Depression, Inflammation, and Obesity

1. Depression, Inflammation, and Obesity Richard C. Shelton, M.D. Charles Byron Ireland Professor Vice Chair for Research UAB Department of Psychiatry and Behavioral Neurobiology

2. Disclosures • Dr. Shelton has been a consultant for Bristol-Myers Squibb Company, Cerecor, Inc., Cyberonics, Inc., Eli Lilly and Company, Forest Pharmaceuticals, Janssen Pharmaceutica, Medtronic, Inc., MSI Methylation Sciences, Inc., Naurex, Inc., Pamlab, Inc., Pfizer, Inc., Ridge Diagnostics, Shire Plc, Takeda Pharmaceuticals. • He has received research support from Alkermes, Inc., Assurex, Inc., Avanir Pharmaceuticals, Inc., Cerecor, Inc., ElanCorp., Forest Pharmaceuticals, Janssen Pharmaceutica, Naurex, Inc., Novartis Pharmaceuticals, Otsuka America, Pamlab, Inc., Pfizer, Inc., Repligen Corp., Ridge Diagnostics, St. Jude Medical, Takeda Pharmaceuticals • He does not serve on speakers bureaus, is not a shareholder, or receive other financial or material support

3. The “Real Course” of MDD How we used to think about depression course: What the course is really like in many (most) patients: Chronic depression Less complete recovery

4. Key Questions • Why: • Are so many patients not recovering? • Does treatment resistance develop over time? • What if: • The cause is something apparently unrelated to the illness itself? • Our treatments are making the problem worse rather than better?

5. Inflammation and Depression “Idiopathic Inflammation” (IL-6, TNFα, CRP) Inflammatory Disease “Therapeutic Cytokines” Inflammatory Mediators (Cytokines) • What is causing the inflammation? • What can we do about it? Antidepressant Response Depression

6. Relationships Between Depression and Obesity • A high proportion of depressed patients are overweight or obese • Obesity: MDD: 45%, Controls 29% • Overweight + obesity MDD: 75.5% • There is a bi-directional relationship between depression and obesity (Luppino Arch Gen Psychiatry 2010) • D>O OR=1.20, O>D OR=1.27 • Depression and obesity are interactive risk factors for metabolic syndrome (CV disease, diabetes) • Overweight and obesity reduce response to antidepressants Bornstein SR, et al. Mol Psychiatry 2006; 11:892-902

7. U.S. Trends in Overweight, Obesity, and Extreme Obesity* 1960-2008 34.3% 33.6% 1970 31.5% AHA Recommendations to Reduce Saturated Fats 13.4% 6% 0.9% *BMI>40 Where did the obesity epidemic come from?

8. Fat Intake is not the Problem (Now) 1970 AHA Recommendations to Reduce Saturated Fats 1948 Framingham Heart Study http://www.abovetopsecret.com/forum/thread606238/pg1

9. Palatability vs.Food Intake How much people eat How good something tastes John M de Castro et all. Physiology &Behavior 2000. 70:343 - 350

10. Average Carbohydrate Intake, U.S. by Year http://blog.photocalorie.com/category/dietary-research/

11. U.S. Trends in HFCS Consumption • High fructose corn syrup • Free fructose • X Obesity prevalence Bray GA, et al. Am J ClinNutr 2004; 79:537–543

12. Fructose-6- phosphate Fructose-1,6- bisphosphate Fructose Glycogen Dihydroxyacetone phosphate Glyceraldehyde-3- phosphate Glyceraldehyde Pyruvate Glycerol Acetyl-CoA Glycerol-3- phosphate Fatty Acids Triglycerides

13. Body Fat Distribution Subcutaneous abdominal adipose tissue (SAAT) • Systemic inflammation/ • Metabolic disease • Diabetes • Cardio/cerebro-vascular disease • MI • Stroke • Hypertension Visceral Fat (IAAT) Images courtesy of Dr. Barbara Gower

14. Depression and Visceral Adipose Tissue Everson-Rose SA, et al. Psychosom Med 2009; 71(4):410-6.

15. Depression Selectively Increases Visceral Fat Over 5 Years * * Vogelzangs N, et al. Arch Gen Psychiatry 2008; 65:1386-1393

16. High IL-6 is Associated with BothObesity and Depression

17. The “Real Course” of MDD • Systemic inflammation: • Type 2 diabetes • Cardiovascular disease • Fibromyalgia (etc.) • Worsening depression • Worsening anxiety • Antidepressant resistance How we used to think about depression course: What the course is really like in many (most) patients: Accumulating visceral fat

18. Key Questions • Why: • Are so many patients not recovering? • Why does treatment resistance develop over time? • What if: • The cause is something apparently unrelated to the illness itself? • Our treatments are making the problem worse rather than better? • How can we deal with this problem?

