medical comorbidity in mood disorders: the link...

MEDICAL COMORBIDITY IN MOOD DISORDERS: THE LINK WITH METABOLIC-INFLAMMATORY SYSTEMS

Learning Objective

• Explain the pathophysiological convergence of mood disorders and cardiometabolic illnesses

Presentation Outline

• Complex interactions between peripheral immune and metabolic changes, and altered brain function as these relate to the development and treatment of mental illness

• Immune-metabolic interactions may impact responses to currently available psychotropic agents and are beginning to support the development of novel interventions

• Studies in immune-stress interactions provide a rationale for recent findings that both anti-inflammatory and pro-inflammatory interventions may be of benefit in the treatment of mood disorders

There are two main types of immunity

Adaptive (Specific) ImmunityInnate (Natural) Immunity• Rapid response• Cells – macrophages, neutrophils,

natural killer cells, dendritic cells

• Memory – none• Specificity – low• Diversity – low (encoded in the

germline)• Proteins – complements and

cytokines

• Slower response• Lymphocytes

• B Lymphocytes• T Lymphocytes

• Memory – yes• Specificity – high (human lymphocytes

can distinguish between 10 billion antigens)

• Diversity – extremely high• Proteins - antibiotics – (B Cells) and

cytokines (helper T cells)

Abbas AK, et al. Basic Immunology: Functions and Disorders of the Immune System, 5e. Fifth Edition. St. Louis, MO: Elsevier Press; 2016.

Innate Immunity – Let’s Meet the Various Members of the Immune System

NeutrophilsMean number per mL – 4400

Humans produce 1011 neutrophils per day. Granules contain bacteria killing lysozymes.

Life span is 1 to 2 daysMonocyte

Mean number per mL – ~ 300

ActivationTissue migrationMacrophage

Activated macrophage


Acquired Immunity – Lymphocytes: Their Role of B and T Lymphocytes

Humoral Immunity

B Lymphocytes

Cell Mediated Immunity

T Lymphocytes

LymphocytesMean number per mL – 2500

2% are in blood, 4% in the skin, 10% bone marrow, 15%

mucosal lymphoid tissues, ~ 65% in spleen and lymph nodes

Life span is days to years

Thymus Bone marrow


Macrophage – Microglia Interactions

Blood-brain barrierBloo

d-br

ain

barri

er

Activated Macrophage (tissue presence –

specially in adipose tissue)

Macrophage Resting Microglia

Activated Microglia (psychosocial stressors)

IL-6TNF-⍺IL-1β


DAMPs = danger-associated molecular patterns;

PAMPs = pathogen-associated molecular patterns;

TLR = toll like receptors;ROS = reactive oxygen species;NO = nitric oxide;CCL2 = chemokine;TSPO = translocator protein;COX-2 = cyclooxygenase 2; IL-1β, IL-6, TNF-α = cytokines.

NFκB = nuclear factor;BDNF = brain-derived neurotrophic

factor; IGF-1 = insulin-like growth factor 1;TGF-β = transforming growth factor

beta;IL-4, IL-10, IL-13 =

anti-inflammatory interleukins.

Bhattacharya A, et al. Psychopharmacology.2016;233(9):1623-1636.

Interplay Between Peripheral Immune Cells, Blood-Brain Barrier, and Microglia-Astrocytes Within the Brain to Drive Neuroinflammation

First Things First –Let’s Review Tryptophan Pathways

Schlittler M, et al. Am J Physiol Cell Physiol. 2016;310(10):C836-C840. Agudelo LZ, et al. Cell. 2014;159(1):33-45.

KYN = KynurenineKATs = Kynurenine AminotransferasesKYNA = Kynurenic AcidQUIN = Quinolinic Acid

Tryptophan

Serotonin

5HIAA

L-KYN

KYNA3-HK

NeurotoxicityQUIN

KATsKMO

IDO

IL-6 and depression1 CRP and depression1

Meta-analyses have also found depression is associated with increased TNF-α and soluble IL-2 receptors2,3

Depression is associated with increased peripheral inflammation

CRP = C-reactive protein TNF = tumor necrosis factor

1Howren MB, et al. Psychosom Med. 2009;71(2):171-186. 2Dowlati Y, et al. Biol Psychiatry. 2010;67(5):446-457. 3Liu Y, et al. J Affect Disord. 2012;139(3):230-239.

