WHY? 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?

NEW SCIENCE AND THERAPIES FOR PATIENTS WITH MENTAL ILLNESS

NEW SCIENCE AND THERAPIES FOR PATIENTS WITH MENTAL ILLNESS

Now is the most

promising time

in the past

two decades

for mental

health research

• Mental illness is a biological brain disease

• Medicines in development based on basic neuroscience research

• A new era has dawned for understanding complex human genetic diseases

• Fostering new approaches to treatment and diagnosis

PAST INVESTMENTS IN BASIC RESEARCHPAST INVESTMENTS IN BASIC RESEARCH

Basic neuroscience

Human genetics

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

Gottesman 1991

Twin studies support a strong genetic component

Concordance rate

Schizophrenia

Bipolar disorder

0 20 40 60 80 100

Dizygotic twins

Monozygotic twins

Tsuang and Faraone 1990

Families are at an increased risk

Lambda

0 5 10 15 20

Siblings

Parents

Children

Half-siblings

Grandchildren

Nephews/Nieces

Aunts/Uncles

General population

Bipolar disorder

Schizophrenia

GENETIC MAPPINGGENETIC MAPPING

1. Determinative mutations; strong effects

2. High penetrance: % of people with the gene that get the illness is high

3. >2000 discovered in humans

4. Tracing gene transmission in families

Dad

Mom

B b

B

b

BB

Bb

Bb

bb

Mendelian genetic diseases: rare variants

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Mendeliandisease

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

Map of Orlando — state level

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Mendeliandisease

Low-frequency variants with intermediate penetrance

Hard to identify

genetically

Variants identifiable by whole-genome

association studies

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

Complex genetic disease

COMPLEX GENETIC DISEASESCOMPLEX GENETIC DISEASES

• Common variants, small effects each gene; rare gene variants, stronger effects

• Additive effects lead to risk of illness

Multiple genes

• Using most sophisticated methods available in human genetics

Need large patient samples

How many samples are needed?

30,000 each from patients with:

• Schizophrenia

• Bipolar disorder

• Controls

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

15% increased risk

20% increased risk

30% increased risk

Rare

Common

Rare

Common

Rare

Common

Number of Cases and Controls in the Study

1,000 5,000 10,000 30,000

GoodPower

NoPower

Power to detect in a psychiatric genetics study

Large, collaborative whole-genome studies

~70% of data or ~6 billion genotypes produced at the Stanley Center/Broad Institute

Bipolar disorder

3 studies combined~4,400 cases, ~6,200 controls

Schizophrenia

7 sites combined~3,500 cases, ~3,500 controls

Wellcome Trust Case Control Consortium

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Variants identifiable by whole-genome

association studies

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

Map of Orlando — city level

WHAT MAKES THIS POSSIBLE?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 GENETICSMETHOD FOR STUDYING COMPLEX GENETICS

• Search for markers in populations, not families

Association study

Affecteds Controls

Where effects are probabilistic, must compare frequencies in cases and controls

Association studies

Manuel Ferreira, Yan Meng

Whole-genome study of 4400 bipolar casesPr

obab

ility

ass

essm

ent

Chromosome

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

0

2

4

6

8

Statistical assessment of gene findings

Cases

Controls

4434

6214

CACNA1C: L-type, voltage-gated calcium channel, alpha1c subunit

ANK3: Ankyrin G

Bidaud et al. (2006)

• Calcium channel blockers have been used to treat bipolar disorder

• Coordinates large protein complexes at specific membrane sites

• Neuronal sodium channels

• Potassium channels

• Lamotrigine used to treat bipolar disorderBennett et al. (2008)

Biological implications of genetic findings

Gargus, Biological Psychiatry 2006

The cardinal feature

of heritable ion

channel disease is a

periodic disturbance

of rhythmic

function in a

constitutionally

hyperexcitable

tissue.

“

”

FINDINGS THUS FAR IN SCHIZOPHRENIAFINDINGS THUS FAR IN SCHIZOPHRENIA

Association findings

Novel gene deletions

Jennifer Stone

Whole-genome study of 3400 schizophrenia cases

Statistical assessment of gene findings

Cases

Controls

3414

3625

1 2 3 4 5 6 7 9 10 118 12 13 14 15 16 17 X18 19 20 21 22

Chromosome

Prob

abili

ty a

sses

smen

t

0

2

4

6

8

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

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Variants identifiable by whole-genome

association studies

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Low-frequency variants with intermediate penetrance

Hard to identify

genetically

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

Frequency of DNA variation in population

New methods rapidly developing

Map of Orlando — street level

NEW TECHNOLOGIES FOR GENETICSNEW 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

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Mendeliandisease

Low-frequency variants with intermediate penetrance

Hard to identify

genetically

Variants identifiable by whole-genome

association studies

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

• 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

IMPORTANT REALIZATIONIMPORTANT REALIZATION

Study Disorder Outcomes

CATIE 1 Schizophrenia74% discontinued study medication by 18 months; little difference in efficacy among antipsychotics

STAR*D 2 Depression28% achieved remission by 14 weeks of treatment with SSRI

STEP-BD 3 Bipolar disorder49% of patients who achieved recovery had recurrence within 2 year follow-up

Antipsychotic metanalysis 4 Schizophrenia Small effects vs. placebo; durability issue

1 Lieberman et al., N Engl J Med, 2005; 353:1209–1223.

2 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.

Largest treatment studies

GENETIC DISCOVERY TO TREATMENTGENETIC 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

Understand functional consequences of variant gene

Identify risk genes

Develop cell-based 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

• Glu 2,3 agonist

• D-cycloserine

• Desmethyl clozaril

• M1 allosteric agonists

• Gaba alpha 2,3 agonists

• PDE-10 inhibitors

• Alpha-7 nicotinic agonists

Possible new drugs in development

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

New approaches to therapy

• 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

SUMMARY OF WHERE WE ARESUMMARY OF WHERE WE ARE

What will this mean for patients?

• Much better diagnostic tools, clearer categories of diagnosis, and more personalized therapy

• Many new targets for new medicines

McCarthy et al., Nat Genet Rev 2008

DNA-based frequency variants and disease susceptibility

Mendeliandisease

Low-frequency variants with intermediate penetrance

Hard to identify

genetically

Variants identifiable by whole-genome

association studies

Frequency of DNA variation in population

Penetranceof disease

High

Intermediate

Modest

Low

Very rare Rare Uncommon Common

Complex genetic disease

• 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

IMPORTANT REALIZATIONIMPORTANT REALIZATION