Depression - This area is password protected

Report
A Mind-Body
Perspective of Major
Depressive Disorder
Rakesh Jain, MD, MPH
R/D Clinical Research, Inc.
Lake Jackson, Texas, USA
Texas Tech Health Sciences
Center – Permian Basin
Midland, Texas, USA
1
Let’s Not Underestimate Our Enemy:
Depression is THE Leading Cause of Disability
Leading Contributors to Disability
10.3
Unipolar Depression
6.76
Ischemic Heart Disease
4.06
Alcohol Use Disorders
Chronic Obstructive Pulmonary…
3.65
Trachea/Bronchus/Lung Cancer
3.07
Hearing Loss, Adult Onset
3.07
Alzheimer's/Dementia
3.01
Cerebrovascular Disease
2.96
0
5
10
15
20
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?
Annual mortality risk (%) by age groups and
diagnoses of mental illness, compared to
England and Wales population in 2008
MDD
UK Population
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
Substance
misuse
Pain
Mood
disorders
Inflammation
Sleep
disorders
Coronary
artery disease
Obesity, insulin, and lipid
abnormalities
Osteoporosis
Neurodegeneration
Neuropsychological impairment
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
% of Study Members With the Condition
70
Number of Adverse
Childhood Experiences
60
0 (n=502)
1 (n=253)
≥2 (n=98)
50
40
30
20
10
0
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
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.
Adapted from Danese A, et al. Arch Pediatr Adolesc Med. 2009;163(12):1135-1143.
5
Association of Depression and Anxiety
With Chronic Physical Conditions
World Mental Health Survey (N=42,249)
6
5
Depression
Anxiety
Depression
and anxiety
P<.05 for all comparisons vs persons
with neither depression nor anxiety
Odds Ratio*
4
3
2
1
0
Asthma
HTN
Arthritis
Heart
Disease
Back/Neck
Pain
Chronic
Headache
Multiple
Pains
*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)
Long-Term Survival After MI in Relation to
Beck Depression Inventory (BDI) Score During Hospitalization
Cardiac Death-Free Survival (%)
100
BDI <5
BDI 5 to 9
BDI 10 to 18
90
BDI ≥19
80
70
N=896
60
0
365
730
1095
1460
1825
Days Postdischarge After MI
Adapted from Lespérance F, et al. Circulation. 2002;105(9):1049-1053.
7
Depression and MI: Importance of
Depression and its Optimum Treatment
Data derived from MIND-IT study, participants had post-MI depression
Event Rate:
Non-responders = 25.6 %
Untreated controls = 11.2 %
Responders = 7.4 %
MI = myocardial infarction.
de Jonge P, et al. Am J Psychiatry. 2007;164:1371-1378.
8
MDD was Associated With
Progression of Atherosclerosis
3-Year Change in Carotid IMT (mm)
0.16
P for Linear Trend=.003
N=324
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0-1
2-4
BDI-II Total Score
IMT=intima-media thickness; BDI-II=Beck Depression Inventory II.
Adapted from Stewart JC, et al. Arch Gen Psychiatry. 2007;64(2):225-233.
5-19
9
Relationship Between Obesity, Metabolic
Syndrome, and Depression
2.5
2.0
1.5
1.0
0.5
0.0
Skilton MR, et al. Biol Psychiatry. 2007;62(11):1251-1257.
Odds Ratio - 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
10
Adipose Tissue: a Potent Source of Inflammation
One more reason for Optimum Weight Management
Shelton RC, Miller AH. Prog Neurobiol. 2010.91: 275-299.