Inflammatory and Fatigue-Level Changes After an Immune Stimulus

Harrison NA, et al. Biol Psychiatry. 2015;78(1):49-57.

45

35

50

40

302520151050

4.54.03.53.0

2.52.01.51.0

.50

Fatig

ue (V

AS)

IL-6

P Base P 4Hrs V Base V 4Hrs P Base P 4Hrs V Base V 4Hrs

P = .069 P < .001P = NS P < .001

A) Change in circulating IL-6 pre- and post-vaccine (V base and V 4Hrs) and placebo injection (P base and P 4Hrs). B) Change in fatigue pre- and post-typhoid vaccination and placebo saline injection.

Plasma IL-6 levels are correlated with cognitive performance in MDD.

Grassi-Oliveira R, et al. Neuro Endocrinol Lett. 2011;32(4):540-544.

Logical Memory Subtests of the Wechsler Memory Scale-Revised was administered to 30 patients with recurrent MDD. There was a statistically significant association between IL-6 levels and

IVR (B = -0.787, P = .000) and DVR (B = -0.695, P = .001).

3020 4010

800.00

600.00

400.00

0.00

200.00

0

IL-6

(pg/

mL)

IVR10 30

800.00

600.00

400.00

0.00

200.00

0 20 40

IL-6

(pg/

mL)

DVR

IVR = immediate verbal recallDVR = delayed verbal recall

Impact of Inflammatory Cytokines on Brain Circuitry

Miller AH, et al. Depress Anxiety. 2013;30(4):297-306.

Withdrawal(wound healing, infection fighting)

Fatigue, anhedonia,motor slowing

Subcortical

Inflammatorycytokines

Hypervigilance(protection from attack)

Arousal,alarm

Cortical

DepressionAnxiety

dACC

Basal ganglia

dACC = dorsal anterior cingulate cortex.

Inflammatory cytokines induce the death of astrocytes.

van Kralingen C, et al. PLoS One. 2013;8(12):e84269.

Astrocytes were stimulated across a 96-hour time course to assess the extent of cell loss following IL-1β and TNF-α treatment. Cell numbers were quantified by counting Hoechst stained nuclei.

Treatment

Nuc

lei (

%)

* **

*

Time (hours)

Cel

l Ind

ex

Time (hours)

Cel

l Ind

ex*P < .05

CNS Inflammation and Pathophysiology of Psychiatric Disorders

Nakagawa Y, et al. Pharmacol Ther. 2015;154:21-35.

v

Elevation of inflammatory cytokines in CSF may alter 5-HT and dopamine metabolism.

5-HT = serotonin; HIAA = hydroxyindoleacetic acid; HVA = homovanillic acid; LN = natural log.

• Inflammatory cytokines and monoamine metabolites were compared in 63 suicide attempters and 47 healthy controls

• MADRS scores correlated significantly with CSF IL-6 levels• IL-6 and TNF-α correlated with CSF 5-HIAA and HVA• Higher cytokine levels were associated with increased suicidality

5.04.5 5.5 6.04.0

3

4

2

1

0

-2

-1

3.5

LN IL

-6

LN 5-HIAA100 300 500

4

3

2

1

0

-2

-1

0 200 400 600

LN IL

-6

HVA

Lindqvist D, et al. Biol Psychiatry. 2009;66(3):287-292.

Increased Density of Microglial Cells in Brain Areas of Patients with MDD

aMCC = anterior midcingulate cortexpACC = pregenual anterior cingulate cortexsACC = subgenual anterior cingulate cortex

Major Depression

Healthy Controls

Steiner J, et al. J Neuroinflammation. 2011;8:94.

Upregulation of Microglial QUIN in the Brains of Suicidal Patients

Steiner J, et al. J Neuroinflammation. 2011;8:94.

20

0

QU

IN +

cel

l den

sity

(cel

ls/m

m3 )

15

10

5

sACC aMCC pACC

P = .042*

P = .003**

P = .015*

P = .028*

P = .006** P = .023* Control (n = 10)Bipolar disorder (n = 5)MDD (n = 7)

Correlation between sgACC and PCC may be a marker of depressive rumination.

y = .0068x – .0911R2 = .477, P < .001

10 20 30 40 50 60 70 80-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6C

orre

latio

n of

sgA

CC

with

PC

C

Rumination score

sgACC = subgenual anterior cingulate cortex

Berman MG, et al. Soc Cogn Affect Neurosci. 2011;6(5):548-555.

