Clinical and Neurobehavioral Changes With Weight Loss Drug Discontinuation and Reinitiation
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-70
SponsorThe University of Texas at Dallas
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Aged 18-70 years.
Currently on tirzepatide.
Currently receiving care from University of Texas- Southwestern (UTSW) Weight Wellness Clinic.
Cognitively capable of understanding and signing informed consent.
Disqualifiers
History of major neurological or psychiatric disorders, including substance use disorders that might confound brain imaging results (e.g., stroke, epilepsy, multiple sclerosis, schizophrenia, major depression requiring hospitalization).
Diagnosis of Type 2 Diabetes.
Current diagnosis of an eating disorder.
Use of medications affecting weight other than tirzepatide.
Trial design
Design model
Single group
Treatments tested in this trial
Discontinuation and Reinitiation of Tirzepatide
Other interventionParticipants 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.
Treatment groups
40 Participants
are divided into 1 treatment groupGroup A: Tirzepatide Discontinuation and Re-Initiation ArmExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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-initiationSecondary outcomes
1
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-initiation2
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-initiation3
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-initiation4
Change From Baseline in Blood-Brain Permeability Levels
This outcome measures within-participant change in neurovascular properties of the blood-brain barrier. Blood-brain barrier permeability to water will be measured using phase-contrast arterial spin tagging (WEPCAST). Higher values indicate greater blood-brain barrier permeability.
Time frame
Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiationOther outcomes
1
Change From Baseline in Gut-Derived Neurotransmitter Levels.
This outcome measure assesses within-participant change in gut-derived neurotransmitter levels associated with tirzepatide discontinuation and re-initiation. Neurotransmitter levels will be measured from stool samples collected at each study timepoint and analyzed for gut-derived neurotransmitters relevant to brain-gut signaling. Changes in values reflect alterations in gut-derived neurotransmitter levels.
Time frame
Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation2
Change From Baseline in Gut Microbiome and Inflammatory Marker Profiles
This outcome measure assesses within-participant change in gut microbiome composition and gut-related inflammatory markers. Exploratory analyses will be conducted on stool samples to evaluate changes in microbial profiles and inflammatory markers associated with tirzepatide discontinuation and re-initiation. Higher or lower values reflect changes depending on the specific marker assessed.
Time frame
Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation3
Change in Multidimensional Brain Health as Measured by the BrainHealth Index
This outcome measure assesses within-participant change in overall brain health using the BrainHealth Index (BHI), a multidimensional composite derived from standardized self-report questionnaires and objective cognitive performance measures developed at the Center for BrainHealth. The BHI integrates measures across three domains: cognitive function/clarity (e.g., attention, learning and memory, reasoning, processing speed, and sleep quality), emotional balance (e.g., mood, stress, anxiety, happiness), and social connectedness (e.g., compassion, social support, resilience, engagement in meaningful activities, and life satisfaction). Component measures are standardized and combined using predefined BrainHealth Index aggregation procedures to generate a single composite score, with higher scores indicating better overall brain health.
Time frame
Between baseline and discontinuation (about 2 weeks after baseline), and between discontinuation and re-initiation (about 4 weeks after start of reinitiation)4
Occurrence and Severity of Withdrawal-Related Symptoms During Medication Discontinuation
This outcome measure assesses within-participant change in withdrawal-related symptom severity during tirzepatide discontinuation. Withdrawal symptoms will be assessed using the Glucagon-like Peptide-1 (GLP-1) Withdrawal Symptom Checklist Brief Version, a self-report questionnaire assessing appetite and physiological symptoms, eating behavior and loss of control, restrictive dieting and compensatory behaviors, psychological/mood distress, and general physical and functional symptoms over the past 7 days. Items are rated on a 5-point scale ranging from 0 (not at all/never) to 4 (very severe/very often). A total symptom severity score is calculated as the mean of items 1-5, yielding a minimum score of 0 and a maximum of 4, with higher scores indicating greater withdrawal-related symptom severity. An additional item assessing overall subjective burden is collected separately for descriptive purposes on a scale of 0 to 4 with higher scores indicating higher burden.
Time frame
Between baseline and discontinuation (about 2 weeks after baseline), and between discontinuation and re-initiation (about 4 weeks after start of re-initiation)Sponsors and contacts
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The University of Texas at Dallas
Lead sponsor
University of Texas Southwestern Medical Center
Collaborator
Source ClinicalTrials.gov