11
MDD, Adiposity, and Inflammatory
Markers
Control Subjects
Interleukin-6
C-Reactive Protein
1.00
0.75
0.75
0.50
0.50
0.25
0.25
0.00
Low (BMI < 30) High (BMI > 30)
ADIPOSITY
0.00
CRP ± SEM (mg/L)
IL-6 ± SEM (pg/ml)
Depressed Subjects
Low (BMI < 30) High (BMI > 30)
ADIPOSITY
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
Daily Mean VAS Score (mm)
Daily Mean VAS Score (mm)
Comparison of 5 Patients With MDD and 5 Matched Healthy Controls
A. Concentration
120
B. Guilt
120
100
100
100
80
80
80
60
60
60
40
40
40
R2=0.4058
20
P=.05
R2=0.6711
20
0
0.5 1.0
1.5
2.0
P=.004*
0
D. Self-Esteem
120
0
2.5
0.5
1.0
1.5
2.0
2.5
E. Suicidal Thoughts
120
0
100
100
80
80
80
60
60
60
40
40
R2=0.735
20
0
0
0.5
1.0
1.5
R2=0.7785
P=.0007*
20
P=.002*
2.5
Daily Mean Log IL-6 (pg/mL)
0
0.5
1.0
1.5
2.0
1.0
2.5
Daily Mean Log IL-6 (pg/mL)
0
1.5
2.0
2.5
F. Tiredness
R2=0.566
P=.02
20
0
2.0
0.5
120
100
40
R2=0.5139
P=.02
20
0
0
C. Sadness
120
0
0.5
1.0
1.5
2.0
2.5
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
“The King is Dead – Long Live the King”: Beyond
the Monoamine Hypothesis of Depression
Gene transcription
cascades
Neurotrophins
Systems Circuitry
Neuronal Circuitry
Intra-cellular
Pathways
Monoamine
neurotransmitterlevel view
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
Berton O, Nestler EJ. Nat Rev Neurosci.2006;7:137-151.
Treatment
Depression
Normal
Examining the Neurotrophic Hypothesis
of Depression
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 ?
Stroke, AD, HD, PD, MS
Psychological stress
SERT
5-HT
L-tryptophan
IFNy, IL-2,
IL-1β, TNFα, IL-6
Melancholic
symptoms
IDO
TRYCATs
Microglial activation
Neuroinflammation
Anxiety
TRYCATs
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;
IDO
Fatigue and
somatic
symptoms
L-tryptophan
Predisposing factors: immune and inflammatory genes
Lowered levels of peptidases (DPP IV and PEP)
Leonard B, Maes M. Neurosci Biobehav Rev. 2012;36:764-785.
Induction of indoleamine
2,3-dioxygenase (IDO) by IF
and some PICs is
associated with depleted
plasma tryptophan, which
may interfere with brain 5HT 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.
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
A Clinician’s View Of Major Depression: 16 out of 9
Symptoms! (All are Important to the Clinician)
Obsessive rumination
Irritability
Brooding
• Depressed mood
• Insomnia or hypersomnia
• Decreased interest
or pleasure
• Psychomotor disturbances
• Significant appetite
or weight change
• Impaired concentration
• Fatigue
Tearfulness
• Worthlessness/guilt
Pain
• Thoughts of death/suicide
Excessive worry over
physical health
Anxiety or phobias
DSM-IV diagnostic criteria
Associated symptoms
APA. DSM-IV-TR. 2000:352,356.
26
Which Interventions to Pick
for Optimally Treating this Mind-Body
Condition – Depression ?
Footnote goes here
27
Cognitive Therapy and Behavioral Activation
Were Advantageous in Delaying Relapse
1.0
0.8
Continued medication (n=28)
Placebo (n=21)
Prior behavioral activation (n=27)
0.7
Prior cognitive therapy (n=30)
Survival
0.9
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time Since End of Treatment (Months)
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
a. Emotional
b. Cognitive
Put the digits
in numerical order
7 4 3 1 5
Patients with depression (n=9)
Controls (n=24)
0.15
0.10
0.05
0.00
-0.05
2
4
6
8
Time (Seconds)
10
12
0.30
BOLD Signal (% Change)
BOLD Signal (% Change)
Is it you?
UGLY
Pre
Post
Control
0.25
0.20
0.15
0.10
0.05
0.00
2
4
6
8 10 12
Time (Seconds)
14
16
18
12 Weeks of Cognitive Therapy
Adapted from DeRubeis RJ, et al. Nat Rev Neurosci. 2008;9(10):788-796. Reprinted with permission from Macmillan Publishers
Ltd.