DMN activity is associated with depressive symptoms.

Posner J, et al. JAMA Psychiatry. 2013;70(4)373-382.

Left Amygdala 0.5 0.4 0.3

Func

tiona

l Con

nect

ivity

(z)

0.2 0.1

0 –0.1 –0.2 –0.3

PCC –0.4 12 17 22 27 32

Depression Severity, HAM-D Score

0.3 Right Amygdala

0.2

Func

tiona

l Con

nect

ivity

(z)

Amygdala 0.1

0

–0.1

–0.2

–0.3 12 14 16 18 20 22 24 26 28 30

Depression Severity, HAM-D Score

Connection strength between the PCC and left amygdala predicted depressive symptoms on the HAM-D (r = 0.65; P < .001; cluster size, 503 voxels) in patients with dysthymia (N = 41).

Cognitive Decline: Patients with Type 2 Diabetes vs. Non-Diabetic Controls

Type 2 diabetes (n = 68) and matched non-diabetic control participants (n = 38), followed up for 4 years.

–0.5

–0.3

–0.1

0.1

0.3

0.5

–0.5

–0.3

–0.1

0.1

0.3

0.5

Baseline 4-year follow-up 4-year follow-upBaseline

Type 2 diabetes

Information processing speed

Attention and executive functioning

Ζ-scoreControl

McCrimmon RJ, et al. Lancet. 2012;379(9833):2291-2299.

Insulin: A Critical Neuropeptide

AMPA-R = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptorNMDA-R = N-methyl-D-aspartate receptorPI3K = phosphoinositide 3-kinasePKB = protein kinase BBAD = BCL2-associated agonist of cell deathCNS = central nervous system.

CNS

Synaptic plasticity

Ca2+

AMPA-R

NMDA-R P13K

Cell death

Synaptic plasticity

Learningmemory

Raf

Cell death

Cell death

ERK1/2

PKB BAD

Caspase-9Survival

FoxO

P13KInsulin Insulin Cell death

Disease

Aβ

Insulin-degradingenzyme

GSK3

Tau

Alzheimer’s disease

?

Pancreas

Insulin

Glucose

Periphery

Blood–brain barrier

van der Heide LP, et al. Prog Neurobiol. 2006;79(4):205-221; McIntyre RS, et al. Expert Opin Pharmacother. 2007;8(11):1615-1628; McIntyre RS, et al. Expert Opin Pharmacother. 2006;7(10):1305-1321.

Hippocampal and Amygdalar Volume Changes in Diabetes Mellitus

den Heijer T, et al. Diabetologia. 2003;46(12):1604-1610.

6.0

6.1

6.2

6.3

6.4

6.5

No Diabetes Diabetes

Hipp

ocam

pal V

olum

e (m

l)

P = .042

Hippocampal volumes and amygdalar volumes (+SE) on brain MRI in participants with diabetes (n = 41) and without diabetes (n = 465). Volumes are adjusted for age and sex and normalized to average head

size. MRI = magnetic resonance imaging

Prefrontal Lobe Network Functional Connectivity:Fasting Insulin Levels AND Insulin Sensitivity in

Lean and Obese Participants

Kullmann S, et al. Hum Brain Mapp. 2012;33(5):1052-1061.

7.5 20 33

2.0

1.5

1.0

0.5

0

-1.0

-0.5

4.5 12

Orb

itofr

onta

l cor

tex

Z va

lues

Insulin sensitivity index(AU)

2.5

P = .0012r2 = .39

33 90 148

2.0

1.5

1.0

0.5

0

-1.0

-0.5

20 55

Orb

itofr

onta

l cor

tex

Z va

lues

Insulin(pmol/l)

2.5

P = .015r2 = .22

Sleep deprivation causes insulin resistance.

Broussard JL, et al. Ann Inter Med. 2012;157(8):549-557.

