1. Michael Bewernitz, Daniela Conrado, OJ Ganesh, Yi Zhang
Diet and Leptin Combination Therapy in Addiction Recovery (R21 Group Proposal)
Michael Bewernitz, Daniela Conrado, OJ Ganesh, Yi Zhang

2. Overall Significance Post addiction weight gain Individual problems
Health
Psychosocial
Society problems
Higher health costs, NIDDK says more than 40% higher
Burden to health and social care system

3. Hypothesis and Innovation
Central Hypothesis: Leptin with diet therapy will curb weight gain and improve midbrain food responses more effectively than either intervention in addiction recovering patients.
Innovation:
A comprehensive approach to tackle the complex weight gain
Nutritional intervention: physiological & psychosocial aspects
Leptin: neuroendocrine, neuropsychological & neurocognitive aspects
Linking brain functionality to physiological weight change via fMRI analysis.

4. fMRI-Imaging of Reward-System Describes Neurobiological Effects
Midbrain reward center: linking appetitive activity to behavioral psychology and neurocognition.
Ventral Tegmental Area (VTA) in midbrain: heightened reactivity to high-calorie foods in obesity; implication in drug addiction & motivation.
Leptin: regulation of both ingestive behaviors and energy expenditure; an anti-obesity agent undergoing multiple clinical trials.
Brain tells us what and how much we eat, and the midbrain reward
circuitry provides important neural control mechanisms.
Drugs and foods can activate similar midbrain reward pathways.
Obese individuals exhibit exaggerated reactivity to stimuli associated with
high-calorie foods in the VTA (and insula, hippo and etc.).
VTA: widely implicated in drug/food rewards, motivation and cognition.
Leptin functions in the VTA to attenuate food intake, preference for
high-fat foods, and reduce dietary weight gain. 4

5. Specific Aims Specific Aim 1:
Determine the synergistic weight reducing effect of a low carb/low fat diet and leptin combination therapy
- Primary Outcome: reduction of weight gain in addiction recovery
Specific Aim 2:
Examine the midbrain food responses by fMRI analysis post diet-leptin combination therapy or monotherapy
- Secondary Outcome: improve midbrain reward responses to food stimulation

6. Study Design Population n=20
Prospective, randomized, double-blind pilot study in veterans whom successfully completed the post-addiction recovery program at multiple NF/SG VHS VA clinics
Population n=20
Action
Timeline
SA1/SA2 measures
Study Onset
No therapy
n=5
Dietary only
n=5
Leptin
only
n=5
Leptin &
Dietary together
n=5
SA1 measures
Month 1
SA1/SA2 measures
Mid-intervention
SA1 measures
Month 2
Ending
SA1/SA2 measures
Efficacy Measures (SA1): Metabolic Panel, Physical assessments
Neural Response Measures (SA2): fMRI images

7. Experimental Timeline
study onset
month 1
mid
month 2
ending
Day 28 42 56 84
Randomization X
Patient history
Dispense therapy
(multiple doses)
Leptin assay
Metabolic panel
Physiological assessment
fMRI
Data Analysis
Analysis Plan: 2x2 factorial ANOVA

8. Pitfalls and Alternatives
Interference of nicotine in measured outcomes.
Consider nicotine as a covariate.
Intra-group variation: responders vs. non-responders.
Extra blood sample: genotype data to compare with pharmacogenomics studies.
Injection site reactions.
Compliance assistance.
Dietary intervention (open-label).
No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. 8 8

9. Future Directions
Proof of concept and feasibility demonstrated by this pilot study:
Protocol adjustment.
Follow-up study.
Further analysis of covariates.
Post recovery follow-up physiological assessments and fMRI analysis.
To compare with fMRI in healthy volunteers.
-With this pilot study, we expect to build foundation (in other words, to demonstrate proof of concept and feasibility) to conduct a follow-up study 9 9

10. Thank you! Thanks and Acknowledgements Dr. Keith Muller
Dr. Philipp Dahm
Beth Auten
CTSI
Thank you!