1

A Mind-Body Perspective of Major Depressive Disorder

Rakesh Jain, MD, MPHR/D Clinical Research, Inc.Lake Jackson, Texas, USATexas Tech Health Sciences Center – Permian BasinMidland, Texas, USA

Let’s Not Underestimate Our Enemy: Depression is THE Leading Cause of Disability

Cerebrovascular Disease

Hearing Loss, Adult Onset

Chronic Obstructive Pulmonary Disease

Ischemic Heart Disease

0 5 10 15 20

2.96

3.01

3.07

3.07

3.65

4.06

6.76

10.3

Leading Contributors to Disability

Percent of Total Disability-Adjusted Life Years (DALYs)*

*DALYs represent total number of years lost to illness, disability, or premature death within a given population. They are calculated by adding number of years of life lost to number of years lived with disability for a certain disease or disorder.

National Institute of Mental Health. http://www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed June 6, 2011. 2

Why is Treatment of Depression so Important?

MDD UK Population

Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008

Life expectancy was reduced by 10.6 years for males and 7.2 years in females with MDD compared with UK population

Chang CK,et al. PLoS One. 2011;6:e19590. 3

A Clinician’s Integrative View of “Mind-Body” Disruptions in Psychiatric Mood Disorders

Pain

Neuropsychological impairmentNeurodegeneration

Mood disorders

Sleep disorders

Osteoporosis

Obesity, insulin, and lipid abnormalities

Coronary artery disease

Substance misuse

Inflammation

Adapted from Goldstein BI, et al. J Clin Psychiatry. 2009;70(8):1078-1090. Adapted from Szelényi J, Vizi ES. Ann N Y Acad Sci. 2007;1113:311-324. 4

Childhood Adversity Represents a Risk for Adulthood Disease

Major depression (panel 1): z=4.94, P<.001. High-sensitivity C-reactive protein (hsCRP) level 3 mg/L (panel 2): z=3.24, P=.001. Clustering of metabolic risk markers (panel 3): z=4.58, P<.001. 1 age-related disease risks (panel 4): z=5.66, P<.001.

32-year prospective study.

Panel 1:Major

Depression

Panel 2:hsCRP >3 mg/L

Panel 3:Clustering of

Metabolic Risk Markers

Panel 4:≥1 Disease Risk

Number of Adverse Childhood Experiences

% o

f S

tud

y M

emb

ers

Wit

h t

he

Co

nd

itio

n

≥2 (n=98)

70

60

50

40

30

20

10

0

0 (n=502)1 (n=253)

Adapted from Danese A, et al. Arch Pediatr Adolesc Med. 2009;163(12):1135-1143. 5

Association of Depression and AnxietyWith Chronic Physical Conditions

World Mental Health Survey (N=42,249)

0

1

2

3

4

5

6

Asthma HTN Arthritis HeartDisease

Back/NeckPain

ChronicHeadache

MultiplePains

Od

ds

Ra

tio*

P<.05 for all comparisons vs persons with neither depression nor anxiety

Depression and anxiety

DepressionAnxiety

*Data show odds ratio with 95% confidence intervals (CI). HTN=hypertension.Scott KM, et al. J Affect Disord. 2007;103(1-3):113-120. 6

Depression Decreased Long-term Survival After Myocardial Infarction (MI)

Days Postdischarge After MI

Long-Term Survival After MI in Relation to Beck Depression Inventory (BDI) Score During Hospitalization

Car

diac

Dea

th-F

ree

Sur

viva

l (%

) BDI <5

BDI 5 to 9

BDI 10 to 18

BDI ≥19

100

90

80

70

600 365 730 1095 1460 1825

N=896

Adapted from Lespérance F, et al. Circulation. 2002;105(9):1049-1053. 7

Depression and MI: Importance of Depression and its Optimum Treatment

Event Rate:Non-responders = 25.6 %Untreated controls = 11.2 %Responders = 7.4 %

Data derived from MIND-IT study, participants had post-MI depression

MI = myocardial infarction.de Jonge P, et al. Am J Psychiatry. 2007;164:1371-1378. 8