140

160

pAK

T-tA

KT

ratio

(%)

80

60

100

120

40

20

00.00 10.000.750.500.250.10 1.00

Dose-response effects of insulin pAKT-tAKT response

5.00

Insulin concentration (nM)

Normal sleepSleep restriction

7 66667 7 7Patients (n)

Diabetes impairs hippocampal neurogenesis via altered metabolic/inflammatory system.

aP < .001 DM+N, DM+D vs CON value; bP < .001 DM+N vs DM+D; cP < .001 DM+D+AG vs DM+D value. Values are means ± SD. CON = control rats injected with vehicle alone; DM+N = streptozotocin-induced diabetic rats without depressive-like behavior; DM+D = streptozotocin-induced diabetic rats with depressive-like behavior; DM+D+AG = aminoguanidine (AG, 10 mg/kg) administrated in DM+D rats for 4 weeks.

a

ab

c

Num

bers

of B

rdU

+ C

ells

80.00

60.00

40.00

20.00

0.00CON DM+N DM+D DM+D

+AG

a

ab

c

Num

bers

of B

rdU

+ C

ells

80.00

60.00

40.00

20.00

0.00CON DM+N DM+D DM+D

+AG

Survival Proliferation

Proliferating cells in rat dentate gyrus

Wang SH, et al. Toxicol Sci. 2009;111(1):72-79.

Being overweight/obese has a negative effect on cognitive function in euthymic patients with bipolar disorder

Yim CY, et al. Eur Psychiatry. 2012;27(3):223-228.

BMI was negatively correlated with:

Attention and psychomotor processing

speed as measured by the Digit Symbol Substitution Test

(P < .01)

Overweight/obese patients with bipolar

disorder had:Significantly lower

scores on the Verbal Fluency Test when

compared with normal weight patients with

bipolar disorder (P < .05)

BMI = body mass index

↑MCP-1

Adiposity, Inflammation, and Depression

HDL = high-density lipoprotein; LDL = low-density lipoprotein; ROS = reactive oxygen species; mmLDL = minimally-modified low-density lipoproteins; MCP-1 = monocyte chemoattractant protein 1

• High caloric intake in the diet leads to increased accumulations of lipids in adipocytes

• Increased lipid content results in an increased release of MCP-1 (CCL2), a chemoattractant that increases the infiltration of macrophages into adipose tissue

• Both adipocytes and macrophages release inflammatory mediators, such as IL-6 and TNF-α, into the peripheral circulation

↑IL-6↑TNF-α

↓Adiponectin↑Visfatin↑Resistin↑Leptin

Liver

↓HDL, ↑LDL↑glucose

↑mmLDL

ROS

↑CRP

Macrophageaccumulation

Normal (lean)abdominal adipocytes

Macronutrient accumulation

Enlargedabdominal adipocytes

Sickness behavior(depression?)

TLR activation

Shelton RC et al. Prog Neurbiol 2010;91(4):275-99.

MDD, Adiposity, andInflammatory Markers

Miller GE et al. Am J Cardiol 2002;90(12):1279-83.

0.50

1.00

0.25

0

Low (BMI < 30) High (BMI > 30)

CR

P ±

SE

M (

mg

/L)

0.50

0.75

0.25

0Low (BMI < 30) High (BMI > 30)

IL-6

±S

EM

(p

g/m

L)

Depressed participantsControl participants

50 MDD patients compared with 50 healthy matched controls

IL-6 CRP

0.75

P < .001 P < .001

Relationship Between Neuroinflammation Marker and Severity of Depressive Symptoms

HAB = high affinity bindersMAB = mixed affinity bindersHAM-D = Hamilton Rating Scale for DepressionTSPO vT = translocator protein total distribution volume

25

20

15

10

0

10

TSPO

vT

(mL/

cm3 )

HAM-D score

5

15 20 25 30 35

HABMAB

r = .63; P = .005

Setiawan E, et al. JAMA Psychiatry. 2015;72(3):268-275.

Central Inflammation in Bipolar Disorder: A [11C]-(R)-PK11195 PET Study

Haarman BC, et al. Brain Behav Immun. 2014;40:219-225.

BD-I = bipolar I disorderPET = positron emission tomography

Inflammation and Social Cognition

Moieni M, et al. Brain Behav Immun. 2015;48:132-138.

% C

orre

ct o

n R

ME

test

Baseline T2

Performance on the Reading the Mind in the Eyes (RME) test at baseline and T2 (peak of inflammatory response for the endotoxin group). Error bars depict the standard error of the mean

Common Electrophysiological Markers Between DM and MDD

EEG Parameter T1DM T2DM MDD Brain RegionResting EEGAlpha band power ↓ ↓ / Posterior temporalBeta band power ↓ ↓ ↑ TemporalGamma band power ↓ / ↑ Posterior temporalTheta band power ↑ ↑ ↑ Frontal and parieto-occipital;

anterior cingulate cortexDelta band power ↑ ↑ ↑ Frontal and parieto-occipital;

anterior cingulate cortexEvent Related PotentialsP300 Latency ↑ ↑ ↑ PosteriorP300 Amplitude ↓ / ↓ Frontal and temporo-parietalN100 Amplitude ↓ ↓ ↓ Central and posterior

EEG = electroencephalogram; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Baskaran A, et al. Neuropsychiatr Dis Treat. 2013;9:143-150.

