Mayada Akil, M.D.Mayada Akil, M.D.Senior Advisor to the DirectorSenior Advisor to the Director

National Institute of Mental HealthNational Institute of Mental Health

Advances in Depression Research:Advances in Depression Research: A Report From NIMH

Depression

• Affects 6.7% of adult population

• Women affected twice as much as men

• Leading cause of disability from all medicalillnesses

Causes of Disability by Illness CategoryUnited States and Canada

15-44 years old

0 5 10 15 20 25 30 35 40

Mental Illness*

Alcohol and drug use

Injuries, including self-inflicted

Respiratory disease

Musculoskeletal disease

Sense organ disease

Cardiovascular disease

Migraine

Infectious disease, excluding HIV

WHO World Health Report 2002

0% 5% 10% 15% 20% 25% 30%

Unipolar depressionAlcohol use

Drug use

Bipolar disorderSchizophrenia

Diabetes

Asthma

Hearing loss

Endocrine disorders

Migraine

Top Causes of DisabilityUnited States and Canada

15-44 years old

WHO, World Health Report 2002

Percent Disability Caused by Noncommunicable Diseases

• Total Costs of “Mental Health Care”

• $71 Billion direct for treatment

• $79 Billion indirect (social services)• Both direct and indirect costs are public sector

– Medicaid is the largest single payer of mental health.

– More than 50% of all mental health expenditures are paidfor by the public sector (Medicaid, Medicare, state and localgovernment)

– Individuals with serious mental illnesses represent thesingle largest diagnostic group (35%) on the SSI rolls.

From the President’s New Freedom Commission on Mental Health, 2003

The Economic Costs of Mental Disorders

The Human Cost

NIMH is one of 27 Institutes and Centers atNIMH is one of 27 Institutes and Centers atthe National Institutes of Health (NIH).the National Institutes of Health (NIH).

NIH, is the primary Federal agency forNIH, is the primary Federal agency forconducting and supporting biomedicalconducting and supporting biomedicalresearch and has a public health mission.research and has a public health mission.

What is the NIMH?What is the NIMH?

Reduce the burden of mentalReduce the burden of mentalillness and behavioralillness and behavioral

disorders throughdisorders through

researchresearch on mind, brain on mind, brainand behaviorand behavior

NIMH MissionNIMH Mission

Goals of the NIMH ResearchAgenda for Depression

1. Understanding the biology

2. Prevention

3. Treatment

Discovery to Recovery

Bench Bedside Practice

Discovery to Recovery:Translation is the Key

Bench Bedside

PathophysiologyDiagnostic tests

BiomarkersNew treatments

Practice

Practical trialsServices research

Decade of Discovery: 2000 - 2010

Identifying the players

Revealing basic principles

Translating Discovery into Recovery

Genes Cells Systems Individual Social

Basic Science Opportunities

• Genetics

• Neuroimaging

• Neuroscience

Genetic influences on psychiatric disorders

0 0.2 0.4 0.6 0.8 1

Reading disability

Schizophrenia

Majordepression

Autism

Hyperactivity

Heritability estimate

McGuffin et al., 2001 (Science)

Many Genes Contribute toVulnerability to Depression

Single gene with large effectSingle gene with large effect

Multiple genes with small effectsMultiple genes with small effects

The Human Genome Map- Completed 4/14/03

The Human Genome Map - Completed 4/14/03

Genes: approx 23,000

Genes with known function: less than 5%

Total: 3 billion basesacross 46 chromosomes

Variation : appr 1 SNP every 1000 bases

Variation is the key to understandingvulnerability to disease

www.hapmap.org

3,000,000 points of variationPredicted by 300,000 SNPs!!!

HapMap gives whole genome studies of variation >10 fold advantage.

5-HTT (SERT) – 1 Gene with 27 Variants

Genes: Who are the players indepression?

Decade of Discovery: 2000 - 2010

Identifying the players

Revealing basic principles

Changing the culture of science

Genes Cells Systems Individual Social

Advances in Neuroimaging

2001 2006 Benefit

Spatial Res. 1x1x3mm3 X 4 Seizure fociLesions in ADNerve fiber changes

Temporal Res. X 10 Angiogram

Brain differences associated with depression

Cg25

Area 25 – altered metabolism and 39% (bipolar) and 48% (unipolar) reduced grey matter volume

6 wks fluox

Cg25

18 mo SSRI

pCg31

Cg25

6 wks fluox PD

pCg31

Cg25

p

A B C D E

Cg25

6 wks parox

Infra-genual Cingulate (Cg 25) Common Target of Pharmacotherapy

Mayberg. Br Med Bulletin 65:193-207, 2003

Reciprocal Cg25-Frontal Changes

pCg31

Cg25

6 wks placebo

+4z

- 4z

Genetic variationGene-environment

AlteredDevelopment

Pathophysiology of Depression

Vulnerable Systems

MoodDisorder

STRESS

Optimizing Existing TreatmentsThrough Practical Clinical Trials

NIMH Practical Trials:“what treatment for which person?”

STEP-BD: Treatment of adults with bipolar disorder4328 enrolled, multiple treatment trials, ongoing, cost: $25M.