MDD was Associated With Progression of Atherosclerosis

3-Y

ear

Cha

nge

in C

arot

id IM

T (

mm

)

BDI-II Total Score

P for Linear Trend=.003N=324

0-1

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

2-4 5-19

0.00

IMT=intima-media thickness; BDI-II=Beck Depression Inventory II.Adapted from Stewart JC, et al. Arch Gen Psychiatry. 2007;64(2):225-233. 9

Obese

Overweight

Normal W

eight

0.00.51.01.52.02.5

NonMetS

MetS

Axi

s T

itle

Relationship Between Obesity, Metabolic Syndrome, and Depression

Association between metabolic syndrome (MetS) and depression in each body mass index (BMI) category. Graph displays odds ratio (OR) for depression after adjustment for age, gender, prior cardiovascular disease, employment status, marital status, smoking status, dietary score, and physical activity. Obesity was defined as BMI ≥30 and overweight status as a BMI between 25 and 30 kg/m2

Odd

s Ra

tio -

Dep

ress

ion

Skilton MR, et al. Biol Psychiatry. 2007;62(11):1251-1257. 10

Adipose Tissue: a Potent Source of InflammationOne more reason for Optimum Weight Management

Shelton RC, Miller AH. Prog Neurobiol. 2010.91: 275-299. 11

MDD, Adiposity, and Inflammatory Markers

0.00

0.25

0.50

0.75

1.00

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

CR

P ±

SE

M (m

g/L)

ADIPOSITY

C-Reactive Protein

Low (BMI < 30) High (BMI > 30)0.00

0.25

0.50

0.75

Interleukin-6

Control SubjectsDepressed Subjects

ADIPOSITY

IL-6

± S

EM

(p

g/m

l)

50 MDD patients compared with 50 healthy matched controls

Miller GE et al. Am J of Cardiol. 2002;90(12):1279-1283. 12

Neuroendocrine, Autonomic, and Immune Dysregulation in MDD

CRH = corticotropin-releasing hormone; NF-κB = nuclear factor kappa B; ACTH = adrenocorticotropic hormone.Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741. Reprinted with permission from Elsevier Limited. 13

Inflammatory Cytokine Levels Were Associated With Symptom Severity in Patients With MDD

Comparison of 5 Patients With MDD and 5 Matched Healthy Controls

R2=0.4058P=.05

Da

ily M

ea

n V

AS

Sco

re (

mm

)

A. Concentration

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120B. Guilt

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.6711P=.004*

C. Sadness

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.5139P=.02

D. Self-Esteem

Da

ily M

ea

n V

AS

Sco

re (

mm

)

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.735P=.002*

Daily Mean Log IL-6 (pg/mL)

E. Suicidal Thoughts

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.7785P=.0007*

Daily Mean Log IL-6 (pg/mL)

F. Tiredness

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.566P=.02

Daily Mean Log IL-6 (pg/mL)

*Correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction; VAS=Visual Analog Scale.Adapted from Alesci S, et al. J Clin Endocrinol Metab. 2005;90(5):2522-2530. 14

Gene transcription cascades

Neurotrophins

Systems Circuitry

Neuronal Circuitry

Intra-cellular Pathways

Monoamine neurotransmitter-

level view

“The King is Dead – Long Live the King”: Beyond the Monoamine Hypothesis of Depression

Marsden WN. Med Hypotheses. 2011.77:508-528. 15

Macro- and Microscopic Structures Involved in Mood Disorders

Schloesser RJ, et al. Neuropsychopharmacology. 2008;33:110-133. 16

Examining the Neurotrophic Hypothesis of Depression

Nor

mal

Trea

tmen

t

Dep

ress

ion

Berton O, Nestler EJ. Nat Rev Neurosci.2006;7:137-151. 17

Glia-Neuron Interaction May Influence Neurotrophic Factors

5-HT=serotonin; BDNF=brain-derived neurotrophic factor; CNS=central nervous system; GLU=glutamate; IDO=indoleamine 2,3 dioxygenase; IFN=interferon; IL=interleukin; NMDA=N-methyl-D-aspartate; QUIN=quinolinic acid; RNS=reactive nitrogen species; ROS=reactive oxygen species; TNF=tumor necrosis factor; TRP=tryptophan.Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741. Reprinted with permission from Elsevier Limited. 18

