Eating Behavior, Overweight and Obesity
Conditions
Keywords
bromocriptine, dopamine agonist, TaqIA polymorphism, eating behavior, food intake, overweight, obesity
Brief summary
The current project applies an integrative three-prong approach to investigate the potential of the dopamine D2 receptor (DRD2) agonist bromocriptine to: 1) increase homeostatic satiation signaling, 2) alter neural circuitry to reduce hedonically motivated food intake, and 3) examines a genetic predisposition that may markedly impact the effectiveness of this medication in those at high risk for T2DM.
Detailed description
Twenty-nine million Americans have diagnosed type 2 diabetes (T2DM), with fewer than half able to meet treatment goals and considerably more are at risk for development of T2DM. Implementation of healthy eating behavior has been identified as a barrier to T2DM treatment and efficacy. The determinants of eating behavior and weight regulation involve a complex interaction among individual-level homeostatic, hedonic, and genetic systems, and the external food environment. The high prevalence of obesity and T2DM suggests hedonic motivation to consume food overrides homeostatic satiation signaling, resulting in excess food intake. Elevated intake increases body mass and promotes T2DM incidence via dysregulation of glucagon-like peptide 1 (GLP-1), amylin, and adiponectin, which in turn can negatively impact T2DM treatment options. Use of a pharmaceutical, such as bromocriptine, to aid in behavioral change is a novel method for treating and ameliorating T2DM and warrants investigation given that previous work has shown reward response to food images mediates T2DM control. Use of functional magnetic resonance imaging (fMRI) techniques to predict and evaluate hedonically-motivated eating behavior can be used to measure sensitivity to reward, and the role it plays in developing obesity, and is therefore an excellent tool to examine the associations among bromocriptine, satiety hormones, reward sensitivity and eating behavior. Moreover, since 20-35% of the population carries the DRD2 TaqIA A1 allele, and 65% of the population is overweight or obese and at high risk for T2DM development or currently diagnosed, as much as 23% of the population may greatly benefit from dopamine agonist treatment. Despite the possibility that bromocriptine may have robust impact on T2DM treatment or as prevention therapy in those that are genetically predisposed, few data are available that directly examine the three systems (homeostatic, hedonic, genetic) available to assess whether a genetically-informed, personalized T2DM treatment is viable.
Interventions
2 capsules, orally administered once
1.6mg (2 0.8mg capsules), orally administered once
Sponsors
Study design
Intervention model description
Participants are randomly assigned to one of two possible intervention arms (active drug vs. placebo) at baseline. Following a 2-week washout period, participants receive the other intervention.
Eligibility
Inclusion criteria
* Baseline BMI between 25 and 35
Exclusion criteria
* Individuals with current fMRI contraindications (e.g., metal implants, braces) * Probable current Axis I psychopathology (e.g., major depression disorder, panic disorder, generalized anxiety disorder, bipolar disorder) * Habitual use of cigarettes or illicit drugs * Pregnancy or breastfeeding * Diagnosis of serious medical problems (e.g., diabetes, cardiovascular disease, stroke) * Current weight loss dieting and/or weight fluctuations great than 10 lbs in the previous 6 weeks * Do not consume dairy * Allergy to bromocriptine, dairy, and nuts
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ad Libitum Food and Beverage Intake (g) | Within 15 minutes of completion of the ad libitum period | Ad libitum food intake of highly-palatable snacks is assessed during each intervention arm. Participants are left alone for 25 minutes to eat as much as they want from a selection of snacks (M&Ms, Skittles, Doritos, cheddar popcorn) and a chocolate milkshake. Both snacks and milkshake are pre- and post-weighed to determine ad libitum food intake. |
| Hedonic Ratings of Food as Measured by a Visual Analog Scale | Up to 5 minutes prior to ad libitum period start | Testing the effects of the drug on hedonic ratings (pleasantness, desire to consume) of milkshake and snacks on a scale from -100 to 100. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable). |
| Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water | Baseline and 2 Weeks | The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake\>h2o anticipation and milkshake\>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to each of these contrasts are extracted and compared between the two arms. The paradigm has 64 trials and each trial starts with the presentation of a cue for 1s signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a period of 6s. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Within 15 minutes of completion of the ad libitum period | Testing the drug by gene (TaqIA) interaction on ad libitum food intake (g).The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant. |
| Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Up to 5 minutes prior to ad libitum period start | Testing the drug by gene (TaqIA) interaction on hedonic ratings (pleasantness, desire to consume) of milkshake on a scale from -100 to 100. Testing the drug by gene (TaqIA) interaction on ad libitum milkshake (g). The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable). |
| Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Baseline and 2 Weeks | The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake\>h2o anticipation and milkshake\>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to these contrasts are extracted and used to test the drug by gene (TaqIA) interaction. The paradigm has 64 trials and each trial starts with the presentation of a cue signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a 6s period. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Cross-over design where participants receive either a single dose of bromocriptine or placebo at the initial visit. After a 2-week washout period, they receive the opposite drug at the cross-over visit. | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (2 Weeks) | Adverse Event | 2 | 0 |
| Washout (2 Weeks) | Lost to Follow-up | 0 | 1 |
| Washout (2 Weeks) | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 22.4 years STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Region of Enrollment United States | 55 Participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 51 |
| other Total, other adverse events | 2 / 54 | 0 / 51 |
| serious Total, serious adverse events | 0 / 54 | 0 / 51 |
Outcome results
Ad Libitum Food and Beverage Intake (g)
Ad libitum food intake of highly-palatable snacks is assessed during each intervention arm. Participants are left alone for 25 minutes to eat as much as they want from a selection of snacks (M&Ms, Skittles, Doritos, cheddar popcorn) and a chocolate milkshake. Both snacks and milkshake are pre- and post-weighed to determine ad libitum food intake.
Time frame: Within 15 minutes of completion of the ad libitum period
Population: Data was collected via an iPad and sometimes recorded no value, as such the decrease in the sample was due to missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Ad Libitum Food and Beverage Intake (g) | Snacks intake | 71.5 g | Standard Deviation 58.5 |
| Bromocriptine | Ad Libitum Food and Beverage Intake (g) | Milkshake intake | 24.9 g | Standard Deviation 61.2 |
| Placebo | Ad Libitum Food and Beverage Intake (g) | Snacks intake | 81.9 g | Standard Deviation 55.9 |
| Placebo | Ad Libitum Food and Beverage Intake (g) | Milkshake intake | 33.6 g | Standard Deviation 66.1 |
Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water
The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake\>h2o anticipation and milkshake\>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to each of these contrasts are extracted and compared between the two arms. The paradigm has 64 trials and each trial starts with the presentation of a cue for 1s signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a period of 6s. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized.
Time frame: Baseline and 2 Weeks
Population: Participants who had issues with neuroimaging data (e.g., excessive motion, errors with image registration) were excluded from the analysis. As such the decrease in sample is due to suboptimal quality fMRI data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water | Milkshake taste > Water taste | -14.32 arbitrary units | Standard Deviation 57.68 |
| Bromocriptine | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water | Milkshake cue > Water cue | 50.24 arbitrary units | Standard Deviation 180.43 |
| Placebo | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water | Milkshake cue > Water cue | 15.66 arbitrary units | Standard Deviation 208.4 |
| Placebo | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water | Milkshake taste > Water taste | 3.75 arbitrary units | Standard Deviation 66.03 |
Hedonic Ratings of Food as Measured by a Visual Analog Scale
Testing the effects of the drug on hedonic ratings (pleasantness, desire to consume) of milkshake and snacks on a scale from -100 to 100. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
Time frame: Up to 5 minutes prior to ad libitum period start
Population: Data was collected via an iPad and sometimes recorded no value, as such the decrease in the sample was due to missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Snack Desire | 11.2 score on a scale | Standard Deviation 22.4 |
| Bromocriptine | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Snack Pleasantness | 32.6 score on a scale | Standard Deviation 15.8 |
| Bromocriptine | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Milkshake Pleasantness | 22.7 score on a scale | Standard Deviation 34.3 |
| Bromocriptine | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Milkshake Desire | -5.1 score on a scale | Standard Deviation 40.2 |
| Placebo | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Milkshake Desire | -5.6 score on a scale | Standard Deviation 41.2 |
| Placebo | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Milkshake Pleasantness | 32.4 score on a scale | Standard Deviation 15.5 |
| Placebo | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Snack Pleasantness | 32.2 score on a scale | Standard Deviation 15.9 |
| Placebo | Hedonic Ratings of Food as Measured by a Visual Analog Scale | Snack Desire | 14.6 score on a scale | Standard Deviation 22.7 |
Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2)
Testing the drug by gene (TaqIA) interaction on ad libitum food intake (g).The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant.
