NEW SCIENCE AND THERAPIES FOR
Download
1 / 42

WHY? - PowerPoint PPT Presentation


  • 126 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' WHY?' - rae-beard


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

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


Dizygotic twins causes of schizophrenia and bipolar illness?

Schizophrenia

Monozygotic twins

Bipolar disorder

0

20

40

60

80

100

Concordancerate

Twin studies support a strong genetic component

Gottesman 1991


Parents causes of schizophrenia and bipolar illness?

Siblings

Bipolar disorder

Children

Schizophrenia

Half-siblings

Grandchildren

Nephews/Nieces

Aunts/Uncles

General population

10

0

5

15

20

Lambda

Families are at an increased risk

Tsuang and Faraone 1990


Dad causes of schizophrenia and bipolar illness?

B

b

B

Bb

BB

Mom

b

Bb

bb

GENETIC MAPPING

Mendelian genetic diseases: rare variants

Determinative mutations; strong effects

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

>2000 discovered in humans

Tracing gene transmission in families


Mendelian causes of schizophrenia and bipolar illness?disease

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


Map of Orlando — state level causes of schizophrenia and bipolar illness?


Mendelian causes of schizophrenia and bipolar illness?disease

Low-frequency variants with intermediate penetrance

Variants identifiable by whole-genome association studies

Hard to identify genetically

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Complex genetic disease

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


COMPLEX GENETIC DISEASES causes of schizophrenia and bipolar illness?

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? causes of schizophrenia and bipolar illness?

  • 30,000 each from patients with:

  • Schizophrenia

  • Bipolar disorder

  • Controls


Number of Cases and Controls in the Study causes of schizophrenia and bipolar illness?

Rare

Rare

Rare

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

15% increased risk

Good

Power

Common

Common

Common

No

Power

20% increased risk

30% increased risk

Power to detect in a psychiatric genetics study


Large, collaborative causes of schizophrenia and bipolar illness?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


Variants identifiable by whole-genome association studies causes of schizophrenia and bipolar illness?

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


Map of Orlando — city level causes of schizophrenia and bipolar illness?


WHAT MAKES THIS POSSIBLE? causes of schizophrenia and bipolar illness?

  • 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 causes of schizophrenia and bipolar illness?

Association study

  • Search for markers in populations, not families


Affecteds causes of schizophrenia and bipolar illness?

Controls

Association studies

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


8 causes of schizophrenia and bipolar illness?

6

4

Probability assessment

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

Whole-genome study of 4400 bipolar cases

Statistical assessment of gene findings

Cases

4434

Controls

6214

Manuel Ferreira, Yan Meng


ANK3 causes of schizophrenia and bipolar illness?: Ankyrin G

  • Coordinates large protein complexes at specific membrane sites

  • Neuronal sodium channels

  • Potassium channels

  • Lamotrigine used to treat bipolar disorder

Bennett et al. (2008)

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

  • Calcium channel blockers have been used to treat bipolar disorder

Bidaud et al. (2006)


causes of schizophrenia and bipolar illness?

The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in a constitutionally hyperexcitable tissue.

Biological implications of genetic findings

Gargus, Biological Psychiatry 2006


FINDINGS THUS FAR IN SCHIZOPHRENIA causes of schizophrenia and bipolar illness?

Association findings

Novel gene deletions


8 causes of schizophrenia and bipolar illness?

6

Probability assessment

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

Whole-genome study of 3400 schizophrenia cases

Statistical assessment of gene findings

Cases

3414

Controls

3625

Jennifer Stone


Deletions of genes in schizophrenia causes of schizophrenia and bipolar illness?

  • 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


Variants identifiable by whole-genome association studies causes of schizophrenia and bipolar illness?

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


Low-frequency variants with intermediate penetrance causes of schizophrenia and bipolar illness?

Hard to identify genetically

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

New methods rapidly developing

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


Map of Orlando — street level causes of schizophrenia and bipolar illness?


NEW TECHNOLOGIES FOR GENETICS causes of schizophrenia and bipolar illness?

  • 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


Mendelian causes of schizophrenia and bipolar illness?disease

Low-frequency variants with intermediate penetrance

Variants identifiable by whole-genome association studies

Hard to identify genetically

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


IMPORTANT REALIZATION causes of schizophrenia and bipolar illness?

  • 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 significantimprovements in diagnosis and therapy


Largest treatment studies causes of schizophrenia and bipolar illness?

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.


GENETIC DISCOVERY TO TREATMENT causes of schizophrenia and bipolar illness?

  • 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 causes of schizophrenia and bipolar illness?

  • 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 causes of schizophrenia and bipolar illness?

  • 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


Identify risk genes causes of schizophrenia and bipolar illness?

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

Paradigm for new treatments for autism, bipolar disorder, and schizophrenia

Understand functional consequences of variant gene


Possible new drugs in development causes of schizophrenia and bipolar illness?

  • Glu 2,3 agonist

  • D-cycloserine

  • Desmethyl clozaril

  • M1 allosteric agonists

  • Gaba alpha 2,3 agonists

  • PDE-10 inhibitors

  • Alpha-7 nicotinic agonists


Drug mechanism causes of schizophrenia and bipolar illness?

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


New approaches to therapy causes of schizophrenia and bipolar illness?

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 causes of schizophrenia and bipolar illness?

  • 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 willlead to a much greater understanding of molecular basis for these and other related disorders


What will this mean for patients? causes of schizophrenia and bipolar illness?

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

  • Many new targets for new medicines


Mendelian causes of schizophrenia and bipolar illness?disease

Low-frequency variants with intermediate penetrance

Variants identifiable by whole-genome association studies

Hard to identify genetically

DNA-based frequency variants and disease susceptibility

Penetrance

of disease

High

Complex genetic disease

Intermediate

Modest

Low

Frequency of DNA variation in population

Very rare

Rare

Uncommon

Common

McCarthy et al., Nat Genet Rev 2008


IMPORTANT REALIZATION causes of schizophrenia and bipolar illness?

  • 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 significantimprovements in diagnosis and therapy


ad