Post on 26-May-2020
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Obesity, Inflammation, and
Depression: When Psychiatric
and Medical Factors Collide
Handout for the Neuroscience Education Institute (NEI) online activity:
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Identify the relationship between depression and
medical factors (inflammatory, endocrine, and
metabolic)
• Consider comorbid medical conditions when
selecting treatment for patients with depression
• Assess the potential utility of biomarkers in the
diagnosis and treatment of depression
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
A 36-year-old man with major depressive disorder is having lab work
done to assess his levels of inflammatory markers. Based on the
current evidence regarding inflammation in depression, which of the
following results would you most likely suspect for this patient?
1. Elevated levels of tumor necrosis factor-alpha (TNF-alpha)
2. Reduced levels of interleukin 6 (IL-6)
3. Both 1 and 2
4. Neither 1 nor 2
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Pretest Question 2
The patient's lab work comes back indicating elevated levels of tumor
necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Elevated
cytokine levels may indirectly lead to:
1. Excessive glutamate neurotransmission
2. Excessive GABA neurotransmission
3. Reduced glutamate neurotransmission
4. Reduced GABA neurotransmission
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Pretest Question 3
A 21-year-old man presents with his first major depressive episode. His
medical history is significant for obesity (BMI 32). After ruling out any
history of bipolar illness, his clinician elects to begin treatment with an
antidepressant. What is true regarding the relationship between obesity
and the likelihood of response to antidepressants?
1. Obesity increases the likelihood of response
2. Obesity has no effect on the likelihood of response
3. Obesity reduces the likelihood of response
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Disease Models in Mood Disorders
• Monoamine hypothesis
• Inflammatory hypothesis
• Excitotoxicity hypothesis
• Neurotrophic hypothesis
• Cellular-metabolic hypotheses
McIntyre R. Ann Clin Psychiatry 2007;19:257.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
What Does Inflammation Have to Do
With Depression?
Altered monoamine synthesis
Increased glutamate activity
Increased oxidative stress
Reduced neurotrophic support
Reduced neurogenesis
HPA axis disturbances
Inflammation Depression
IL-6 TNF-α
IFN-γ
Miller AH et al. Biol Psychiatry 2009;65(9):732-41; Dowlati Y et al. Biol Psychiatry 2010;67:446-57;
Howren MB et al. Psychosom Med 2009;71:171-86.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
kynurenine
IDO quinolinic
acid (NMDA
agonist)
Chronic Low-Grade Inflammation Can
Affect Neurotransmitter Synthesis
tryptophan
IL-6
TNF-α
IFN-γ
TRY OH
5HTP
AAADC 5HT
Miller AH et al. Biol Psychiatry 2009;65(9):732-41;
Dowlati Y et al. Biol Psychiatry 2010;67:446-57.
IDO
Glu,
oxidative
stress
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
BH
BH
Chronic Low-Grade Inflammation Can
Affect Neurotransmitter Synthesis
tetrahydro-bio
pterin
IFN-α
Miller AH et al. Biol Psychiatry 2009;65(9):732-41.
DA BH
tyrosine NE
NOS BH
NO
NOS BH
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
PKA CaMK
Chronic Low-Grade Inflammation Can Affect Neurotrophic Support and Neurogenesis
monoamine
CREB
BDNF
synapto-
genesis
neuro-
plasticity
neuro-
genesis
cell
survival
IL-6
TNF-α
IFN-γ
Dowlati Y et al. Biol Psychiatry 2010;67:446-57; Miller AH et al. Biol Psychiatry 2009;65:732-41;
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
HPA Axis Stress Response
hypothalamus
pituitary
adrenal gland
hippocampus gluco-
corticoid
stressor
Miller AH et al. Biol Psychiatry 2009;65:732-41; Pace TW et al. Brain Behav Immun 2007;21:9-19;
Pariante CM. Ann NY Acad Sci 2009;1179:144-52.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Interaction Between Endocrine and
Inflammatory Factors
hypothalamus
pituitary
adrenal gland
hippocampus gluco-co
rticoid
stressor IL-6 TNF-α
IL-6 TNF-α
Pace TW et al. Brain Behav Immun 2007;21:9-19;
Dowlati Y et al. Biol Psychiatry 2010;67:446-57.
