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

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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., Elan Corp., 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

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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

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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?

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Inflammation and Depression Inflammatory Disease Idiopathic Inflammation ( IL-6, TNF, CRP) Inflammatory Mediators (Cytokines) Depression Therapeutic Cytokines What is causing the inflammation? What can we do about it? Antidepressant Response

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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

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

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

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

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

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U.S. Trends in HFCS Consumption Bray GA, et al. Am J Clin Nutr 2004; 79:537543 High fructose corn syrup Free fructose X Obesity prevalence

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

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

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

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

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High IL-6 is Associated with Both Obesity and Depression

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

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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?

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We Cant Just Drug This Away! Blumenthal SR, et al. JAMA Psychiatry 2014

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BH4 is a Cofactor for Monoamine Synthesis L-methylfolate z

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

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

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The Sugar Roller Coaster http://www.masterthyself.com

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

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Favorable Effects of a Eucaloric Low Carbohydrate Diet Std: -1.1kg LowCho: -1.6kg *p