Neurotransmitter–Receptor–Intracellular–Gene Transcription Interactions

Racagni G, et al. World J Biol Psychiatry. 2011;12:574-587. 19

Circuitry in Depression: Examining Two Models

An amygdala-centric circuit largely inspired

by structural brain imaging and

postmortem studies

Another circuit model generated with a

greater emphasis on functional imaging

results

Krishnan V, Nestler RJ. Am J Psychiatry. 2010;167(11):1305-1320. 20

Inflammation and Depression: the Brain-Body Link

Capuron L, Miller AH. Pharmacol Ther. 2011;130:226-238. 21

Depression and Inflammation:What is the link ?

Induction of indoleamine 2,3-dioxygenase (IDO) by IF

and some PICs is associated with depleted plasma

tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic

and depressogenic tryptophan catabolites (such

as kynurinate, and quinolinic acid)

All abovementioned factors cause neuroprogression, that is a combination of

neurodegeneration, neuronal apoptosis, and

lowered neurogenesis and neuroplasticity.

Stroke, AD, HD, PD, MS Psychological stress

IFNy, IL-2,IL-1β, TNFα, IL-6

Microglial activation Neuroinflammation

IFNy, IL-2,IL-1β, TNFα, IL-6

Peripheral CMI activation and inflammation

CVD; COPD; RA; SLE; IBD; HIV Diabetes; Metabolic syndrome Postpartum period; Hemodialysis IFNα-immunotherapy;

Predisposing factors: immune and inflammatory genes Lowered levels of peptidases (DPP IV and PEP)

Melancholic symptoms

Anxiety

Fatigue and somatic symptoms

SERT5-HT

L-tryptophan

IDO

TRYCATs

TRYCATs

IDO

L-tryptophan

Leonard B, Maes M. Neurosci Biobehav Rev. 2012;36:764-785. 22

A “Tripartite” Model of Mind-Body Link: Inflammatory, Autonomic, and HHPA Axis Abnormalities

Jain R, et al. Curr Diab Rep. 2011;11:275-284. 23

The Multi-channel Connections Between Mind and Body in Inflammatory Signaling

Capuron L, Miller AH. Pharmacol Ther. 2011;130:226-238. 24

What Are the Treatment Implications of This Emerging Mind-Body Neurobiology?

Footnote goes here 25

• Depressed mood

• Decreased interest or pleasure

• Significant appetite or weight change

• Fatigue

• Insomnia or hypersomnia

• Psychomotor disturbances

• Worthlessness/guilt

• Impaired concentration

• Thoughts of death/suicide

A Clinician’s View Of Major Depression: 16 out of 9 Symptoms! (All are Important to the Clinician)

Irritability

Brooding

Pain

Tearfulness

Anxiety or phobias

Obsessive rumination

Excessive worry over physical health

Associated symptoms

DSM-IV diagnostic criteria

APA. DSM-IV-TR. 2000:352,356. 26

Which Interventions to Pick for Optimally Treating this Mind-Body Condition – Depression ?

Footnote goes here 27

Sur

viva

l

Time Since End of Treatment (Months)

Continued medication (n=28)Placebo (n=21)Prior behavioral activation (n=27)

Prior cognitive therapy (n=30)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 18 20 22 24

Cognitive Therapy and Behavioral Activation Were Advantageous in Delaying Relapse

Participants were initially assigned to 16 weeks of antidepressant treatment (n=100), cognitive therapy (n=45), and behavioral activation (n=43); treatment responders on antidepressants were randomized to continue with medication or placebo; relapse was defined as HAM-D score of 14; recurrence was defined with same criteria during second year of follow-up

Adapted from Dobson KS, et al. J Consult Clin Psychol. 2008;76(3):468-477. 28

Impact of Cognitive Therapy on Amygdala and Prefrontal (Dorsolateral PFC) Activity in MDD