29
CBT and Inflammation: Symptoms and
Neurobiological Marker Improvement
Change in IL-6
Comparison of Depressive Symptoms Over First
Six Months After CABG in UC-CBT and UC groups
0
Pg/mL
35
BDI Scores
30
25
-10
-20
-30
20
Effect Size (UC-CBT vs UC)=.61
15
Change in CRP
10
0
5
0
Baseline
3 Months
6 Months
usual care (UC) group
usual care plus cognitive behavioral therapy (UC-CBT) group
CRP=C-reactive protein; CABG=coronary artery bypass graft.
Doering LV et.al. Altern Ther Health Med. 2007;13(3):18-21.
Pg/mL
-5
-10
-15
-20
-25
Effect Size (UC-CBT vs UC)=.85
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
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.
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)
31
Physical Exercise and Mental Health
Is It Time to Start Prescribing It?
32
Neurobiology of Exercise: a Complex Cascade That
Also involves Neurotransmitters and Receptors
Structure
Cognitive Controls
External Input
• Visual
• Olfactory
• Acoustic
• Gustatory
• Somatosensory
Hippocampus, Cortex
Executive Controls
Prefrontal and Cingulate Cortex
Emotional Controls
Amygdala, Prefrontal Cortex
Motivational Controls
Internal Feedback
“Consequences of exercise”
Neural
Function
Repair
Plasticity
Protection
Neurogenesis
Transcription
NA, 5-HT,GABA,
Glutamate, Glycine
BDNF/TrkB
ERK/CREB
NFKB
Learning and
Memory
Reward,Wanting,Selection
Hypothalamus, Accumbens, VTA
Motor Controls
Humoral
Factors
CNS
Motor Cortex
Striatum, Brainstem, Cerebellum,
Spinal Cord
Primary Afferents
Muscle
DA
↓
Parkinson’s
Disease
↑
ROS
ANS
and
Endocrine
Systems
Schizophrenia
Depression
Sleep Disorders
Obesity
Energy
Balance
Diabetes
CVD
Immune
Control
Metabolic Consequences
Liver, WAT, Pancreas
Thermal Consequences
Alzheimer’s
Dementia
Behavior
• Social
• Sexual
• Coping
• Addictive
• Escape
• Fight &
Flight
• Stress
• Sleep
• Ingestive
Cardiovascular Consequences
“Exercise”
Disease
Gastrointestinal Control
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.
Immune Disorder
IBD, Constipation,
Colon Cancer
33
Clinical and Neurobiological Evidence for Exercise
and Wellness: Receptors are Involved Here, too!
100
VAMS Ratings
75
50
Blank
Euphoria - Run
Euphoria - Rest
Tension - Run
Tension - Rest
Energy - Run
Energy - Rest
Fear - Run
Fear - Rest
Fatigue - Run
Fatigue - Rest
Happiness - Run
Happiness - Rest
Sadness - Run
Sadness - Rest
Anger - Run
Anger Rest
Confusion - Run
0
Confusion - Rest
25
Items
VAS Scores before and after exercise
Euphoria and Happiness were significantly different (P<0.05)
Boecker H et al. Cereb Cortex. 2008;18(11):2523-2531.
Reduction in opioid receptor availability
after exercise (red is P<0.05)
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
3.2
Physical activity
Successful aging
3.0
IL-6 (pg/ml)
2.84
2.8
2.69
2.6
2.54
2.60
2.4
2.48
2.2
0
Nicklas BJ, et al. J Am Geriatr Soc. 2008;56:2045-2052.
6 mo
12 mo
36
Effect of Different Types of Exercise
1.6
1.4
1.2
Effect 1.0
size
0.8
0.6
0.4
0.2
0.0
1.47
1.34
0.63
Aerobic
Exercise
Resistance
Training
Mead GE, et al. Cochrane Database of Syst Rev. 2008 Oct 8;(4):CD004366.
Mixed
37
Depression and Aerobic Exercising:
Emerging Evidence of Efficacy
p=0.03
N = 80
Hamilton Rating Scale for
Depression - 17
16
T
T
p=0.04
12
T
8
4
0
Control
12 Weeks Duration
Low Dose
Public Health Dose
HAM-D 17 Reduction from Baseline
Low Dose: 7.0-kcal/kg/week energy expenditure
PHD: Public Health Dose -17.5-kcal/kg/week energy expenditure
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
You're 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.