SSRI therapy decreases incidence of cytokine-induced depression.

BAS = Brief Anxiety Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; SSRI = selective serotonin reuptake inhibitor.

De Knegt RJ et al. Ailment Pharmacol Ther 2011;34(11-12):1306-17.

4 24

(a) Reported sadness (MADRS)

Cum

. Inc

. (%

)

12

4 24

(c) Impaired concentration (MADRS)

Cum

. Inc

. (%

)

12Week

50

20

70

100

4 24

40

(b) Inner tension (MADRS)

Cum

. Inc

. (%

)

12

60

50

20

70

100

4 24

40

(c) Hostile feelings (BAS)

Cum

. Inc

. (%

)

12

60

Week

EscitalopramPlacebo50

20

70

100

40

60

50

20

70

100

40

60

30

30

30

30

Different Targets/Agents: Repurposing Opportunities

Metabolic:

• Glucagon-like peptide I (GLP-1) • Exenatide, liraglutide,

taspoglutide, albiglutide, lixisenatide

• Dipeptidyl peptidase IV inhibitors (DPP-IV)• Alogliptin, anagliptin,

gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, vildagliptin

• Insulin

• Others

Inflammatory:

• JAK-STAT

• Monoclonal antibodies (e.g., Infliximab)

• Disease-modifying antirheumatic drugs (DMARDs)

• Others (e.g., minocycline)

Intranasal insulin enhances executive function in bipolar disorder.

McIntyre RS, et al. Bipolar Disord. 2012;14(7):697-706.

Insulin Placebo

Trails A Trails B Trails A Trails B

5.48

19.09

3.915.97C

hang

e sc

ore

Intranasal Insulin: Efficacious in AD and MCI

AD = Alzheimer’s disease; MCI = mild cognitive impairment.

-3-2-10123

Placebo Low Dose (20 IU) High Dose (40 IU)

Females

Males

Delayed story recall

Claxton A, et al. J Alzheimers Dis. 2013;35(4):789-797.

If bipolar disorder is progressive, can we prevent bipolar disorder onset?

OAA = oral antidiabetic agent

2.0

1.5

0.5

1.0

Diabetesfree

DiabeteswithoutOAAs

Haz

ard

ratio

2.5

Diabeteswith

OAAs

3.0

0

2.31 (1.88, 2.85)

1.06 (0.91, 1.24)1.00

Wahlqvist ML, et al. BMC Med. 2012;10:150.

If bipolar disorder is progressive, can we prevent bipolar disorder onset?

1 30 64 69 107/8 126 158

33 61 72 111 123 158

GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2

78

Glicentin MPGF

Oxyntomodulin

Intestine

CNS (Brainstem,

Hypothalamus)

GlicentinOxyntomodulinGLP-17-36amide

GLP-2IP-2

Glucagon GLP-1 GLP-2

GRPP = glicentin-related polypeptide; IP = intervening peptide; MPGF = major proglucagon fragment

Lovshin JA, et al. Diabetes Care. 2015;38(1):132-139.

The GLP-1 receptor is expressed in diverse CNS nuclei in the non-human primate.

CNS Site Monkey Rodent Cortex - - -

Forebrain NAc ++ ++

Striatum AMGD +++ +

Thalamus PVN + ++

Hypothalamus ARc ++++ ++++

Midbrain DTg ++++ +++

Hindbrain NTS/AP ++++ ++++

Spinal Cord Dorsal Horn ++++ ++++

Adapted from Heppner KM, et al. Endocrinology. 2015;156(1):255-267.