increased CRF
increased ACTH
increased
glucocorticoids
dysregulation of
glucocorticoid
receptors
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
HPA Axis Changes in MDD
hypothalamus
pituitary
adrenal gland
hippocampus gluco-
corticoid
stressor
Miller AH et al. Biol Psychiatry 2009;65:732-41; Pace TW et al. Brain Behav Immun 2007;21:9-19;
Pariante CM. Ann NY Acad Sci 2009;1179:144-52.
dysregulation of
glucocorticoid
receptors
increased
glucocorticoids
reduced
hippocampal volume
increased CRF
increased ACTH
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Varicella zoster virus–specific responder cell frequency (VZV-RCF) results at baseline, 6 weeks, 52 weeks, and 104 weeks in non-depressed controls, depressed patients who are not being treated with antidepressants, and depressed patients who are being treated with antidepressants
Irwin M R et al. Clin Infect Dis 2013;56(8):1085-93.
Depression and Response to Zoster Vaccine
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
What Does Inflammation Have to Do
With Obesity?
• White adipose tissue (main site for fat storage)
contains adipocytes that secrete hormones and
inflammatory cytokines
• IL-6, TNF-alpha, and CRP are consistently
elevated in obesity (chronic low-grade
inflammatory state?)
• Upregulation of kynurenine pathway in obesity
Shelton RC, Miller AH. Prog Neurobiol 2010;91(4):275-99.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
What Does Obesity Have to Do With
Depression?
Lopresti AL, Drummond PD. Prog Neuro-Psychopharmacol Biol Psychiatry 2013;45:92-9.
Neurotransmitter imbalances
Dysregulated inflammatory pathways
Increased oxidative stress
Reduced neurogenesis
HPA axis disturbances
Obesity Depression
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
What Does Obesity Have to Do With Depression?
• Daumit et al. 2003: 29% of men and 60% of women with
severe and persistent mental illness were obese
compared to 17.7% of men and 28.5% of women in the
general population
• Dickerson et al. 2006: 50% of women and 41% of men
with psychiatric illness were obese compared to 27% of
women and 20% of men in a non-psychiatric matched
comparison group
• Luppino et al. 2010: meta-analysis of 15 longitudinal
studies showed that depression was associated with
increased rates of obesity
• Abdominal obesity in particular may be characteristic of
depression (Carpiniello et al. 2012; Rivenes et al. 2009;
van Reedt Dortland et al. 2013) Lopresti AL, Drummond PD. Prog Neuro-Psychopharmacol Biol Psychiatry 2013;45:92-9.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Metabolic Markers in Depression
• BMI – Higher BMI higher risk of depression
– Depression higher risk of increased BMI
• Leptin – Low levels depressive symptoms*
– Acute administration antidepressant response
• Omega-3 fatty acids
– Reduced total, docosahexaenoic acid (DHA), and
eicosapentaenoic acid (EPA) in depression
*Some data suggest that leptin is elevated in overweight depressed patients. Leptin resistance?
Haroon E et al. Neuropsychopharmacology 2012;37:137-62; Schmidt HD et al.
Neuropsychopharmacology 2011;36:2375-94; Lin PY et al. Biol Psychiatry 2010;68(2):140-7.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Obesity and Depression
