Depression, Inflammation, and Obesity
Richard C. Shelton, M.D.
Charles Byron Ireland Professor
Vice Chair for Research
UAB Department of Psychiatry
and Behavioral Neurobiology
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
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
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?
Inflammation and Depression
Inflammatory
Disease
“Idiopathic
Inflammation”
(IL-6, TNFα, CRP)
“Therapeutic
Cytokines”
 Inflammatory Mediators
(Cytokines)
 Antidepressant
Response
Depression
• What is causing the
inflammation?
• What can we do
about it?
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
U.S. Trends in Overweight, Obesity,
and Extreme Obesity* 1960-2008
1970
31.5%
34.3%
33.6%
AHA Recommendations
to Reduce Saturated Fats
13.4%
6%
0.9%
*BMI>40
Where did the obesity epidemic come from?
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
Palatability vs.
Food Intake
How much
people eat
How good something tastes
John M de Castro et all. Physiology & Behavior 2000. 70:343 - 350
Average Carbohydrate Intake, U.S. by Year
http://blog.photocalorie.com/category/dietary-research/
U.S. Trends in HFCS Consumption
 High fructose corn syrup
 Free fructose
X Obesity prevalence
Bray GA, et al. Am J Clin Nutr 2004; 79:537–5
Fructose
Fructose-6phosphate
Glyceraldehyde
Fructose-1,6bisphosphate
Dihydroxyacetone
phosphate
Glycogen
Glyceraldehyde-3phosphate
Pyruvate
Glycerol
Acetyl-CoA
Glycerol-3phosphate
Fatty Acids
Triglycerides
Body Fat
Distribution
Systemic inflammation/
Metabolic disease
Subcutaneous
• Diabetes
abdominal
• Cardio/cerebro-vascular
adipose tissue
disease (SAAT)
• MI
• Stroke
Visceral Fat
• Hypertension
(IAAT)
Images courtesy of
Dr. Barbara Gower
Depression and Visceral Adipose Tissue
Everson-Rose SA, et al.
Psychosom Med 2009;
71(4):410-6.
Depression Selectively Increases
Visceral Fat Over 5 Years
0.09
0.079*
0.08
Beta Weights
0.07
0.061 *
0.06
0.05
0.04
0.033
0.03
0.02
0.01
0.003
0
BMI
% body fat
Saggital diameter
Vogelzangs N, et al. Arch Gen Psychiatry 2008; 65:1386-1393
Visceral fat
High IL-6 is Associated with Both
Obesity and Depression
The “Real Course” of MDD
Systemic inflammation:
• Type 2 diabetes
• Cardiovascular disease
• Fibromyalgia (etc.)
• Worsening depression
• Worsening anxiety
What the course is really like in many
(most) patients:
• Antidepressant
resistance
How we used to think about depression course:
Accumulating visceral fat
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?
“We Can’t Just Drug This Away!”
Blumenthal SR, et al.
JAMA Psychiatry 2014
BH4 is a Cofactor for
Monoamine Synthesis
L-methylfolate
Tryptophan
BH4
Tryptophan hydroxylase
5-hydroxytryptophan
Aromatic L-amino acid
decarboxylase
Serotonin
Tyrosine
z
Tyrosine hydroxylase
BH2
3,4-DOPA
Aromatic L-amino acid
decarboxylase
Dopamine
Dopamine β
hydroxylase
Norepinephrine
L-Methylfolate [(6S)-5-methyl-5,6,7,8tetrahydropteroyl-L-glutamic acid] 15 mg.
Augmentation in SSRI Non-Responders
HDRS-17
QIDS-SR
0
Pooled Treatment Effect
-1
-2
Placebo
L-Methylfolate
-2.62
-3
-3.04
-4
-5
-6
-4.7
-5.58
Papakostas GI, et al. Am J Psychiatry 2012;169:1267-1274
Obesity and Inflammation Moderate Response
to (6S)-5-methyl-5,6,7,8-tetrahydropteroyl-Lglutamic acid (L-methylfolate)
Biomarkers and Combinations
BMI <30
BMI >30
CRP
TNFα
-4.28
-4.33
Leptin
BMI≥30 + BMI≥30 + BMI≥30 +
CRP≥med Leptin≥med TNFα≥med
2
Pooled Treatment Effect
1
0.99
0
-1
-2
-3
-4
-5
-6
-7
-4.66
-3.94
-5.05
-5.23
-6.31
The “Sugar Roller Coaster”
http://www.masterthyself.com
Carbohydrates: Glycemic Index
Low
Glycemic Index
Medium
Glycemic Index
High
Glycemic Index
Rice
http://en.wikipedia.org/wiki/Glycemic_index
Favorable Effects of a Eucaloric
Low Carbohydrate Diet
Change in IAAT
Std: -1.1kg
LowCho: -1.6kg
*p < .005
**p < .001
***p < .0001
*
Gower BA, et al. Clin Endocrinol 2013; 79:550-557
A Low Carbohydrate Diet Reduces
Abdominal Fat and Depression
Change in Depression Scores (BDI)
10
5
0
-5
0 -10
Mediated by
change in TNFα
0
20
40
60
80
100
Change in Intra-abdominal Adipose Tissue
Slide courtesy of Dr. Barbara Gower
Resuehr HES et al. (submitted)
Baseline BMI 27-30.
One of these every day
This many pounds per year
=
10 lbs
=
11 lbs
=
20 lbs
=
21-42 lbs
Exercise Reduced
Depression 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
Monitored Exercise Reduces Depression
16
14
BDI-II Score
12
10
*
8
Total Sample
BDI >= 10
6
**
4
2
0
Baseline
*t=4.68, p<001
**t-3.60, t=0.001
6 months
Data courtesy of Drs. Molly Bray and Matthew Herring
Depression: Lifestyle Recommendations
 Eat more:
 Eat less:
• Fruits, vegetables
• Nuts (almonds, pecans)
• Legumes
• Carbohydrates★
–Especially  GI
• Meat (esp. red meat)
–Pod beans (soybeans, green • Saturated fatty acids
beans, peanuts)
• Fish (not fried)
• Monounsaturated fatty acids
–Butter
–Stick margarine
–Fish oil, olives, olive oil
Graduated exercise
10,000 steps
per day
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
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.
Marcas Bamman, 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