GLP-1RA Exert Neuroprotective Effects in a Diversity of Preclinical Models

GLP-1R agonists: ↑ neurite outgrowth ↑ neuronal differentiation↑ synaptic plasticity (long-term potentiation, cognition

within the hippocampus)↑ associative and behavioral learning↓ neuronal degeneration

GLP-1R agonists in AD models:• liraglutide ↓neuronal tau pathology in murine tauopathy model

• liraglutide ↑neurotrophic, ↑neuroprotective effects in amyloid-β (Aβ) toxicity models of AD

Liraglutide Prevents Degenerative Processes in Mouse Model of ADSaline

(8 weeks)

LIRA(8 weeks)

Load

/sec

tion

Saline LIRA0

20

4060

Amyloid plaque load

Plaq

ues/

sect

ion

Saline LIRA0.0

0.1

0.2

0.3

Dense-core plaques

Saline LIRA

Load

/sec

tion

020

80

4060

100120140

Inflammationresponse

Saline LIRANeu

rons

/sec

tion

0

42

68

Neurogenesis

aa

aa

LIRA also improved indicators of memory function (e.g., object recognition, water maze performance) and synapse formation in AD models

McClean PL, et al. J Neurosci. 2011;31(17):6587-6594. Han WN, et al. Neurobiol Aging. 2013;34(2)576-588.

aP < .001 vs saline. LIRA = liraglutide

Liraglutide improves memory retention and total hippocampal CA1 pyramidal neuron numbers in 10-month-old mice in an

age-related sporadic AD (SAMP8) model.

Liraglutide preserved hippocampal CA1 pyramidal neuron numbers: Liraglutide (100 μg/kg/day) also significantly increased (14.3 ± 0.3%) total CA1 pyramidal neuron numbers (204,744 ± 5442, P < .01) as compared to age-matched vehicle-dosed SAMP8 control mice (P < .01).

Hansen HH, et al. J Alzheimers Dis. 2015;46(4):877-888.

*** ***N

umbe

r of t

rials

of f

irst a

void

ance

(mea

n ±

SEM

)***

***

16-

14-

12-

10-

8-

6-

4-

2-

0

*** ***

Num

ber o

f tria

ls o

f crit

erio

n(m

ean

±SE

M)

16-

14-

12-

10-

8-

6-

4-

2-

0

***P < .001 (one-way ANOVA, Dunnet’s post-hoc test)***P < .001 (one-way ANOVA, Dunnet’s post-hoc test)

Liraglutide Improves Cognitive Function In Adults With Mood Disorders

Standardized effect size (Cohen’s d) for neuropsychological tests.*P < .05; **P < .01, ***P < .001.DSST = Digit Symbol Substitution Test; RAVLT = Rey Auditory Verbal Learning Test; TMT = Trail Making Test.

0.52**

0.91**

0.290.41*

0.61***

0.38

0.64**

Baseline

Endpoint70

80

40

30

50

60

20

10

0TMTB STROOP

incongruentRAVLT

acquisitionRAVLTdelayedrecall

DSSTTMTA STROOPcongruent

Unpublished data. ClinicalTrials.gov Identifier: NCT02423824.

Liraglutide: Recalibrating the Circuits Subserving Cognition in Mood Disorders

BaselineEndpoint

1.5

2.0

1.0

0.5

01 532 4

Comparison between baseline and week 4in dlPFC NAA/Cr Ratio

Pilot data. ClinicalTrials.gov Identifier: NCT02423824.

Liraglutide: Recalibrating the Circuits Subserving Cognition in Mood Disorders (cont.)

0.4

0.5

∆% T

MTB 0.2

-0.1

-0.20 0.150.100.05

Correlation between Changes from baseline to endpointin dlPFC NAA/Cr ratio and TMTB score

0.1

0.3

0

∆% NAA/Cr

Pilot data. ClinicalTrials.gov Identifier: NCT02423824.

Decreased Fractional Anisotropy in Overweight/Obese Bipolar Patients vs. Normal Weight Bipolar Patients

Kuswanto CN, et al. Psychol Med. 2014;44(3):533-541.

Rig

ht o

ccip

ital l

obe

0.20

0.18

0.16

0.14

0.12

0.22

0.24

Subject groups

Normal weight Overweight and obese*

***

Healthy Controls

First-episode Mania

n = 26 n = 28*P < .05; **P < .01.

Minocycline

Soczynska JK, et al. Behav Brain Res. 2012;235(2):302-317.

• Second-generation, semi-synthetic tetracycline analog with antimicrobial properties

• Highly lipophilic, easily penetrates the blood-brain barrier in contrast to tetracycline

• Principal metabolite: 9-hydroxyminocycline (inactive)

Antidepressant-Like Effects of Minocycline Monotherapy on the Forced Swim Test

Molina-Hernandez M, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(2):380-386.

