Depression. Affects 6.7% of adult population Women affected twice as much as men Leading cause of disability from all medical illnesses

Transcription

1 Advances in Depression Research: A Report From NIMH Mayada Akil, M.D. Senior Advisor to the Director National Institute of Mental Health

2 Depression Affects 6.7% of adult population Women affected twice as much as men Leading cause of disability from all medical illnesses

3 Causes of Disability by Illness Category United States and Canada years old 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

4 Top Causes of Disability United States and Canada years old Unipolar depression Alcohol use Drug use Bipolar disorder Schizophrenia Diabetes Asthma Hearing loss Endocrine disorders Migraine 0% 5% 10% 15% 20% 25% 30% Percent Disability Caused by Noncommunicable Diseases WHO, World Health Report 2002

5 The Economic Costs of Mental Disorders 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 paid for by the public sector (Medicaid, Medicare, state and local government) Individuals with serious mental illnesses represent the single largest diagnostic group (35%) on the SSI rolls. From the President s New Freedom Commission on Mental Health, 2003

6 The Human Cost

7 What is the NIMH? NIMH is one of 27 Institutes and Centers at the National Institutes of Health (NIH). NIH, is the primary Federal agency for conducting and supporting biomedical research and has a public health mission.

8 NIMH Mission Reduce the burden of mental illness and behavioral disorders through research on mind, brain and behavior

9 Goals of the NIMH Research Agenda for Depression 1. Understanding the biology 2. Prevention 3. Treatment

10 Discovery to Recovery Bench Bedside Practice

11 Discovery to Recovery: Translation is the Key Bench Bedside Practice Pathophysiology Diagnostic tests Biomarkers New treatments Practical trials Services research

12 Decade of Discovery: Genes Cells Systems Individual Social Identifying the players Revealing basic principles Translating Discovery into Recovery

13 Basic Science Opportunities Genetics Neuroimaging Neuroscience

14 Genetic influences on psychiatric disorders Reading disability Major depression Schizophrenia Hyperactivity Autism Heritability estimate McGuffin et al., 2001 (Science)

15 Many Genes Contribute to Vulnerability to Depression

16 Single gene with large effect

17 Multiple genes with small effects

18 The Human Genome Map- Completed 4/14/03

19 The Human Genome Map - Completed 4/14/03 Total: 3 billion bases across 46 chromosomes Genes: approx 23,000 Genes with known function: less than 5% Variation : appr 1 SNP every 1000 bases Variation is the key to understanding vulnerability to disease

20 3,000,000 points of variation Predicted by 300,000 SNPs!!! HapMap gives whole genome studies of variation >10 fold advantage.

21 Genes: Who are the players in depression? 5-HTT (SERT) 1 Gene with 27 Variants

22 Decade of Discovery: Genes Cells Systems Individual Social Identifying the players Revealing basic principles Changing the culture of science

23 Advances in Neuroimaging Benefit Spatial Res. 1x1x3mm 3 X 4 Seizure foci Lesions in AD Nerve fiber changes Temporal Res. X 10 Angiogram

24 Brain differences associated with depression Area 25 altered metabolism and 39% (bipolar) and 48% (unipolar) reduced grey matter volume Cg25

25 Infra-genual Cingulate (Cg 25) Common Target of Pharmacotherapy A B C D E pcg31 pcg31 pcg31 Cg25 6 wks fluox p Cg25 18 mo SSRI Cg25 6 wks fluox PD Cg25 6 wks parox Cg25 6 wks placebo +4z Reciprocal Cg25-Frontal Changes - 4z Mayberg. Br Med Bulletin 65: , 2003

26 Pathophysiology of Depression Genetic variation Gene-environment Altered Development Vulnerable Systems S T R E S S Mood Disorder

27 Optimizing Existing Treatments Through Practical Clinical Trials

28 NIMH Practical Trials: what treatment for which person? TADS: Treatment of adolescents with depression 439 enrolled, completed 2004, cost: $17M. CATIE: Effectiveness of antipsychotic drugs 1460 enrolled, completed 2005, cost: $67M. STAR*D: Adults with treatment resistant depression 4041 enrolled, completed 2005, cost: $35M. STEP-BD: Treatment of adults with bipolar disorder 4328 enrolled, multiple treatment trials, ongoing, cost: $25M.