12 Weeks of Cognitive Therapy

0.15

0.10

0.05

0.00

-0.052 4 6 8 10 12

Time (Seconds)

BO

LD

Sig

na

l (%

Ch

an

ge

)

Time (Seconds)

BOLD

Sig

nal (

% C

hang

e)

0.30

0.15

0.10

0.05

2 4 6 8 10 12 14 16 18

0.00

0.20

0.25PrePostControl

a. Emotional b. Cognitive

Is it you?UGLY

Put the digits in numerical order7 4 3 1 5

Patients with depression (n=9)

Controls (n=24)

Adapted from DeRubeis RJ, et al. Nat Rev Neurosci. 2008;9(10):788-796. Reprinted with permission from Macmillan Publishers Ltd. 29

0

5

10

15

20

25

30

35

Baseline 3 Months 6 Months

BD

I Sco

res

Comparison of Depressive Symptoms Over First Six Months After CABG in UC-CBT and UC groups

usual care (UC) group

usual care plus cognitive behavioral therapy (UC-CBT) group

CBT and Inflammation: Symptoms and Neurobiological Marker Improvement

-30

-20

-10

0

Effect Size (UC-CBT vs UC)=.61

Pg/

mL

Change in IL-6

Effect Size (UC-CBT vs UC)=.85-25

-20

-15

-10

-5

0Change in CRP

Pg

/mL

CRP=C-reactive protein; CABG=coronary artery bypass graft.Doering LV et.al. Altern Ther Health Med. 2007;13(3):18-21. 30

Psychotherapy and Receptor Changes: Is this even possible?

This is first direct demonstration of a specific neurotransmitter

mechanism involved in neurobiology of psychotherapy.

Increased serotonin 5-HT1A receptor binding in multiple cortical regions following psychotherapy in

patients with MDD

Significant increase in 5-HT1A density in PSY group compared to

FLU group in frontal, temporal, and parietal cortex (angular gyrus,

medial prefrontal cortex, orbitofrontal cortex)

Short-term psychodynamic psychotherapy (PSY, n=8) or fluoxetine (FLU, 20 mg/d, increased up to 40 mg/d if needed, n=15) for 16 weeks

Karlsson H, et al. Psychol Med. 2010;40:523-528. 31

Physical Exercise and Mental HealthIs It Time to Start Prescribing It?

32

Neurobiology of Exercise: a Complex Cascade That Also involves Neurotransmitters and Receptors

Function DiseaseStructure

Executive ControlsPrefrontal and Cingulate Cortex

Emotional ControlsAmygdala, Prefrontal Cortex

External Input• Visual• Olfactory• Acoustic• Gustatory• Somatosensory

ANSand

Endocrine Systems

DA↓

Parkinson’s Disease

↑ROS

Alzheimer’sDementia

Schizophrenia

Depression

Sleep Disorders

Obesity

Diabetes

CVD

Immune Disorder

IBD, Constipation, Colon Cancer

Learning and Memory

Immune Control

Gastrointestinal Control

MuscleCardiovascular Consequences

Metabolic ConsequencesLiver, WAT, Pancreas

Thermal Consequences

Behavior• Social• Sexual• Coping• Addictive• Escape• Fight &

Flight• Stress• Sleep• Ingestive

Motor ControlsMotor CortexStriatum, Brainstem, Cerebellum, Spinal Cord

Motivational ControlsReward,Wanting,SelectionHypothalamus, Accumbens, VTA

Cognitive ControlsHippocampus, Cortex

NeuralPrimary Afferents

“Exercise”

Internal Feedback“Consequences of exercise”

Humoral Factors

CNS

Energy Balance

RepairPlasticityProtectionNeurogenesisTranscriptionNA, 5-HT,GABA, Glutamate, GlycineBDNF/TrkBERK/CREBNFKB

ANS=autonomic nervous system; BDNF=brain-derived neurotrophic factor; CNS=central nervous system; CREB=cyclic adenosine monophosphate response element-binding protein; CVD=cardiovascular disease; DA=dopamine; ERK=extracellular signal-regulated kinase; 5-HT=5-hydroxytryptamine; GABA=gamma amino butyric acid; IBD=inflammatory bowel disease; NA=noradrenaline; NFκB=nuclear factor of kappaB; ROS=reactive oxygen species; TrkB=tyrosine residue kinase receptor-type 2; VTA=ventral tegmental area; WAT=white adipose tissue. Reprinted by permission from Macmillan Publishers Ltd: Dishman RK et al. Obesity. 2006;14(3):345-356. 33

Clinical and Neurobiological Evidence for Exercise and Wellness: Receptors are Involved Here, too!