N = 7/group, systemic injection 23, 5, and 1 hour prior to Forced Swim Test

0

5

10

15

20

25

30

35

40

Vehicle Minocycline (50mg/kg)

Minocycline (60mg/kg)

Minocycline (80mg/kg)

Immobility

Swimming

Climbing

* *

**

Adjunctive Minocycline Treatment for Bipolar Depression

0 10 20 30 40 50 60

1

Improvement

Response

Remission

%Improvement: 20%ΔResponse: 50%ΔRemission: score ≤ 10

Effect Size (full analysis set)=.325Effect Size (responders)=.702

Soczynska J.K. Bipolar Disorder 2017; 19(3):213.

Forest Plot of Pooled Effect Sizes of Adjunctive Anti-Inflammatory Agents for Bipolar Depression

Rosenblat JD, et al. Bipolar Disord. 2016;18(2):89-101.

O3FA = omega-3 fatty acidsNSAIDs = nonsteroidal anti-inflammatory drugNAC = N-acetylcysteine.

A Randomized Double-blind Placebo-Controlled Trial of Adjunctive Infliximab in the

Treatment of Adults with Bipolar I/Il Depression: Efficacy in Persons

Reporting Childhood Trauma

Changes in MADRS Total Scores From Baseline to Week 12 in Infliximab- or Placebo-Treated Individuals With BD With No Versus

Individuals With Clinically Significant History of Physical Abuse

Effect of Gut Microbiota on Mood-Related Behavior

GF = germ-freeSPF = specific-pathogen free

Zheng P et al. Mol Psychiatry. 2016;21(6):786-796.

16S rRNA gene sequencing reveals changes to microbial diversity in MDD

Zheng P, et al. Mol Psychiatry. 2016;21(6):786-796.

Emerging Evidence: Increased Remission Rates With Add-On Exercise

IDS-C = Inventory of Depressive Symptomatology, Clinician-Rated; NNT = number needed to treat; KKW = kcal per kg per week.

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 curve4-KKW group: fitted curve 4-KKW group: percent

16-KKW group: percent

NNT = 7.8 for higher dose exercise group

100908070605040302010

00 1 2 3 4 5 6 7 8 9 10 11 12

Perc

ent w

ith ID

S-C

30re

mis

sion

Week

Trivedi MH, et al. J Clin Psychiatry. 2011;72(5):677-684.

Cytokine Antagonism as an Antidepressant Treatment

CGI = Clinical Global ImpressionINFLIX = infliximabTRD = treatment-resistant depression.Hs-CRP = high-sensitivity C-reactive protein

InfliximabPlacebo

60

50

40

30

20

0

10

Med + Low High

Perc

ent r

espo

nder

s du

ring

stud

y

Hs-CRP (tertiles)

4 123 101 62Baseline 8

Infusion Infusion Infusion

n = 30

n = 30INFLIX

(5 mg/kg)

PLACEBO

Randomization

Clinician-administered psychiatric assessments (HAM-D, CGI)adverse events evaluation

blood draw for inflammatory markers and safety labs

TRD Pts(N = 60)

StratificationMale vs Female

CRP >2 vs CRP ≤2

30

25

20

15

10

0

5

4 12

Adju

sted

mea

n H

AM-D

-17

Weeks3 101 62Baseline 8

InfliximabPlacebo

Raison CL et al. JAMA Psychiatry 2013;70(1):31-41.

Pro-inflammatory state may predict short-term response to ketamine

Niciu MJ, et al. J Clin Psychiatry. 2014;75(5):e417-e423. Machado-Vieira R, et al. Mol Psychiatry. 2016;[Epub ahead of print].

In 108 patients with TRD receiving a single ketamine infusion, increased BMI predicted enhanced short-term antidepressant response. In 80 patients with TRD, lower levels of the anti-inflammatory adipokine

adiponectin predicted improved antidepressant responses at 1-day post-treatment.

Increased Inflammation Associated With Enhanced Response to L-methylfolate

BMI = body mass index; hsCRP = high-sensitivity C-reactive protein; IL = interleukin; TNF-α = tumor necrosis factor α.

Shelton RC, et al. J Clin Psychiatry. 2015;76(12):1635-1641.