CATIE: Effectiveness of antipsychotic drugs1460 enrolled, completed 2005, cost: $67M.

STAR*D: Adults with treatment resistant depression4041 enrolled, completed 2005, cost: $35M.

TADS: Treatment of adolescents with depression439 enrolled, completed 2004, cost: $17M.

STAR D

Rush AJ, et al. Biol Psychiatry. 2003;54(5):573-583.

The Sequenced Treatment Alternativesto Relieve Depression Trial (STAR*D):

4,041 enrolled• Is the patient’s depression resistant to treatment with

an SSRI?

• Would switching medications or augmenting theinitial drug be more likely to achieve a remission?

• How do the side effects of the various medicationscompare?

• How effective is psychotherapy compared withmedication for treatment-resistant depression?

• What is the cost-effectiveness of the varioustreatments?

*Defined as nonremission

Obtain Consent

Level 2

Follow-upSatisfactoryResponse

Unsatisfactory Response*

CIT

Level 1

Randomize to OptionsAcross allAcceptableStrategies

SER BUP VEN CT CIT +BUP

CIT +BUS

CIT +CT

SwitchOptions

AugmentationOptions

STAR D: Defining Evidence For Protocols (Level 2)

33

Level 1 Baseline Characteristics of EnrolledParticipants (N=3038): Demographics

N=3038N=1832N=1206

11%9%14%% Hispanic

7%8%6%% Other

17%13%22%% African-American

76%79%72%% White

Race

62%60%65%Sex-% female

40 (13) years38 (12)44 (13)Age – Mean (SD)

TotalSpecialty CarePrimary Care

STAR D: Defining Evidence For Protocols (Level 3)

Randomize to OptionsAcross allAcceptableStrategies

MRT NTP L-2 Tx +Li

L-2 Tx +THY

AugmentationOptions

SwitchOptions

TreatmentOptions

Strategies

STAR D: Defining Evidence For Protocols (Level 4)

Randomize

TCP VEN + MRTTreatmentOptions

Defining Outcomes in MajorDepression

Return of a depressive episode during recoveryRecurrence

Return of a depressive episode during remissionRelapse

A long period of remission (HAMD-17 ≤7 for≥6 months)

Recovery

A brief period of improvement in which patientis asymptomatic (HAMD-17 ≤7)

Remission

Proposed Definition and CriterionOutcome

Frank E, et al. Arch Gen Psychiatry. 1991;48(9):851-855.Rush and Trivedi Psychiatric Annals 1995

STAR D: Preliminary Results

• Roughly 30% of patients inremission after 12 weeks on CIT

• Switching to Bupropion SR(n=239), Sertraline (n=238) orVenlafaxine ER (n=250) achievedremission in 25% of non responders

STAR D: Preliminary Results

• Augmentation with Buproprion SR(n=565) or Buspar (n=286) lead toremission in about 30% of nonresponders.

Relation Between Maternal Remission Status andChange in Child’s Specific Diagnoses

Source: Weissman et al. JAMA March 22/29, 2006

STAR D: Preliminary Results

•Having two copies of one version ofa gene that codes for the serotonin2A receptor increased the odds of agood response to antidepressanttreatment by 18%.

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0 100 200 300 400 500 600 700

SNPs Ordered by Physical Position

Invers

e S

um

of

Ran

ks

remission

responsers7991012

rs2178865

The Genetics of Response and Remission in STAR*D Sample

MacMahon et al, AJHG, in press

5-HT2a rec

Questions we have Answers to so far

• Is the patient’s depression resistant to treatment with anSSRI?

• Yes in 70% of the cases

• Would switching medications be more likely to achieve aremission?

• Yes in 25% of the cases• Would augmenting the initial medication with another one be

more likely to achieve a remission?• Yes in ~30% of the cases• Does remission in a mother improve have a positive effect on

her child’s mental health?• Yes.• Can we identify genes involved in treatment response?• Yes.

Treatment

Efficacy/Tolerability of the treatment

Patient Adherence to the treatment

Are Essential for Sustained Recovery

www.nimh.nih.govwww.nimh.nih.gov

Research = Hope

National Institute of Mental HealthFunding by Mechanism

FY 1998 – FY 2005

0100,000200,000300,000400,000500,000600,000700,000800,000900,000

1,000,0001,100,0001,200,0001,300,0001,400,0001,500,000

1998 1999 2000 2001 2002 2003 2004 2005P.B

Fiscal Year

Do

llars

in T

ho

usa

nd

s

Grants Contracts IRP RMS Total

How Does a Practical Clinical Trial Differfrom a Traditional Clinical Trial?

Symptoms and Function(effectiveness)

Symptoms (efficacy)Outcome

MonthsWeeksDuration

Treatment vs. TreatmentTreatment vs. PlaceboDesign

Recruitment relies oncommunity practice settings,including private practicesand state facilities.

Recruitment relies on patientscoming to academic healthcenters.

Setting

InclusiveExclusivePopulation

Practical Clinical TrialsTraditional Clinical Trials

Relation Between Maternal Response Level andChange in Child Diagnoses and Symptoms

Source: Weissman et al. JAMA March 22/29, 2006