Time frame: Within 15 minutes of completion of the ad libitum period
Population: Data was collected via an iPad and sometimes recorded no value, as such the decrease in the sample was due to missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Snacks intake | 72.1 g | Standard Deviation 64.3 |
| Bromocriptine | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake intake | 26.1 g | Standard Deviation 57.9 |
| Placebo | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake intake | 23.3 g | Standard Deviation 67.2 |
| Placebo | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Snacks intake | 70.7 g | Standard Deviation 50.2 |
| Placebo - TaqIA A1 | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Snacks intake | 75.2 g | Standard Deviation 46.1 |
| Placebo - TaqIA A1 | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake intake | 35.5 g | Standard Deviation 66.7 |
| Placebo - TaqIA A2/A2 | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Snacks intake | 91.4 g | Standard Deviation 67.7 |
| Placebo - TaqIA A2/A2 | Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake intake | 30.9 g | Standard Deviation 67.1 |
Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2)
The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake\>h2o anticipation and milkshake\>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to these contrasts are extracted and used to test the drug by gene (TaqIA) interaction. The paradigm has 64 trials and each trial starts with the presentation of a cue signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a 6s period. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized.
Time frame: Baseline and 2 Weeks
Population: Participants who had issues with neuroimaging data (e.g., excessive motion, errors with image registration) were excluded from the analysis. As such the decrease in sample is due to suboptimal quality fMRI data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake cue > Water cue | 99.14 arbitrary units | Standard Deviation 139.86 |
| Bromocriptine | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake taste > Water taste | -27.21 arbitrary units | Standard Deviation 41.91 |
| Placebo | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake taste > Water taste | 1.16 arbitrary units | Standard Deviation 70.73 |
| Placebo | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake cue > Water cue | -8.44 arbitrary units | Standard Deviation 209.51 |
| Placebo - TaqIA A1 | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake cue > Water cue | 71.54 arbitrary units | Standard Deviation 176.11 |
| Placebo - TaqIA A1 | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake taste > Water taste | -14.64 arbitrary units | Standard Deviation 45.95 |
| Placebo - TaqIA A2/A2 | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake cue > Water cue | -51.4 arbitrary units | Standard Deviation 229.74 |
| Placebo - TaqIA A2/A2 | Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) | Milkshake taste > Water taste | 25.82 arbitrary units | Standard Deviation 80.29 |
Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2)
Testing the drug by gene (TaqIA) interaction on hedonic ratings (pleasantness, desire to consume) of milkshake on a scale from -100 to 100. Testing the drug by gene (TaqIA) interaction on ad libitum milkshake (g). The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
Time frame: Up to 5 minutes prior to ad libitum period start
Population: Data was collected via an iPad and sometimes recorded no value, as such the decrease in the sample was due to missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bromocriptine | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Desire | 3.7 score on a scale | Standard Deviation 38.8 |
| Bromocriptine | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Pleasantness | 27.7 score on a scale | Standard Deviation 2.5 |
| Placebo | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Pleasantness | 15.1 score on a scale | Standard Deviation 38.8 |
| Placebo | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Desire | -18.1 score on a scale | Standard Deviation 40.3 |
| Placebo - TaqIA A1 | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Pleasantness | 29.9 score on a scale | Standard Deviation 29.7 |
| Placebo - TaqIA A1 | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Desire | 16.6 score on a scale | Standard Deviation 20.9 |
| Placebo - TaqIA A2/A2 | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Desire | -21.5 score on a scale | Standard Deviation 36.2 |
| Placebo - TaqIA A2/A2 | Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) | Pleasantness | 12.2 score on a scale | Standard Deviation 27.8 |