Post on 19-Apr-2019
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
Abbas AK, et al. Basic Immunology: Functions and Disorders of the Immune System, 5e. Fifth Edition. St. Louis, MO: Elsevier Press; 2016.
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
Abbas AK, et al. Basic Immunology: Functions and Disorders of the Immune System, 5e. Fifth Edition. St. Louis, MO: Elsevier Press; 2016.
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
Abbas AK, et al. Basic Immunology: Functions and Disorders of the Immune System, 5e. Fifth Edition. St. Louis, MO: Elsevier Press; 2016.
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.