• Baseline obesity predicts subsequent
depression (and vice versa)1,2
• Higher BMI is linked to increased prevalence,
severity, and chronicity of depression3
• Obesity reduces response to antidepressants4,5
• Diet and exercise interventions reduce
depression in obese, medically ill patients6
1. Luppino FS et al. Arch Gen Psychiatry 2010;67(3):220-9.
2. Vogelzangs N et al. Arch Gen Psychiatry 2008;65(12):1386-93.
3. Simon GE et al. Gen Hosp Psychiatry 2008;30(1):32-9.
4. Oskooilar N et al. J Clin Psychiatry 2009;70(11):1609-10.
5. Kloiber S et al. Biol Psychiatry 2007;62(4):321-6.
6. Herring M et al. Arch Intern Med 2012;172(2):101-11.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Interaction Between Metabolic,
Endocrine, and Inflammatory Factors
• Diabetes and metabolic syndrome are
associated with abnormal HPA activity
• Leptin is decreased by chronic stress; ghrelin is
increased by chronic stress
• Expanded adipocytes oxidative stress and
increased proinflammatory cytokines
• BMI positively correlates with IL-6 and hsCRP
• Exercise reduces inflammatory markers Tyrka AR et al. Horm Metab Res 2012;44(7):543-9; Carpenter LL et al. Acta Psychiatr Scand 2012;Epub
ahead of print; Woods JA et al. Immunol Allergy Clin North Am 2009;29:381-93; Arikawa AY et al. Med Sci
Sports Exerc 2010;43:1002-9; Nathan C. Mol Med 2008;14:485-92; Shelton RC, Miller AH. Prog Neurobiol
2010;91:275-99; Capuron L et al. Psychological Med 2010;41:1517-28.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Clinical Implications
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Have We Identified Inflammatory,
Endocrine, or Metabolic Biomarkers?
• Now
– None?
• Projected
– Select initial treatment
• Positive, negative, or prescriptive moderator
– Change/maintain treatment
• Mediator; ideally changes prior to clinical improvement,
allowing treatment decisions to be made earlier
– Design clinical trials
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
40 50 60 70 80 90
100
5
0
5-
10-
15-
20-
25-
30-
35-
40-
45-
body weight (kg)
HA
MD
17-
score
change a
t th
e e
nd p
oin
t
Fig. 1. Scatter plot of the association between the baseline body weight and the
17-item Hamilton Depression Rating Scale (HAMD-17) reduction at the end point
Lin CH et al. J Affective Disord 2014;161:123-6.
Preliminary Data: Body Mass Affects
Treatment Response in Depression
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
-5
-4
-3
-2
-1
0
1
2
L-m
eth
ylfo
late
– P
lace
bo
Dif
fere
nce
Total Sample BMI <30 BMI >30
Preliminary Data: BMI Affects Treatment
Response to L-methylfolate
n=74
p=0.017
p=0.01
-0.41
n=40
p=0.001
p<0.001
-0.75
HDRS-28:
CGI-S:
HDRS:
Effect Size:
n=32
p=0.648
p=0.391
0.14
Fava M et al. Oral presentation at NCDEU 2012.
-2.74
0.99
-4.66
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
L-methylfolate in Depression
Stratified by Biomarkers
Papakostas G et al. Poster presented at APA 2012.
Variable Pooled Mean
Change vs. PBO
95% CI p-value
Biomarker
SAM/SAH≥2.71
SAM/SAH<2.71
-0.380
-2.398
(-2.239, 1.479)
-4.312, -0.485)
0.689
0.014
hsCRP≥2.25 mg/L
hsCRP<2.25 mg/L
-1.668
-1.918
(-3.843, 0.507)
(-3.637, -0.199)
0.133
0.029
4-HNE≥3.28 mcg/mL
4-HNE<3.28 mcg/mL
-2.471
-0.796
(-4.483, -0.459)
(-2.579, 0.988)
0.016
0.382
Genetic marker
MTHFR 677 CC
MTHFR 677 CT/TT
-0.948
-2.004
(-2.611, 0.715)
(-4.315, 0.308)
0.264
0.089
MTR 2756 AA
MTR 2756 AG/GG
-0.632
-3.686
(-2.484, 1.221)
(-5.881, -1.491)
0.504
0.001
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Genetic Variants for Synthesis of L-methylfolate
With Downstream Effects on Monoamines
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Preliminary Data: CRP Level Affects
Differential Treatment Response
Uher R et al. Am J Psychiatry 2014;Epub ahead of print.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Limitations With Using Biomarkers in
Major Depressive Disorder
• Identified biomarkers are not specific to MDD
– Biomarkers are also altered in disorders that are
commonly comorbid with depression, even in the
absence of MDD
• Identified biomarkers are neither necessary nor
sufficient to cause MDD
• Panel of biomarkers rather than single
biomarker may show clinical utility
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Change in Inflammatory Markers
With Depression Treatment
Good response
• Reduced
inflammatory markers
during treatment
Poor response
• Increased
inflammatory markers
at baseline
• Increased
inflammatory markers
during treatment
Haroon E et al. Neuropsychopharmacology 2012;37:137-62;
Schmidt HD et al. Neuropsychopharmacology 2011;36:2375-94.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Depressive Symptoms in Patients With Chronic Illness:
Improved With Anti-inflammatory Strategies?
