking tirzepatide, after stopping it for 3-4 weeks, and after restarting it for 6-8 weeks. Participants will attend three in-person visits lasting approximately 3-4 hours each, during which they will complete interviews, questionnaires, and cognitive tasks; provide a urine sample (pregnancy screening for females); undergo a brain scan using magnetic resonance imaging (MRI) and MR spectroscopy (MRS); and receive a kit to provide a small stool sample. Participants will also complete two brief check-in phone calls between visits and the online BrainHealth Index between sessions, which includes surveys and cognitive tasks. All changes to tirzepatide use will occur under the supervision of a study physician to support participant safety and comfort, and the total study duration is approximately 13 weeks.
This study specifically recruits individuals currently being prescribed for tirzepatide. The experimental design will consist of a brief discontinuation of the drug for roughly 3-4 weeks followed by a reinitiation of the medication. Prescription and administration of tirzepatide is done as part of normal patient care and is not a component of the study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
40
Participants will temporarily pause their tirzepatide medication for 3-4 weeks and then restart it for 6-8 weeks under the supervision of a study physician. The medication change is done only for research purposes to study how stopping and restarting tirzepatide affects brain activity, appetite, mood, and other health measures. During this period, participants will complete MRI scans, behavioral assessments, questionnaires, and provide stool samples across three study visits.
Center for BrainHealth
Dallas, Texas, United States
Change From On-Treatment to Discontinuation and Re-Initiation in Food Cue-Evoked BOLD Response in Reward and Salience Brain Regions
This outcome measures within-participant change in blood-oxygen-level-dependent (BOLD) signal during a food cue reactivity task, assessed using functional magnetic resonance imaging (fMRI). BOLD response will be quantified as the mean percent signal change in predefined reward- and salience-related regions of interest (including the ventral striatum and insula) during food image presentation relative to non-food control images. Higher BOLD values indicate greater neural responsivity to food cues.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Resting-State Functional Connectivity Within Salience and Executive Control Networks
This outcome measures within-participant change in resting-state functional connectivity, assessed using fMRI. Connectivity strength will be calculated using correlation coefficients between predefined brain regions within salience and executive control networks. Higher values indicate stronger functional connectivity.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Brain Neuromelanin Signal
This outcome measure assesses within-participant change in neuromelanin signal intensity in the substantia nigra. Neuromelanin-sensitive magnetic resonance imaging (MRI) will be used to quantify signal intensity within a predefined substantia nigra region of interest. Higher values indicate greater neuromelanin-related signal intensity.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Brain Glutamate Levels
This outcome measures within-participant change in neurochemical and dopaminergic markers associated with reward processing. Glutamate levels will be measured in the medial prefrontal cortex using magnetic resonance spectroscopy (MRS). Higher values indicate greater metabolite concentration or signal intensity.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in State Food Craving Severity
This outcome measure assesses within-participant change in momentary food craving severity. Food cravings will be measured using the Food Cravings Questionnaire-State (FCQ-S), a self-report instrument assessing current craving intensity. Scores range from 15 to 75, with higher scores indicating greater food craving severity.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Trait Food Craving Severity.
This outcome measure assesses within-participant change in habitual food craving frequency and intensity. Trait-level food cravings will be assessed using the Food Cravings Questionnaire-Trait, a self-report questionnaire. Scores range from 39 to 234, with higher scores indicating more frequent and intense food cravings.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Addictive-Like Eating Symptoms.
This outcome measure assesses within-participant change in addictive-like eating behaviors. Addictive-like eating symptoms will be assessed using the Yale Food Addiction Scale 2.0, a self-report measure of addictive-like eating based on diagnostic criteria. Symptom counts range from 0 to 11, with higher scores indicating greater severity of addictive-like eating behavior.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Intrusive Food-Related Thoughts.
This outcome measure assesses within-participant change in the frequency of intrusive food-related thoughts. Intrusive food-related cognitions will be assessed using the Food Noise Questionnaire, a self-report measure consisting of five items assessing persistent and intrusive thoughts about food. Total scores range from 0 to 20, with higher scores indicating greater food noise and more frequent intrusive food-related thoughts.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Dietary Pattern Quality.
This outcome measure assesses within-participant change in dietary behaviors and overall eating patterns. Dietary patterns will be assessed using the Rapid Eating Assessment for Participants - Shortened Version, a self-report questionnaire evaluating habitual dietary behaviors. Total scores range from 13 to 39, with higher scores indicating poorer dietary patterns.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Attentional Bias Toward Food Cues.
This outcome measure assesses within-participant change in attentional bias toward food-related stimuli. Attentional bias will be assessed using a Food-Modified Stroop Task, a performance-based behavioral task. Attentional bias is quantified as the difference in reaction time (milliseconds) between food-related and neutral stimuli. Greater reaction time differences indicate stronger attentional bias toward food cues.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Perceived Loss of Control Over Eating.