19. “We Can’t Just Drug This Away!” Blumenthal SR, et al. JAMA Psychiatry 2014

20. BH4 is a Cofactor forMonoamine Synthesis L-methylfolate z BH4 Tryptophan Tyrosine Tryptophan hydroxylase Tyrosine hydroxylase BH2 3,4-DOPA 5-hydroxytryptophan Aromatic L-amino acid decarboxylase Aromatic L-amino acid decarboxylase Serotonin Dopamine Dopamine β hydroxylase Norepinephrine

21. L-Methylfolate [(6S)-5-methyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid] 15 mg. Augmentation in SSRI Non-Responders • Papakostas GI, et al. Am J Psychiatry 2012;169:1267-1274

22. Obesity and Inflammation Moderate Response to (6S)-5-methyl-5,6,7,8-tetrahydropteroyl-L-glutamic acid (L-methylfolate)

23. The “Sugar Roller Coaster” http://www.masterthyself.com

24. Carbohydrates: Glycemic Index Low Glycemic Index Medium Glycemic Index High Glycemic Index Rice http://en.wikipedia.org/wiki/Glycemic_index

25. Favorable Effects of a EucaloricLow Carbohydrate Diet Std: -1.1kg LowCho: -1.6kg Change in IAAT *p < .005 **p < .001 ***p < .0001 * Gower BA, et al. ClinEndocrinol 2013; 79:550-557

26. A Low Carbohydrate Diet Reduces Abdominal Fat andDepression 0 10 -5 5 Change in Depression Scores (BDI) Mediated by change in TNFα 0 -10 0 20 40 60 80 100 Change in Intra-abdominal Adipose Tissue Slide courtesy of Dr. Barbara Gower Baseline BMI 27-30. ResuehrHES et al. (submitted)

27. This many pounds per year 10 lbs = = 11 lbs One of these every day = 20 lbs = 21-42 lbs

28. Exercise ReducedDepression in Most Studies • Exercise exerts modest antidepressant effects, but… • None have used state-of-the-art exercise • Almost none have examined mechanisms mediating the effect Krough J., et al. J Clin Psychiatry 2011; 72:529-538

29. Monitored Exercise Reduces Depression * ** *t=4.68, p<001 **t-3.60, t=0.001 Data courtesy of Drs. Molly Bray and Matthew Herring

30. Depression: Lifestyle Recommendations Eat more: Eat less: Carbohydrates★ Especially GI Meat (esp. red meat) Saturated fatty acids Butter Stick margarine • Fruits, vegetables • Nuts (almonds, pecans) • Legumes • Pod beans (soybeans, green beans, peanuts) • Fish (not fried) • Monounsaturated fatty acids • Fish oil, olives, olive oil • Graduated exercise 10,000 steps per day

31. Summary • Many healthy depressed patients show evidence of inflammation (e.g., IL-6, TNFα) • Obesity may be the primary source of inflammation • Obesity is associated with a reduced response to antidepressants • The chronic course of depression is associated with accumulation of visceral fat • Also other chronic stress states (e.g., ELT) • A low carbohydrate diet or monitored exercise may reduce depression by attacking the cause of the problem

32. Collaborators UAB Nutrition Sciences Barbara Gower, Ph.D. UAB Neurology Daniel Marson, Ph.D. Erik Roberson, M.D., Ph.D. UAB Epidemiology Molly Bray, Ph.D. Matthew Herring, Ph.D. UAB Center Exercise Med. MarcasBamman, Ph.D. • Vanderbilt Institute for • Obesity and Metabolism • Kevin Niswender, M.D. • Heidi Silver, Ph.D. • Funding Agencies • NIH, Brain & Behavior Research Foundation • Our patients, research participants, and their families