Depression

7/18/2012
Discovery of Blood
Biomarkers to Diagnose
Depression
Eva E. Redei
1
Outline
• What is depression?
–Definition throughout history
– Alarming statistics
• Who is vulnerable?
• How is it diagnosed?
– Why do we need laboratory diagnostic tests?
– Multi‐marker panel to diagnose MDD, subtypes,
predict treatment outcomes, and aid in discovery of
novel antidepressants
Eva E. Redei 2012 2
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Depression
“...every ray of hope destroyed and not a wish to
gild the gloom”
‐Robert Burns (1759‐1796)
Depression throughout History
• Hippocrates (c. 460 BC ‐ 370 BC) of Ancient Greece:

Imbalance of the humors
– Melancholia from melas (black) and khloe (bile)
• Galen (129 AD – c. 200 AD) of Pergamon (Turkey):

sadness, dejection, despondency often fear anger, delusions and
obsessions
• Avicenna (c. 980 AD– 1037 AD) Persian: described

melancholia similarly to our current definition of depressive type
of mood disorder.
Eva E. Redei 2012 4
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• Robert Burton (1599‐1640): “The Anatomy of
Melancholy”. “This Melancholy of which we are to treat, is
a habit, a serious ailment, a settled humour…not errant, but
fixed: and as it was long increasing…, it will hardly be removed”.
• Emil Krapelin (1856‐1926): origin of psychiatric disease to be
biological and genetic malfunction.
• Henry Maudsley (1835‐1918): Influenced Darwin proposed the
term affective disorder.
• Charles Darwin (1809‐1882): “The expression of the
emotions in man and animals”. Genetically
determined aspects of behavior.
Eva E. Redei 2012 5
• Sigmund Freud (1856‐1939): Founder of psychoanalysis.
Melancholia could result from mourning for an objective loss
and of a subjective one when the individual’s ego is
compromised.
• Currently:
– Depression is either endogenous (melancholic) considering
a biological condition, or reactive (neurotic) a reaction to a
stressful events, and/or
– depression is caused by a chemical imbalance in
neurotransmitters in the brain.
Eva E. Redei 2012 6
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Depression Categories
Unipolar Bipolar
• Major Depressive Disorder • Bipolar type I: One or more
(MDD): One or more major manic episodes; often accompanied
depressive episodes by depressive episodes
• Dysthymia: Depressed mood for • Bipolar type II: One or more
most days during the past two years hypomanic episodes and at least one
major depressive episode
• Depressive disorder not
Cyclothymia: Two‐year period of
otherwise specified: Depressive • cycling hypomanic symptoms and
symptoms do not fit neatly in the depressive symptoms that fail to
DSM‐IV criteria for the other disorders meet DSM‐IV criteria for MDD
• Mixed state: Meet criteria for
both manic episode and major
depressive episode almost every day
for at least one week
Eva E. Redei 2012 7
Outline
– Definition throughout history
–Alarming statistics
Eva E. Redei 2012 8
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Any Mental Disorder Among Adults
100
90
Percent of U.S. Adult Population
80
70
60
50
40 46.4
30
20 26.2
10
5.8
0
Lifetime 12‐month 12‐month
Prevalence Prevalence Prevalence
Classified as
Severe
Eva E. Redei 2012 9
NIMH STATISTICS
Treatment for Any Mental Disorder
50
45
Percent of those with disorder
40
35
36.0
30
25
20
15
10 12.0
5
0
12‐month received marginally
healthcare use adequate treatment
Eva E. Redei 2012 10
NIMH STATISTICS
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Major Depression in Adults
25
Recurrence rates
are over 50 percent
Percent of U.S. Adult Population
20
after the first
15
16.5 depressive episode;
70 percent with two
10 episodes; and over 90
percent with three or
6.7
5 more episodes.
2.0
0
Lifetime 12‐month 12‐month
Prevalence Prevalence Prevalence
Classified as
Severe
NIMH STATISTICS
DEMOGRAPHICS
• Sex: Women are 70% more likely than men to
experience depression during their lifetime
• Race: Non‐Hispanic blacks are 40% less likely than