VAS Scores before and after exerciseEuphoria and Happiness were significantly different (P<0.05)

Reduction in opioid receptor availability after exercise (red is P<0.05)

Con

fusi

on -

Res

t

Con

fusi

on -

Run

Ang

er R

est

Ang

er -

Run

Sad

ness

- R

est

Sad

ness

- R

un

Hap

pine

ss -

Res

t

Hap

pine

ss -

Run

Fat

igue

- R

est

Fat

igue

- R

un

Fea

r -

Res

t

Fea

r -

Run

Ene

rgy

- R

est

Ene

rgy

- R

un

Ten

sion

- R

est

Ten

sion

- R

un

Eup

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- R

est

Eup

horia

- R

un

Bla

nk

0

25

50

75

100

Items

VA

MS

Ra

tin

gs

Boecker H et al. Cereb Cortex. 2008;18(11):2523-2531. 34

Exercise’s Effects on Hippocampal Cell Proliferation and Neurogenesis

Ki 67 positive newly generated

cells

DCX positive young neuronal

cells

# p<0.10*** p<0.001

Van der Borght K, et al. Hippocampus. 2009;19:928-936. 35

Physical Exercise: a Modulator of Inflammatory Cytokines

2.54 2.60

2.48

2.84

2.69

2.2

2.4

2.6

2.8

3.0

3.2

0 6 mo 12 mo

IL-6

(pg

/ml)

Physical activity Successful aging

Nicklas BJ, et al. J Am Geriatr Soc. 2008;56:2045-2052. 36

Effect of Different Types of Exercise

0.63

1.341.47

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

AerobicExercise

ResistanceTraining

Mixed

Effect size

Mead GE, et al. Cochrane Database of Syst Rev. 2008 Oct 8;(4):CD004366. 37

HAM-D 17 Reduction from Baseline 12 Weeks Duration Low Dose: 7.0-kcal/kg/week energy expenditure

PHD: Public Health Dose -17.5-kcal/kg/week energy expenditure

Depression and Aerobic Exercising: Emerging Evidence of Efficacy

p=0.03

p=0.04

T

TT

N = 80

Ham

ilto

n R

atin

g S

cale

fo

r D

epre

ssio

n -

17

0

4

8

12

16

Control Low Dose Public Health Dose

Dunn AL, et al. Am J Prev Med. 2005;28(1):1-8. 38

39

Yoga as a Mind-Body Intervention

Mean thalamic GABA levels in subjects with Major Depressive Disorder (MDD) and low back pain (LBP) (n=2) compared to normal subjects (n=19) before (Scan 1) and after (Scan 2) a 12-week yoga intervention

Stress Yoga-Based Practices

Sympathetic Nervous System (SNS) Parasympathetic Nervous System

Hypothalamic-pituitary-adrenal Axis Hypothalamic-pituitary-adrenal Axis

GABA Activity GABA Activity

Streeter CC, et al. Med Hypotheses. 2012;78:571-579. 40

Mindfulness Based Cognitive Therapy (MBCT)

Footnote goes here 41

Walking Down the Street

On the other side of the street you see somebody you know.

You smile and wave.

The person does not wave back and keeps walking.

You're walking down the street.

