Transcript Document

NEW SCIENCE AND THERAPIES FOR
PATIENTS WITH MENTAL ILLNESS
Now is the most
promising time
in the past
two decades
for mental
health research
WHY?
PAST INVESTMENTS IN BASIC RESEARCH
Basic neuroscience
• Mental illness is a biological brain
disease
• Medicines in development based
on basic neuroscience research
Human genetics
• A new era has dawned for
understanding complex human genetic diseases
• Fostering new approaches to treatment and diagnosis
 Example from autism spectrum disorder
How can we come to understand the
underlying molecular causes of schizophrenia
and bipolar illness?
The single largest risk is the sequence of a patient’s genes
Twin studies support a strong genetic
component
Dizygotic twins
Schizophrenia
Monozygotic twins
2
DZ twins
MZ twins
Bipolar disorder
1
00
20
20
40
40
60
60
80
80
100
100
Concordance rate
Gottesman 1991
Families are at an increased risk
Parents
parents
Bipolar disorder
Siblings
siblings
Schizophrenia
Children
children
Half-siblings
half sibs
BP
Grandchildren
grandchildren
SCZ
Nephews/Nieces
nephews/nieces
Aunts/Uncles
aunts/uncles
GeneralGeneral
population
population
0
0
55
10
10
15
15
20
20
Lambda
Tsuang and Faraone 1990
GENETIC MAPPING
Mendelian genetic diseases: rare variants
1. Determinative mutations; strong effects
2. High penetrance: % of people with the gene
that get the illness is high
Dad
3. >2000 discovered in humans
Mom
4. Tracing gene transmission
in families
B
b
BB
Bb
Bb
bb
B
b
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Mendelian
disease
Intermediate
Modest
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
Map of Orlando — state level
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Mendelian
disease
Complex genetic disease
Intermediate
Low-frequency
variants with
intermediate
penetrance
Modest
Hard to
identify
genetically
Variants
identifiable by
whole-genome
association
studies
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
COMPLEX GENETIC DISEASES
Multiple genes
• Common variants, small effects each gene;
rare gene variants, stronger effects
• Additive effects lead to risk of illness
Need large patient samples
• Using most sophisticated methods available
in human genetics
How many samples are needed?
30,000 each from patients with:
• Schizophrenia
• Bipolar disorder
• Controls
Power to detect in a psychiatric genetics study
Number of Cases and Controls in the Study
Rare
15% increased risk
Common
1,000
5,000
10,000
30,000
0
0
0
3
0
0
1
52
0
1
14
98
0
30
93
100
0
0
0
21
0
0
10
96
0
8
61
100
0
83
100
100
0
0
7
92
0
13
75
100
0
68
100
100
10
98
100
100
Rare
20% increased risk
Common
Rare
30% increased risk
Common
Good
Power
No
Power
Large, collaborative
whole-genome studies
~70% of data or ~6 billion genotypes produced at the Stanley Center/Broad Institute
Bipolar disorder
Schizophrenia
3 studies combined
~4,400 cases, ~6,200 controls
7 sites combined
~3,500 cases, ~3,500 controls
Wellcome Trust
Case Control
Consortium
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Intermediate
Variants
identifiable by
whole-genome
association
studies
Modest
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
Map of Orlando — city level
WHAT MAKES THIS POSSIBLE?
• Sequence of human genome
• Dense map of markers or signposts across the
genome — like signs along the highway
• Methods for measuring signs or markers that allow
for measurement of 1–2 million markers at once in
an individual human sample of DNA
• Computer programs allow interpretation of results
• Methods only 2+ years old
METHOD FOR STUDYING COMPLEX GENETICS
Association study
• Search for markers in populations, not families
Association studies
Where effects are probabilistic, must compare
frequencies in cases and controls
Affecteds
Controls
Whole-genome study of 4400 bipolar cases
Statistical assessment of gene findings
Cases
4434
Controls
6214
Probability assessment
8
6
4
2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17 18 19 20 21 22
23
Chromosome
Manuel Ferreira, Yan Meng
ANK3: Ankyrin G
Bennett et al. (2008)
• Coordinates large protein complexes
at specific membrane sites
• Neuronal sodium channels
• Potassium channels
• Lamotrigine used to treat bipolar
disorder
CACNA1C: L-type, voltagegated calcium channel,
alpha1c subunit
• Calcium channel blockers have
been used to treat bipolar disorder
Bidaud et al. (2006)
Biological implications of genetic findings
“
The cardinal
feature of heritable
ion channel disease
is a periodic
disturbance of
rhythmic function in
a constitutionally
hyperexcitable
tissue. ”
Gargus, Biological Psychiatry 2006
FINDINGS THUS FAR IN SCHIZOPHRENIA
Association findings
Novel gene deletions
Whole-genome study of 3400 schizophrenia cases
Statistical assessment of gene findings
Cases
3414
Controls
3625
Probability assessment
8
6
4
2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17 18 19 20 21 22 X
Chromosome
Jennifer Stone
Deletions of genes in schizophrenia
An excess of DNA deletions in genes in samples
of patients vs. controls
• Per patient very small increase
• Biological implications being evaluated will be
clues to underlying causal pathways