non‐Hispanic whites to experience depression
during their lifetime
• Age: Compared to adults over the age of 60
– 18‐29 year olds are 70% more likely during lifetime,
but 200% more for 12 month prevalence
– 30‐44 year olds 120% more likely during lifetime, and
80% more for 12 month prevalence
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12 month Prevalence of Major Depression in
Teens
20
Percent of U.S. teen population 18
16
14 15.0
15.4
12
10
12.2
8
7.5 7.4
6
0
Females Males 13‐14 15‐16 17‐18
NIMH STATISTICS
Postpartum Depression
Occurs in 15‐20% of adult women;
26‐32% of adolescents
Symptoms peak at 3‐6 months
Can become chronic
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Late‐Life Depression
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Outline
• Who is vulnerable? Etiology?
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In your opinion, what causes depression?
Other Reasons
Shock/Major
Stress
Event
Sadness Too Much
Rejection/ Work/Fatigue
Loneliness
Loss of Loved Lack of Self
One Confidence
Etiology
1. Genetic predisposition
– Major Depressive Disorder aggregates in families, vulnerability is
affected by a large number of genes.
2. Internal Environment
– Hormonal environment
3. External Environment
– Early life stress, abuse, loss
– Stress, trauma, loss before the onset of depression
BUT, also many chronic diseases:
Parkinson’s
Alzheimer’s
Cardiovascular diseases
Chronic autoimmune diseases: lupus, MS, and many more
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Why Study Genetic Predisposition?
• The neurobiological basis of individual differences
• The etiology of diseases that should lead to the
discovery of new and more specific drug treatments
• The treatment response differences: DNA testing will
be used to predict which patients will respond to
specific drugs or be susceptible to particular side
effects
YESTERDAY:
HUMAN GENOME PROJECT
Ion Proton DNA Sequencer
TODAY Decodes a Human Genome in
One Day for $1,000
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7/18/2012
Hormonal changes elicit depression
• Premenstrual Dysphoric Disorder – Rising levels of Estrogen
• Postpartum Depression – Declining levels of Estrogen
• Perimenopausal Depression – Declining levels of Estrogen
• Hypothyroidism – Low levels of Thyroid Hormones
• Cushing Disease/Syndrome – High levels of Cortisol
• Diabetes – High levels of Glucose; low Insulin
• Aging – Low levels of Testosterone
Early life stress and genetics
Heath & Nelson, 2003
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Stress, trauma, loss before the onset
of depression
1. Episodes of depression are often associated
with stressful life events
2. Chronic stress leads to elevated morning
cortisol levels, similar to melancholic
depressed patients
3. Stress and depression have similar
consequences manifested in increased
prevalence or worsened presentation of
various illnesses Eva E. Redei 2012 25
Stress and depression have similar consequences
manifested in increased prevalence or worsened
presentation of various illnesses
Alcoholism, Drug Abuse Type II Diabetes
Coronary Heart Disease Asthma
Hypertension Crohn’s Disease
Anxiety Disorders Systemic Lupus
Ulcerative Colitis Erythematosus
Obesity Multiple Sclerosis
and many more……
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Outline
–Why do we need laboratory
diagnostic tests?
– Multi‐marker panel to diagnose MDD, subtypes, predict
treatment outcomes, and aid in discovery of novel
antidepressants
Diagnosis
• “The diagnosis of mental disorders must rest with
the patients’ reports of the intensity and
duration of symptoms, signs from their mental
status examination, and clinician observation of
their behavior including functional impairment.
• These clues are grouped together by the clinician
into recognizable patterns known as syndromes.
When the syndrome meets all the criteria for a
diagnosis, it constitutes a mental disorder.”
Eva E. Redei 2012
Mental Health, The report of the Surgeon General 28