• Lethargy
• Decreased appetite
• Increased sleeping
• Decreased mood
• Decreased interest in activities
• Decreased sexual activity
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Targeting Inflammation and its Effect:
Neurotransmission
• Monoamine synthesis/BH4 pathway
– L-methylfolate added to SSRI superior to placebo
• 2 trials
– SAMe added to SRI superior to placebo
• Glutamate/oxidative stress
– Ketamine rapid, short-term improvement in mood and suicidal ideation
• Several other NMDA antagonists under investigation
– N-acetylcysteine preliminary positive data in bipolar depression
Papakostas G et al. Poster presented at EPA 2011; Papakostas GI et al. Am J Psychiatry
2010;167:942-8; Berk M et al. J Affective Disord 2011;135(1-3):389-94; Magalhaes PV et al.
Rev Bras Psiquiatr 2011;33(4):374-8.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Targeting Inflammation and its Effect:
Anti-inflammatory Strategies
• TNF-alpha antagonists
– Etanercept superior to placebo for improving depressive
symptoms in psoriasis (independent of disease improvement)
– Infliximab (Raison et al. 2013)
• COX-2 inhibitors
– Celecoxib added to reboxetine superior to placebo
– Celecoxib added to fluoxetine superior to placebo
• Acetylsalicylic acid
– Added to fluoxetine increased remission rate (open-label)
• P38 MAPK cytokine signaling pathway
– GW856553 Phase II depression trial
Mendlewicz J et al. Int Clin Psychopharmacol 2006;21:227-31; Akhondzadeh S et al.
Depression Anxiety 2009;26(7):607-11; Muller N et al. Mol Psychiatry 2006;11:680-4;
Tyring S et al. Lancet 2006;367:29-35.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Minocycline
• Second-generation, semi-synthetic tetracycline analog with antimicrobial properties
• Highly lipophilic; easily penetrates the BBB, in contrast to tetracycline
• Principal metabolite: 9-hydroxyminocycline (inactive)
Soczynska JK et al. Behav Brain Res 2012;235(2):302-17.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
The Role of GLP-1 in Neuronal Activity
and Neurodegeneration
0
25
50
75
100
125
150
Saline LiraglutideN
o.
of
Iba1 p
osit
ive c
ell
s/u
nit
0
10
20
30
40
50
60
Saline Liraglutide
#/s
ecti
on
*** ***
Effect of liraglutide on amyloid plaque count Inflammation response (IBA-1 stain)
GLP-1: glucagon-like peptide 1.