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Intermediate
Variants
identifiable by
whole-genome
association
studies
Modest
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
New methods rapidly developing
Intermediate
Low-frequency
variants with
intermediate
penetrance
Modest
Hard to
identify
genetically
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
Map of Orlando — street level
NEW TECHNOLOGIES FOR GENETICS
• High-throughput DNA sequencing: ability to sequence
all genes in 1000 patient samples and 1000 controls
• More detailed map of the human genome
• Next 2–5 years WILL see this technology
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Mendelian
disease
Intermediate
Low-frequency
variants with
intermediate
penetrance
Modest
Hard to
identify
genetically
Variants
identifiable by
whole-genome
association
studies
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
IMPORTANT REALIZATION
• Science’s ability to unravel the underlying causes of
severe mental illness is upon us
• Technologies are rapidly progressing
• What is limiting? Not the intellectual approach
• For the first time in the
history of the field there is
a way forward that can lead
to significant improvements
in diagnosis and therapy
Largest treatment studies
Study
Disorder
Outcomes
CATIE 1
Schizophrenia
74% discontinued study medication by 18
months; little difference in efficacy among
antipsychotics
STAR*D 2
Depression
28% achieved remission by 14 weeks of
treatment with SSRI
STEP-BD 3
Bipolar disorder
49% of patients who achieved recovery had
recurrence within 2 year follow-up
Antipsychotic
metanalysis 4
Schizophrenia
Small effects vs. placebo; durability issue
1 Lieberman
2
et al., N Engl J Med, 2005; 353:1209–1223.
Trivedi et al., Am J Psychiatry, 2006; 163 :28–40.
3 Perlis
et al., Am J Psychiatry, 2006; 163: 217–224.
4 Leucht
et al., Mol Psychiatry, 2008; 1–19.
GENETIC DISCOVERY TO TREATMENT
• Many examples of discovering genetic predispositions
to disease and translating the discoveries into
important, new treatments
• As technology for discovering genes for disease have
evolved, technologies for translating the discoveries
into treatments have also evolved
Impact of genetics on biomedicine
Discovery of drug targets:
• Statins and HMG Coa reductase
• Proscar and benign prostatic hyperplasia
(5-alpha reductase)
• Gleevec and CML (aberrant kinase)
• Herceptin antibody to Her2 for breast cancer
• New approaches to Alzheimer’s
Approaches to therapy: other illnesses
Fragile X syndrome:
• a disease of abnormal brain development
• molecular defect known
• animal models created based on human defect
• abnormal physiology clarified
• new treatments discovered based
on abnormal physiology
• good results in animal model with
human defect
• in early development for humans
• mGluR5 antagonists
Paradigm for new treatments for autism,
bipolar disorder, and schizophrenia
Identify risk genes
Develop cellbased assays
Develop mouse model with a quantifiable
phenotype; a consequence of variant gene
Identify chemicals that reverse cell-based and animal-based phenotype
Human trials in genetically defined variant
Test in broader group of patients with the illness
Possible new drugs in development
• Glu 2,3 agonist
• D-cycloserine
• Desmethyl clozaril
• M1 allosteric agonists
• Gaba alpha 2,3 agonists
• PDE-10 inhibitors
• Alpha-7 nicotinic agonists
New approaches to therapy
Drug mechanism
Stage of research
mGlur2,3 agonist
Expanded human trials
Desmethyl clozaril
Human trials
Alpha-7 nicotinic
receptor agonist
Human trials
Gaba alpha 2,3 agonist
Early human trials
New approaches to therapy
Drug mechanism
Stage of research
D-cycloserine: novel regimen,
use with psychotherapy
Proven in acrophobia,
anxiety
Phosphodiesterase 10
inhibitors
Animal research,
excellent results
SUMMARY OF WHERE WE ARE
• Significant progress on new therapies is possible, even
in genetically determined disease where development of
the brain is awry
• Significant progress toward identifying underlying
causes of schizophrenia, bipolar disorder, and autism,
with genetic technologies evolving rapidly
• The coming 5–10 years will lead to a much greater
understanding of molecular basis for these and other
related disorders
What will this mean for patients?
• Much better diagnostic tools, clearer categories of
diagnosis, and more personalized therapy
• Many new targets for new medicines
DNA-based frequency variants and disease susceptibility
Penetrance
of disease
High
Mendelian
disease
Complex genetic disease
Intermediate
Low-frequency
variants with
intermediate
penetrance
Modest
Hard to
identify
genetically
Variants
identifiable by
whole-genome
association
studies
Low
Very rare
Rare
Uncommon
Common
Frequency of
DNA variation in
population
McCarthy et al., Nat Genet Rev 2008
IMPORTANT REALIZATION
• Science’s ability to unravel the underlying causes of
severe mental illness is upon us
• Technologies are rapidly progressing
• What is limiting? Not the intellectual approach
• For the first time in the
history of the field there is
a way forward that can lead
to significant improvements
in diagnosis and therapy