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Major Depressive Disorder: Diagnostic Criteria
At least five of the following symptoms have been present during the same two‐week period
and represent a change from previous functioning; at least one of the symptoms is either (1)
depressed mood, or (2) loss of interest or pleasure.
1. depressed mood most of the day, nearly every day
2. markedly diminished interest or pleasure in all, or almost all, activities
3. significant weight loss or weight gain when not dieting
4. insomnia or hypersomnia nearly every day
5. psychomotor agitation or retardation nearly every day
6. fatigue or loss of energy nearly every day
7. feelings of worthlessness or excessive or inappropriate guilt
8. diminished ability to think or concentrate, or indecisiveness
9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide
Clinical diagnosis of depression in primary
care: a meta‐analysis (N=50,371)
Alex Mitchell, et al.. The Lancet. 2009 Eva E. Redei 2012 30
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Diagnosis
The diagnosis of mental disorders is more difficult than
diagnosis of somatic, or general medical, disorders,
since there is no
• definitive lesion,
• abnormality in brain tissue that can identify the
illness, or
• laboratory test
Mental Health, The report of the Surgeon General
Anatomical Markers of Depression
MRI brain maps of differences in
tissue thickness between high‐ vs.
low‐risk for familial depression. Blue
and purple denote thinner areas in the
high‐risk group; yellow, orange, and red are Regional blood flow and/or glucose
significantly thicker areas; green areas metabolism. (A) Ventromedial frontal cortex
show little to no difference in tissue is hyperactive, while (B) Dorsolateral frontal
thickness. cortex is hypoactive in depression.
Myrna Weissman, 2009 Koenig and Grafman, 2009
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Molecular Biomarkers
• Trait: Independent of disease state; genetic markers
of susceptibility (DNA)
• State: Changes by disease state, BUT changes occur in
the brain!
– Gene expression markers of disease states (RNA)
– Protein markers of disease states (Protein)
The stigma of depression and the lack
of biological markers
• Most mental health conditions are referred to as
disorders, rather than as diseases, because diagnosis
rests on clinical criteria. The term “disease”
generally is reserved for conditions with known
pathology or detectable physical change.
• The term “disorder,” on the other hand, is reserved
for clusters of symptoms and signs associated with
distress and disability (i.e., impairment of
functioning), yet whose pathology and etiology are
unknown and no physical change can be detected.
Mental Health, The report of the Surgeon General
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7/18/2012
Outline
–Multi‐marker panel to diagnose
MDD, subtypes, predict treatment
outcomes, and aid in discovery of novel
antidepressants
What are the most urgent tasks
• Objective laboratory diagnosis for different types
of depression
• Individualized treatments based on exact,
objective diagnosis and individual vulnerabilities
(genetic or environmental)
• Development of antidepressants with novel
mechanism of action; closer to etiologies
• ACKNOWLEDGE THAT DEPRESSION IS A DISEASE
LIKE ANY OTHER DISEASE – IT NEEDS TO BE
CURED!!!!
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NEW YORK TIMES MAGAZINE
32 Innovations That Will Change Your Tomorrow
Blood test looks promising in diagnosing depression
A preliminary study finds certain biological markers in the
blood of teens with depression that are absent in healthy
counterparts. It could lead to the first diagnostic testing for
depression.
Los Angeles Times
Teen Depression Can Be Diagnosed With New Blood Test,
Northwestern University Says
Huffington Post
Scientists develop first blood test to diagnose depression
Translational Psychiatry (2012) FoxNews.com