Cytokine Antagonism May Be Counterproductive for Many With MDD

InfliximabPlacebo

60

50

40

30

20

0

10

Med + Low High

Perc

ent r

espo

nder

s du

ring

stud

y

Hs-CRP (tertiles)

4 123 101 62Baseline 8

Infusion Infusion Infusion

n = 30

n = 30INFLIX

(5 mg/kg)

PLACEBO

Randomization

Clinician-administered psychiatric assessments (HAM-D, CGI)adverse events evaluation

blood draw for inflammatory markers and safety labs

TRD Pts(N = 60)

StratificationMale vs Female

CRP >2 vs CRP ≤2

30

25

20

15

10

0

5

4 12

Adju

sted

mea

n H

AM-D

-17

Weeks3 101 62Baseline 8

InfliximabPlacebo

Raison CL et al. JAMA Psychiatry 2013;70(1):31-41.

Antidepressant Effectsof Whole-Body Hyperthermia (WBH)

Janssen CW, et al. JAMA Psychiatry. 2016;73(8):789-95.

30

25

20

15

10

5

00 1 2 3 4 5 6

Week

Mea

n 17

-item

HAM

-D s

core

(16)

(14)

(15)

(14) (12)

(15) (15)(15)

(11) (11)

d = 2.23P < .001 d = 2.11

P = .001d = 1.66P = .02 d = 1.66

P = .02

71% of sham-treated participantsbelieved they had received WBH

Inflammation as a Treatment for Major Depression

In a small study of 7 severely depressed inpatients, the administration of LPS at 5 PMproduced a significant reduction in depressive symptoms the next day (P = .018).

The improvement was maintained in 2 of the 7 patients, whereas the other 5 relapsed following a night of recovery sleep.

LPS increased IL-6 and TNF, and suppressed REM sleep.

Reductions in depressive symptoms were highly correlated with increased IL-6 after LPS administration (rs = .95, P < .001).

10

Week of therapy

20

Baseline Post-stimulation

2

Post-stimulation

1

Pre-stimulation

40

0

30

Stimulation

LPS = lipopolysaccharides

Bauer J, et al. Biol Psychiatry. 1995;38(9):611-621.

NSAID Use May Promote Antidepressant Resistance

Gallagher PJ, et al. Am J Psychiatry. 2012;169(10):1065-1072.

Observational data from 1528 outpatients confirmed the observation in STAR*D trial that use of NSAIDs is associated with non-response to antidepressant medications.

NSAID = nonsteroidal anti-inflammatory drugSTAR*D = Sequenced Treatment Alternatives to Relieve Depression.

Muscle as a “Peripheral” Anti-Inflammatory: Implications for “Central” Mental Health Issues

Schlittler M, et al. Am J Physiol Cell Physiol. 2016;310(10):C836-C840.

Muscle Biopsy from Quadriceps for mRNA levels for various enzymes. 30 mg of muscle tissue was extracted and analyzed for mRNA expression

KAT = kynurenine aminotransferase (1, 2, 3, 4); PGC-1a1 = peroxisome proliferator-activated

receptor-gamma coactivator.

= Control Recreational Exerciser (8 subjects)= Endurance Athletes (9 subjects)

Exercise Biopsy Results

Mindfulness: An Anti-Inflammatory Agent

TSST = Trier Social Stress Test; MBSR = Mindfulness-Based Stress Reduction (8 weekly 2.5 hour sessions + 1 full-day session + daily home-based practice, 45 minutes to 1 hour); HEP = Health Enhancement Program (matched MBSR in structure, instructor expertise, and content).

Raw cortisol data showing (a) response to the TSST and (b) diurnal cortisol rhythm for each group at each assessment.

N = 49 community volunteers randomly assigned to either

MBSR or HEP. TSST used to induce psychological stress and

inflammation produced using topical application of capsaicin

cream to forearm skin.

RESULTS: MBSR resulted in a significantly smaller post-stress

inflammatory response compared to HEP, despite equivalent levels

of stress hormones.

Rosenkranz MA, et al. Brain Behav Immun. 2013;27(1):174-184.

Conclusions

• Obesity and diabetes metastasize to the brain

• Inflammation and metabolic alteration critical mediators

• Targeting the metabolic and homeostatic network

• Capable of mitigating domains of psychopathology

• Implications for primary prevention and preemptive treatment

medical comorbidity in mood disorders: the link...

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