Holscher C. Vitam Horm 2010;84:331-54.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Targeting Neuroendocrine Function
• Glucocorticoid receptor
– Mifepristone (antagonist) efficacy in open-label and
placebo-controlled trials of psychotic depression
(main effects on psychotic symptoms)
Belanoff JK et al. Biol Psychiatry 2002;52:386-92; Simpson GM et al. J Clin Psychiatry 2005;66:598-602;
DeBattista C et al. Biol Psychiatry 2006;60:1343-9; Flores BH et al. Neuropsychopharmacology
2006;31:628-36; Blasey CM et al. Contemp Clin Trials 2009;30:284-8.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Targeting Metabolic Function
• Diet
– Omega-3 fatty acids meta-analysis shows positive
evidence of efficacy in unipolar and bipolar
depression; EPA is the effective component (vs. DHA)
• Exercise
– Seems to reduce depressive symptoms
• Possibly through an anti-inflammatory mechanism
Sarris J et al. J Clin Psychiatry 2012;73(1):81-6; Sublette ME et al. J Clin Psychiatry 2011;72(12):1577-84; Barbour KA, Blumenthal JA. Neurobiol Aging 2005;26(suppl 1):119-23; Mead
GE et al. Cochrane Database Syst Rev 2009;CD004366.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Targeting Metabolic Function: Meta-analysis of Weight Loss Interventions
Studies evaluated reduction in depressive symptoms but in most cases
did not include patients with MDD. Significant reductions in depressive
symptoms occurred with intervention regardless of change in weight.
Fabricatore AN et al. Int J Obes 2011;35(11):1363-76.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Exercise: Evidence of Efficacy
• Meta-analysis of 58 randomized trials
– Moderate to vigorous exercise (aerobic or resistance)
vs. control condition (no treatment or wait list control)
– General population: significantly lower depression
scores with exercise vs. control treatment (effect size:
-0.80)
– Clinically depressed population: significantly lower
depression scores with exercise vs. control treatment
(effect size: -1.03)
– Aerobic exercise = resistance exercise
Rethorst CD et al. Sports Med 2009;39(6):491-511.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Emerging Evidence: Increased
Remission Rates With Add-On Exercise
TREAD: patients with inadequate response to SSRI received
add-on exercise (low: 4 kcal/kg/week or high: 16 kcal/kg/week)
16-KKW group: fitted curve
4-KKW group: fitted curve 4-KKW group: percent
16-KKW group: percent
NNT=7.8 for higher-dose
exercise group
100
90
80
70
60
50
40
30
20
10
0 0 1 2 3 4 5 6 7 8 9 10 11 12
Pe
rce
nt
wit
h ID
S-C
30 r
em
iss
ion
Week
Trivedi et al. J Clin Psychiatry 2011;72:677-84. NNT=number needed to treat;
KKW=kcal per kg per week
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Exercise: Cochrane Review
• Meta-analysis of 30 randomized trials in
depressed population
– Moderate clinical effect of exercise [pooled
standardized mean difference (SMD): -0.67]
– 4 trials (n=326) with adequate allocation concealment,
intent-to-treat analysis, and blinded outcome
assessment: small clinical effect (pooled SMD: -0.31)
Rimer J et al. Cochrane Database Syst Rev 2012;(7):CD004366.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Exercise and Hippocampal Neurogenesis
Siette J et al. Biol Psychiatry 2013;73:435-42.
Connectivity Presynaptic
density
Place recognition
memory
0
0.2
0.4
0.6
0.8
1
1.2
Baseline 8 Weeks
Mean E
xplo
ration
Ratio
0
0.2
0.4
0.6
0.8
1
1.2
Baseline 8 Weeks Mean E
xplo
ration
Ratio
Aged rats
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Exercise in Depression:
Optimal Dose, Intensity, Duration?
• 10–16 weeks duration > 4–9 weeks duration
– p = 0.0273
• 45–59 minutes > 30–44 minutes and 60+
minutes
– p = 0.0010 and p = 0.0122
• 5 times/week > 2–4 times/week
• No significant differences across categories of
exercise intensity (% maximum heart rate)
Rethorst CD et al. Sports Med 2009;39(6):491-511.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Summary
• Several potential biomarkers for depression
have been found to be associated with onset
and severity of depression as well as treatment
response
• These include inflammatory, endocrine, and
metabolic factors
• However, no single biomarker has predictive
value
• Identification of these factors may ultimately lead
to a panel of biomarkers as well as new
treatment strategies targeting these biomarkers