Published online 17 April 2012
Depression in Teens Could Be Diagnosed with Blood Test
Discovery of blood transcriptomic A blood test based on 11 genetic markers could make early‐
onset diagnosis easier and possibly relieve the stigma of
markers for depression in animal models depression
and pilot validation in subjects with Scientific American
early‐onset major depression
AND
K Pajer1,5, B M Andrus2,5, W Gardner1,3, A Lourie3, NBC, WebMD, ABC,CBS, CNN, WGN, WTTW, Voice of
B Strange3, J Campo3, J Bridge3, K Blizinsky2, America, AMA, NPR, The Daily Beast, Health Day, The New
K Dennis2, P Vedell4, G A Churchill4 and E E Redei2,5 Scientist, Boston Globe, BBC, over 700 articles……………..
Novel Approach
• Identified candidate blood markers from two animal
models:
– Genetic model of depression
– Chronic stress model of depression
• “Translated” putative blood markers to human
• Test these blood markers in human subjects with
major depression, starting with teens.
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Unique Genetic Animal Model of MDD
• Mirrors at least five of MDD diagnostic criteria
• Control strain genetically close, but not impaired
• We selectively bred Wistar Kyoto rats, strain well‐
known for depressive characteristics
• Animals on the extremes of depressive behavioral
tests selected for breeding; sibling mating avoided
until G5 generation. Currently at 26‐27th generation.
Pajer et al., Translational Psychiatry, 2012
Transcriptomics of Genetic Model of MDD
• Genome‐wide gene expression analyses of
blood, frontal cortex, amygdale,
hippocampus, and striatum of the depressed
(WMI) and non‐depressed strains (WLI)
• 11 candidate transcripts showing significant,
and same‐directional expression differences in
blood and one or more of the brain regions
between the two strains
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7/18/2012
Chronic Stress Animal Model of MDD
• Temporarily mirrors at least five of MDD diagnostic
criteria
• Genetically distinct strains of rats exposed to
prolonged, repeated psychological stress for 14 days.
• Genome‐wide gene expression analyses of blood of
chronically stressed (CRS) and not‐stressed (NS)
groups.
• 15 transcripts with significant differences between
CRS and NS groups selected as chronic stress markers.
MDD vs. No Disorder
• MDD = 14, No Disorder = 14
– MDD group: 8 girls & 5 boys; mean age 16.6 years
– No Disorder group: 12 girls & 2 boys; mean age 16.3
years
• A panel of 11 blood markers differentiated
participants with early‐onset MDD from the ND
group
• The genes expressing these transcripts belong to
three broad functional categories: those
involved in transcription, neurodevelopment
and neurodegeneration.
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MDD vs. MDD + Anxiety Disorder
• MDD = 5, MDD + Anxiety = 9
• A non‐overlapping panel of 12 transcripts
distinguished subjects with MDD alone from
those with comorbid anxiety.
Early Stress Markers
• MDD = 9, No Disorder = 8
– MDD group: 6 girls & 3 boys; mean age 16.8
years
– No Disorder group: 7 girls & 1 boys; mean age
16.4 years
• Four transcripts, originating from the chronic
stress animal model, significantly correlated
with maltreatment scores in youths
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Criteria for a Successful Biological Diagnostic Test
Five criteria for a successful diagnostic test
1. The disease should represent a substantial burden at the public
health level and should have a prevalent, asymptomatic phase. ✔
2. The asymptomatic phase should be recognizable. ✔
3. The diagnostic test should have reasonable sensitivity ?, specificity
?, be of low risk and low cost ✔, and be acceptable to the patients
and the physicians both.
4. Curative potential should be substantially better in early compared
with advanced stages of disease. ✔
5. Treatment of patients whose disease is detected by the diagnostic
test should decrease cause‐specific mortality, morbidity and/or
disease burden. Likely Eva E. Redei 2012 45