This outcome measure assesses within-participant change in perceived loss of control over eating behavior. Perceived loss of control will be assessed using the Loss of Control Over Eating Scale-Short Form, a self-report questionnaire assessing the subjective experience of being unable to control eating. Total scores range from 0 to 28, with higher scores indicating greater perceived loss of control over eating.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Psychological Responsiveness to Food Availability.
This outcome measure assesses within-participant change in psychological responsiveness to the food environment. Responsiveness to food availability will be assessed using the Power of Food Scale, a self-report questionnaire measuring the psychological impact of food availability independent of actual consumption. Scores are calculated as a mean item score ranging from 1 to 5, with higher scores indicating greater psychological impact of food availability.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Uncontrolled Eating Behavior.
This outcome measure assesses within-participant change in uncontrolled eating behavior. Uncontrolled eating will be assessed using the Uncontrolled Eating subscale of the Three-Factor Eating Questionnaire, a self-report measure of tendencies toward loss of control over eating. Subscale scores range from 0 to 36, with higher scores indicating poorer regulation of eating behavior.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Mood Disturbance.
This outcome measure assesses within-participant change in mood disturbance. Mood will be assessed using the Profile of Mood States-Second Edition, a validated self-report questionnaire assessing multiple mood domains including tension, depression, anger, vigor, fatigue, and confusion. Mood disturbance will be quantified using the Total Mood Disturbance score, which ranges from -32 to 200, with higher scores indicating greater overall mood disturbance (reflecting higher negative mood and lower vigor).
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Perceived Stress.
This outcome measure assesses within-participant change in perceived psychological stress. Perceived stress will be measured using the Perceived Stress Scale (PSS), a self-report questionnaire assessing the degree to which situations in one's life are appraised as stressful over the past month. Scores range from 0 to 40, with higher scores indicating greater perceived stress.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Emotional Health and Psychological Well-Being.
This outcome measure assesses within-participant change in emotional health and psychological well-being. Emotional functioning will be assessed using the NIH Toolbox Emotion Battery, a self-report assessment comprising multiple domains, including negative affect, psychological well-being, stress and self-efficacy, and social relationships. Domain scores are reported as standardized T-scores (mean = 50, standard deviation = 10; typical range \~20-80). For negative affect domains, higher scores indicate worse emotional health, whereas for well-being and social functioning domains, higher scores indicate better emotional health.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Quality of Life.
This outcome measure assesses within-participant change in quality of life. Quality of life will be assessed using the World Health Organization Quality of Life-BREF, a 26-item self-report questionnaire assessing perceived quality of life across physical health, psychological health, social relationships, and environmental domains. Total scores range from 26 to 130, with higher scores indicating better overall quality of life.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Withdrawal-Related Psychological Symptoms.
This outcome measure assesses within-participant change in withdrawal-related psychological and behavioral distress during tirzepatide discontinuation. Withdrawal symptoms will be assessed using a Withdrawal Symptom Checklist, a self-report questionnaire assessing appetite and physiological symptoms, eating behavior and perceived control, restrictive dieting and compensatory behaviors, mood and emotional distress, and general physical and functional impairment associated with medication withdrawal. Items are rated on a 5-point scale ranging from 0 (not at all/never) to 4 (very severe/very often) and summed to create a total score. Total scores range from 0 to 128, with higher scores indicating greater withdrawal-related psychological and behavioral distress.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Sleep Quality as Measured by the Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-report questionnaire assessing subjective sleep quality over the past month. Global scores range from 0 to 21, with higher scores indicating poorer sleep quality.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Addiction-Related Problem Severity
This outcome measure assesses within-participant change in addiction-related problem severity across multiple functional domains. Addiction-related severity will be assessed using the Addiction Severity Index, a standardized semi-structured interview administered by trained study personnel. The Addiction Severity Index evaluates seven domains: medical status, employment/support status, alcohol use, drug use, legal status, family/social functioning, and psychological status, based on both past 30-day functioning and lifetime history. Domain-specific composite scores range from 0 to 1, with higher scores indicating greater addiction-related problem severity.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Substance Use Frequency and Quantity.
This outcome measure assesses within-participant change in substance use behavior. Substance use frequency and quantity will be measured using the Timeline Follow-Back (TLFB) method, which captures the number of days and amount of alcohol, nicotine, and cannabis use over the past 30 days. Higher values indicate more frequent or greater substance use.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
Change From Baseline in Risky and Impulsive Behavior.
This outcome measure assesses within-participant change in engagement in risky, impulsive, and self-destructive behaviors. Behaviors will be assessed using the Risky, Impulsive, and Self-Destructive Behavior Questionnaire, a 38-item self-report measure. Frequency responses are binned and summed to create a total score ranging from 0 to 152, with higher scores indicating greater engagement in risky, impulsive, and self-destructive behaviors.
Time frame: Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation
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