42
Mindlessness and Vulnerability
to Depression
Old patterns
intrude
Nonawareness
Memory
bias
Rumination
Wish for
things to be
different
Depression
Poor
problem
solving
43
Mindfulness and Prevention
of Relapse into Depression
Safe
“platform”
Old patterns
intrude
Freedom to
choose not to
“go there”
Mindful
awareness
Low mood
Wish for
things to be
different
Calm
Connected
Creative
44
Volumetric Changes Over 8 Weeks of Mindfulness Based
Therapy – Focus on Amygdala
Stressed but otherwise healthy individuals (N 1⁄4 26) participated in 8week 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 CT
Pla+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
Pharmacotherapy
Cognitive-Behavioral Therapy
Limbic
Hyperactivity
Dorsal Cortex
Emotional/
Cognitive
Dysregulation
Pleasure Circuit
Dampening
Pharmacotherapy +
Cognitive-Behavioral Therapy +
Positive Activity Interventions
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
High subjective
well-being
symptoms
Incomplete
mental
illness
Complete
mental health
Struggling Flourishing
High mental
illness
symptoms
Floundering Languishing
Complete
mental
illness
Low mental
illness
symptoms
Incomplete
mental health
Low subjective
well-being
symptoms
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
45
40
35
30
25
20
15
10
5
0
HAM-D: 23.2
HAM-D: 8.2
X
X
p=.007
N=10
1
2
p<.001*
sBDNF Levels (ng/dL)
BDNF (ng/dL)
Antidepressant Treatment May Normalize
BDNF Levels
50
40
30
20
10
N=28
Baseline Follow-Up Controls
Patients
BDNF Levels After 12 Weeks
of Antidepressant Treatment1
N=18
Controls
BDNF Levels After 8 Weeks of
Antidepressant Treatment2
*Value is for difference between baseline and follow-up in treated
samples.
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
Change in BDNF – Effect Size
Relationship Between Change in BDNF Levels, Duration of
Treatment, and Treatment Response in MDD Patients
r = 0.65
p=0.02
r = 0.52
p=0.01
Meta-regression based on 10 case control and 13 clinical trial
studies assessing 1504 subjects
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
Why is Achieving Sustained Remission So
Important in Major Depression?
Footnote goe here
59
The Kupfer Curve: the Life Story of
Depression
Response Remission
“Normalcy”
Relapse
Recovery
Relapse
Recurrence
Symptoms
Syndrome
Work with your doctor to
avoid relapse and recurrence
Treatment Phases
Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.
Acute
Continuation
Maintenance
60
What Is Remission?
It Depends on Whom You Ask
What is the
score on rating
instrument?
Are the
symptoms
gone?
A Researcher’s
Definition
Are the symptoms gone?
Am I functioning well?
Do I feel optimistic and
self-confident?
A Patient’s Definition
A Clinician’s Definition
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
Cumulative Probability of Relapse
1.00
Residual Symptoms:
• Sleep disturbance
• Sad mood
• Appetite/weight
change
• Concentration
• Outlook
• Suicidal ideation
• Involvement
• Energy/fatigue
• Psychomotor
Overall 40% relapse rate
0.75
0.50
Residual Symptom Domains
0 domains
1 domain
2 domains
3 domains
4 domains
5 domains
0.25
0.00
0
10
20
30
40
50
60
QIDS Relapse Time (Weeks)
Increasing number of symptom domains leads to increased risk of relapse (x2[5]=17.7155, P=0.0033)
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?
3-year follow-up study (38 patients, 30 controls)
Gray matter density decline in nonremitted patients vs remitted patients
Statistically smaller areas in nonremitted patients were: anterior
cingulum, hippocampus, amygdala, DL-PFC, and DM-PFC
DL-PFC, dorsolateral prefrontal cortex
DM-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?
A meta-analysis of head-to-head SSRIs vs. SNRIs trials
Remission as the outcome measured
Odds Ratio
IV, Random, 95% CI
In (odds ratio)
1.5
1
0.5
0
100
200
300
400
500
600
-0.5
-1
-1.5
0.2 0.5 1
Favors
SSRIs
5
2
Favors
SNRIs
Number of Patients in
Each Trial (N)
SNRI remission rates were 5.7% higher
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
66

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