29 STAR D Rush AJ, et al. Biol Psychiatry. 2003;54(5):

30 The Sequenced Treatment Alternatives to Relieve Depression Trial (STAR*D): 4,041 enrolled Is the patient s depression resistant to treatment with an SSRI? Would switching medications or augmenting the initial drug be more likely to achieve a remission? How do the side effects of the various medications compare? How effective is psychotherapy compared with medication for treatment-resistant depression? What is the cost-effectiveness of the various treatments?

31 Level 1 Obtain Consent CIT Satisfactory Response Follow-up Unsatisfactory Response* Level 2 *Defined as nonremission

32 STAR D: Defining Evidence For Protocols (Level 2) Randomize to Options Across all Acceptable Strategies SER BUP VEN CT CIT + BUP CIT + BUS CIT + CT Switch Options Augmentation Options

33 Level 1 Baseline Characteristics of Enrolled Participants (N=3038): Demographics Primary Care Specialty Care Total N=1206 N=1832 N=3038 Age Mean (SD) 44 (13) 38 (12) 40 (13) years Sex-% female 65% 60% 62% Race % White 72% 79% 76% % African-American 22% 13% 17% % Other 6% 8% 7% % Hispanic 14% 9% 11% 33

34 STAR D: Defining Evidence For Protocols (Level 3) Randomize to Options Across all Acceptable Strategies Treatment Options MRT NTP L-2 Tx + Li L-2 Tx + THY Strategies Switch Options Augmentation Options

35 STAR D: Defining Evidence For Protocols (Level 4) Randomize Treatment Options TCP VEN + MRT

36 Defining Outcomes in Major Depression Outcome Remission Recovery Relapse Recurrence Proposed Definition and Criterion A brief period of improvement in which patient is asymptomatic (HAMD-17 7) A long period of remission (HAMD-17 7 for 6 months) Return of a depressive episode during remission Return of a depressive episode during recovery Frank E, et al. Arch Gen Psychiatry. 1991;48(9): Rush and Trivedi Psychiatric Annals 1995

37 STAR D: Preliminary Results Roughly 30% of patients in remission after 12 weeks on CIT Switching to Bupropion SR (n=239), Sertraline (n=238) or Venlafaxine ER (n=250) achieved remission in 25% of non responders

38 STAR D: Preliminary Results Augmentation with Buproprion SR (n=565) or Buspar (n=286) lead to remission in about 30% of non responders.

39

40 Relation Between Maternal Remission Status and Change in Child s Specific Diagnoses Source: Weissman et al. JAMA March 22/29, 2006

41 STAR D: Preliminary Results Having two copies of one version of a gene that codes for the serotonin 2A receptor increased the odds of a good response to antidepressant treatment by 18%.

42 The Genetics of Response and Remission in STAR*D Sample 0.06 remission response rs rs HT2a rec 0.04 Inverse Sum of Ranks SNPs Ordered by Physical Position MacMahon et al, AJHG, in press

43 Questions we have Answers to so far Is the patient s depression resistant to treatment with an SSRI? Yes in 70% of the cases Would switching medications be more likely to achieve a remission? 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.

44 Treatment Efficacy/Tolerability of the treatment Patient Adherence to the treatment Are Essential for Sustained Recovery

45 Research = Hope

46 Dollars in Thousands 1,500,000 1,400,000 1,300,000 1,200,000 1,100,000 1,000, , , , , , , , , ,000 0 National Institute of Mental Health Funding by Mechanism FY 1998 FY P.B Fiscal Year Grants Contracts IRP RMS Total

47 How Does a Practical Clinical Trial Differ from a Traditional Clinical Trial? Population Setting Design Traditional Clinical Trials Exclusive Recruitment relies on patients coming to academic health centers. Treatment vs. Placebo Practical Clinical Trials Inclusive Recruitment relies on community practice settings, including private practices and state facilities. Treatment vs. Treatment Duration Outcome Weeks Symptoms (efficacy) Months Symptoms and Function (effectiveness)

48 Relation Between Maternal Response Level and Change in Child Diagnoses and Symptoms Source: Weissman et al. JAMA March 22/29, 2006