42

Non-awareness

Old patterns intrude

Wish for things to be

different

Rumination Depression

Memory bias

Poor problem solving

Mindlessness and Vulnerabilityto Depression

43

Low mood

Old patterns intrude

Wish for things to be

different

Mindful awareness

Freedom to choose not to

“go there”

Safe “platform”

CalmConnected

Creative

Mindfulness and Preventionof Relapse into Depression

44

Volumetric Changes Over 8 Weeks of Mindfulness Based Therapy – Focus on Amygdala

Stressed but otherwise healthy individuals (N 1⁄4 26) participated in 8-week mindfulness-based stress reduction intervention

Holzel BK, et al. SCAN. 2010;5:11-17. 45

Volumetric Changes in Hippocampus With 8 Weeks of Mindfulness Based Therapy

16 healthy, meditation-naïve participants were obtained before and after they underwent 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry,

and compared with waiting list control group of 17 individuals.

Holzel BK, el al. Psychiatry Res. 2011;191:36-43. 46

ANS and Inflammatory Responses, Stress, and Meditation

50 healthy women (mean age=41.32, range=30–65), 25 novices and 25 experts, were exposed to each of the conditions (yoga, movement control, and passive-video control) during three separate

visits.

Kiecolt-Glaser JK et al. Psychosom Med. 2010;72:113-121. 47

Mindfulness Based Cognitive Therapy (MBCT) – Promising New Therapy

M-ADM = Medication (anti-depressant continuation)MBCT= Mindfulness based CTPla+Clin = Placebo plus clinical management

Segal Z, et al. Arch Gen Psychiatry. 2010;67(12):1256-1264. 48

Neurobiological Driven Rationale: Combination May be the Gold Standard Therapy in Depression

Limbic Hyperactivity

Dorsal Cortex Emotional/Cognitive

Dysregulation

Pleasure Circuit Dampening

Pharmacotherapy Cognitive-Behavioral Therapy

Positive Activity Interventions

Pharmacotherapy +Cognitive-Behavioral Therapy +Positive Activity Interventions

Layous K, et al. J Altern Complement Med. 2011;17:675-683. 49

Complete and Several Types of Incomplete States of Mental Health

Incomplete mental illness

Complete mental health

Incomplete mental health

Complete mental illness

High subjective well-being symptoms

Low subjective well-being symptoms

Low mental illness

symptoms

High mental illness

symptoms

Struggling Flourishing

LanguishingFloundering

Slade M. BMC Health Serv Res. 2010;10:26. 50

Pharmacological Interventions in Depression

51

Functional Connectivity Across the “Big Three” Monoamine Systems: Serotonin, Norepinephrine, and Dopamine

Kennedy SH, et al. J Affect Dis. 2011;132 (Suppl 1):S21-S23. 52

Atypical and Other Augmentations with Antidepressants: What is the Receptor-based Biological Rationale for these Augmentation Strategies?

Mathew SJ, et al. Neuropsychopharmacology. 2008;33:20080-2092. 53

BDNF Levels After 8 Weeks of Antidepressant Treatment2

HAM-D: 23.2 HAM-D: 8.2

N=10p=.007

p<.001*

N=28 N=18

*Value is for difference between baseline and follow-up in treated samples.

BDNF Levels After 12 Weeks of Antidepressant Treatment1

0

2530354045

05

101520

1 2

X

X

30

40

50

10

20

Baseline Follow-Up Controls

ControlsPatientssB

DN

F L

evel

s (n

g/d

L)

BD

NF

(n

g/d

L)

Antidepressant Treatment May Normalize BDNF Levels

1. Aydemir O, et al. Prog Neuropsychopharm Biol Psych. 2005;29(2):261-265. 2. Gonul AS, et al. Eur Arch Psychiatry Clin Neurosci. 2005;255(6):381-386. 54

Relationship Between Change in BDNF Levels, Duration of Treatment, and Treatment Response in MDD Patients

r = 0.65p=0.02

r = 0.52p=0.01

Meta-regression based on 10 case control and 13 clinical trial studies assessing 1504 subjects

Ch

ang

e i

n B

DN

F –

Eff

ect

Siz

e

Brunoni AR, et al. Int J Neuropsychopharmacology. 2008;11(8):1169-1180. 55

How Norepinephrine Interacts With Serotonin: Role of Receptors

Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:254. 56

Bio-Psycho-Social Interactions in Depression Occur at the Cellular and Sub-cellular Level

Mathew SJ, et al. Neuropsychopharmacology. 2008;33:20080-2092. 57

Relationship Between H1 and M1 Antagonism: Using Anti-psychotics as a Proxy to Examine This Issue

Matsui-Sakata A, et al. Drug Metab Pharmacokinet. 2005;20(5):368-378. 58

Footnote goe here

Why is Achieving Sustained Remission So Important in Major Depression?

