Obesity, Inflammation, and Depression: When Psychiatric ...cdn.neiglobal.com/content/encore/congress/2014/slides_at-enc15-14cng-02.pdfWhat Does Inflammation Have to Do With Obesity?

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:


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


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


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


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


Disease Models in Mood Disorders

• Monoamine hypothesis

• Inflammatory hypothesis

• Excitotoxicity hypothesis

• Neurotrophic hypothesis

• Cellular-metabolic hypotheses

McIntyre R. Ann Clin Psychiatry 2007;19:257.


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.


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


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


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.


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.


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


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


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


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.


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


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.


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.


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.


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.


Clinical Implications


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


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


-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


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


Genetic Variants for Synthesis of L-methylfolate

With Downstream Effects on Monoamines


Preliminary Data: CRP Level Affects

Differential Treatment Response

Uher R et al. Am J Psychiatry 2014;Epub ahead of print.


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


Change in Inflammatory Markers

With Depression Treatment

Good response

• Reduced

inflammatory markers

during treatment

Poor response

• Increased


at baseline

• Increased


during treatment

Haroon E et al. Neuropsychopharmacology 2012;37:137-62;

Schmidt HD et al. Neuropsychopharmacology 2011;36:2375-94.


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


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.


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.


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.


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.


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.


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.


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.


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.


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


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.


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


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.


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

Documents

Obesity, Inflammation, and Depression: When Psychiatric ...cdn.neiglobal.com/content/encore/congress/2014/slides_at-enc15-14cng-02.pdfWhat Does Inflammation Have to Do With Obesity?