Next Steps
For validity:
Large study of MDD with and without anxiety
For specificity:
Larger study with MDD and other psychiatric
disorders
Diagnostic array
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One day we will
• Diagnose subtypes of depression
• Know when to give antidepressants
and what kind
• Develop novel antidepressants
• Eliminate stigma by knowledge
Somewhere over the rainbow…….
48
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Collaborators
The Lab (past and present) Others
Leah Solberg Wood Kathleen Pajer (Dalhousie University)
Claire C. Will William Gardner (Dalhousie and Ohio)
Amber Baum Jonathan Flint (Oxford)
Nasim Ahmadiyeh Gary Churchill (The Jackson Lab)
Jennifer Slone Wilcoxon Peter Vedell (The Jackson Lab)
Andreja Volenec Jacques Samarut (Univ. of Lyon)
Kelsey Budd Dan Steiner (Univ. of Chicago)
Brandon Strange (Ohio State)
Sergei Revskoy John Campo (Ohio State University)
Fraser Aird Jeff Bridge (Ohio State University)
Kelsey Budd Andrea Lourie (Ohio State University)
Kristen Debus Hao Chen (University of Tennessee)
Pradeep Shukla Rob Williams (University of Tennessee)
Brian Andrus Laura Herzing (Northwestern)
Daniel Schaffer Kazu Shimomura (Northwestern)
Laura Sittig Fred Turek (Northwestern)
Tim Ullmann Larry Jameson (Northwestern)
Elif Tunc‐Ozcan Jelena Radulovic (Northwestern)
Kate Blizinsky David Mohr (Northwestern)
Neha Mehta Lei Wang (Northwestern)
Kathryn Harper Special thanks to Bill Pare!!
Eva E. Redei
Outline
– Multi‐marker panel to diagnose subtypes,
predict treatment outcomes, and
aid in discovery of novel
antidepressants
25
7/18/2012
CURRENT ANTIDEPRESSANTS:
History of Monoamine Deficiency Hypothesis
 1951, Irving Selikoff and Edward Robitzek: patients treated with new anti‐
tuberculosis agents, isoniazid and iproniazid “ exhibited renewed vigor”
 1952, Delay and Buisson; 1953, Lurie and Salzer; isoniazid improved depression
in two thirds of their patients. The mode of antidepressant action of isoniazid is
still unclear. Ipronazid proved to be a potent monoamine oxidase inhibitor.
 1957, a compound that Kunh generated to improve the efficacy of
chlorpromazine became imipramine, the first tricyclic antidepressant, that were
shown by the 1960s to inhibit norepinephrine reuptake.
 1965, Joseph Schildkraut to publish his paper called "The Catecholamine
Hypothesis of Affective Disorders"
 1969‐1987 researchers modified antihistamine‐derived compounds to target the
serotonin system resulting in the first SSRI, fluoxetine.
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Thus, discovery of antidepressants led to the
monoamine deficiency hypothesis of
depression, and this led to more monoamine‐
related antidepressants….
Antidepressant efficacy: STAR D:
 Major Depressive Disorder, ages 18‐75, Clinical
sample with other disorders
 Citalopram 20–60 mg 12‐14 wks (n=2876)
47%
50
40 32.9%
Percent
30
20
10
0
Response Remission
Trivedi MH et al. Am J Psychiatry. 2006;163:28 Eva E. Redei 2012 54
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Recurrence of Major Depressive Episode
Recurrence is less for those who remitted fully
– Remitted: 33.5%
– Responded but not remitted fully: 58.6%
Rush et al, . Am J Psychiatry. 2006
Diagnostic and Statistical Manual of Mental Disorders ‐
Fourth Edition, Text Revision (DSM‐IV‐TR)
• Specify depression as:
– Mild; Moderate; Severe without Psychotic Features; Severe with
Psychotic Features
– Single Episode/Recurrent
– In Partial/Full Remission
– Chronic
– Melancholic/ Atypical
– Postpartum Onset
– Seasonal Affective Disorder, e.t.c.
BUT, antidepressant treatments are the same
for most
28

Depression

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7/18/2012

• Hippocrates (c. 460 BC ‐ 370 BC) of Ancient Greece:

• Galen (129 AD – c. 200 AD) of Pergamon (Turkey):

• Avicenna (c. 980 AD– 1037 AD) Persian: described

• Perimenopausal Depression – Declining levels of Estrogen

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