59

Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.

The Kupfer Curve: the Life Story of Depression

Response Remission Recovery

Relapse RecurrenceRelapse“Normalcy”

Symptoms

Syndrome

Treatment Phases

Pro

gressio

n

to d

isord

er

Work with your doctor toavoid relapse and recurrence

Acute MaintenanceContinuation

60

What Is Remission?It Depends on Whom You Ask

A Researcher’s Definition

A Clinician’s Definition

A Patient’s Definition

What is thescore on rating

instrument?Are the

symptoms gone?

Are the symptoms gone? Am I functioning well? Do I feel optimistic and

self-confident?

Zimmerman M et al. Am J Psychiatry. 2006.163(1):148-150. 61

Remission’s Importance: Its Impact on Patient’s Lives

Impacts Physical Functioning1,2

Impacts Social Functioning1,2

Impacts Children’s Mental Well-being3

Impacts Occupational Functioning1,2

Impacts Marital Functioning4

Increased relapse risk; faster relapse5,6

1. Sobocki P et al. Int J Clin Pract. 2006;60(7):791-798. 2. Keller MB. JAMA. 2003;289(23):3152-3160. 3. Weissman MM et al. JAMA. 2006;295(12):1389-1398. 4. Bromberger JT et al. J Nerv Ment Dis. 1994;182(1):40-44. 5. Thase M et al. Am J Psychiatry. 992;149(8):1046-1052. 6. Judd LL et al. J Affect Disord. 1998;50(2-3):97-108. 62

STAR*D Reveals its Secrets:the Dangers of Residual Symptoms

Residual Symptoms:• Sleep disturbance• Sad mood• Appetite/weight

change• Concentration• Outlook• Suicidal ideation• Involvement• Energy/fatigue• Psychomotor

Increasing number of symptom domains leads to increased risk of relapse (x2[5]=17.7155, P=0.0033)

Overall 40% relapse rate

0 domains1 domain2 domains3 domains4 domains5 domains

1.00

0.75

0.50

0.25

0.00

0 10 20 30 40 50 60

QIDS Relapse Time (Weeks)

Cu

mu

lati

ve P

rob

abil

ity

of

Rel

ap

se

Residual Symptom Domains

QIDS=16-item Quick Inventory of Depressive Symptomatology.Nierenberg AA et al. Psychol Med. 2010;40(1):41–50. 63

What Does a Prospective Study Reveal About Differences Between Nonremitters and Remitters?

Statistically smaller areas in nonremitted patients were: anterior cingulum, hippocampus, amygdala, DL-PFC, and DM-PFC

3-year follow-up study (38 patients, 30 controls)Gray matter density decline in nonremitted patients vs remitted patients

DL-PFC, dorsolateral prefrontal cortexDM-PFC, dorsomedial prefrontal cortex

Frodl TS et al. Arch Gen Psychiatry. 2008;65(10):1156-1165. 64

Remission Rates with SSRIs vs SNRIs Debate: What is the Latest?

SNRI remission rates were 5.7% higher

A meta-analysis of head-to-head SSRIs vs. SNRIs trials Remission as the outcome measured

Odds RatioIV, Random, 95% CI

1 2Favors SNRIs

0.2 0.5 5Favors SSRIs

600300 400200

1.5

1

0.5

0

-0.5

-1

-1.5

100 500

Number of Patients in Each Trial (N)

In (

odds

rat

io)

Machado M et al. J Clin Pharm Ther. 2010;35(2):177-188. 65

In Conclusion…

• Depression is truly a Mind-Body Disorder

• Evidence supporting this concept is strong

• Utilizing this Mind-Body approach to understanding and treating Depression will lead to improved outcomes for patients

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