#CHAIR2016. September 15 17, 2016 The Biltmore Hotel Miami, FL. Sponsored by

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1 #CHAIR2016 September 15 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

2 Bending the Illness Curve: A New Treatment Model for Early Stage Psychoses Jeffrey A. Lieberman, M.D. Columbia University College of Physicians and Surgeons New York State Psychiatric Institute New York Presbyterian Hospital CUMC

3 Jeffrey A. Lieberman, M.D. Disclosures Research/Grants*: Alkermes; Novartis Corporation/Vanda Pharmaceuticals* Advisory Board*: Clinatara; Intracellular Therapies, Inc.*; Pierre Fabre* Other Financial or Material Support: Repligen Corporation * Dr. Lieberman received no direct financial compensation or salary support for participating in these research, consulting, or advisory board activities.

4 #CHAIR2016 Learning Objective 1 Proactively address the duration of untreated psychosis in individuals with schizophrenia.

5 #CHAIR2016 Learning Objective 2 Refer appropriate patients to an early psychosis program.

6 Marshall M, et al. Arch Gen Psychiatry. 2005;62(9): Association Between Duration of Untreated Psychosis and Outcome in Cohorts of First- Episode Patients: A Systematic Review

7 Neurodevelopmental Versus Neurodegenerative Can we change the course or prevent the illness?

8 Natural History of Schizophrenia Rationale for Early Detection and Intervention Stages of Illness Healthy Premorbid Prodromal Onset/Progression Chronic/Residual End-Stage Worsening Severity of Signs and Symptoms Abnormal Brain Development No Sxs Deterioration Margin of Prevention Neurochemcal Dysregulation Psychotic Sxs Neurodedeneration Psychotic Sxs Negative Sxs Cognitive Sxs Gestation/Birth 10 Puberty Years Lieberman JA, et al. Biol Psychiatry. 2001;50(11):

9 Limitations of Existing Interventions Long Duration of Untreated Illness High Attrition Rates High Relapse Rates

10 Rationale Goal is to reduce DUP and provide specialized early stage psychosis services to promote recovery, prevent relapse and reduce disability

11 Governing Principles Disability: Limiting disability is the central focus; disability influenced by treatment and environment Recovery: Core value of empowerment and a personal journey in which the individual acquires the skills and personalized supports necessary to optimize recovery Shared decision-making: Shared decision-making facilitates recovery and provides a framework within which the preferences of consumers can be integrated with provider recommendations for available treatments

12 Roadmap for Pathway to Care Onset of Symptoms Help Seeking Referral to Mental Health Services (Could receive criterion treatment in MHS) Referral to EIS

13 OnTrack NY Team Intervention Evidence-based Pharmacological Treatment and Health Supported Employment/Education Outreach/ Engagement Recovery Needs (SUD, Social Skills, FPE) Sshare Psychotherapy and Support Peer Support Recovery Family Support/ Education Suicide Prevention Shared Decision Making 4.0 FTE

14 Inclusion Criteria for OnTrackNY Non-affective psychosis (schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder NOS (DSM-IV), or other specified/unspecified schizophrenia spectrum and other psychotic disorder (DSM-5) Age Onset of psychosis must be 1 week and 2 yrs New York State resident

15 Exclusion Criteria for OnTrackNY Any history indicating developmental delays (IQ < 70) Primary diagnosis of substance induced psychosis, psychotic mood disorder, or psychosis secondary to a general medical condition Serious or chronic medical illness significantly impairing function independent of psychosis

16 Characteristics of OnTrackNY Enrollees through 7/2016 N = 373 Mean age = 21, 16% under 18 71% Male, 28% Female, 1% Transgender 42% White (non-hispanic), 39% Black (non-hispanic), 10% Asian, 3% Multiracial, 2% Other, 3% Missing 23% Hispanic, 76% Not Hispanic; 1% Missing 50% Medicaid, 40% Private, 2% No insurance, 8% Other Average time since onset of psychosis: 7.6 months

17 % Receiving Treatment Over Time (7/16)

18 % of Patients Hospitalized in Last 3 Months Through 7/16

19 % of Patients Working or in School Through 7/16

20 % of Patients Receiving Antipsychotic Medication

21 % of Clients Participating in Work or School During Last Three Months Through 10/15

22 Consolidated Appropriations Act, 2016: Mental Health Block Grants $50,000,000 increase over FY 2015 for the Mental Health Block Grant program Increases the set-aside to 10 percent SAMHSA directed to continue its collaboration with NIMH to ensure that funds from the set-aside are only used for programs showing strong evidence of effectiveness and targets the first episode of psychosis.

23 States with Early Psychosis Services, 2016 WA OR ID MT WY ND SD MN WI MI NY VT NH ME MA RI CA NV AZ UT CO NM NE KS OK TX IA MO AR LA IL MS IN OH KY TN AL GA PA WV VA NC SC FL NJ DE MD 32 States ~120 Clinics

24 Are We Ready for Disease Modification of Psychotic Disorders?

25 Prediction of Psychosis in Youth at High Clinical Risk - NAPLS Outcomes Risk of conversion 35% during f/u period 5 features improved prediction: genetic risk for schizophrenia, decline in function, unusual thought content, suspiciousness, social impairment, substance abuse Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1): Major Results Cumulative survival distribution function modeling time to conversion to psychosis in 291 clinical high-risk (prodromal) patients and 134 demographically comparable normal control subjects (dashed line).

26 Utility of a Biomarker to Diagnose Disease Diagnosis = Negative Diagnosis = Positive Test Result = Positive False Positive True Positive Positive Predictive Value: TP/(TP+FP) Test Result = Negative True Negative False Negative Negative Predictive Value: TN/(TN+FN) Specificity: TN/(TN + FP) Sensitivity: TP/(TP + FN)

27 Limbic Cortical Hyperactivity in Schizophrenia Basal-state cerebral blood volume (a measure of metabolic activity) in the hippocampus is a focal, proximal biomarker that Predicts progression to psychosis Correlates with psychotic symptom severity As psychosis emerges, abnormal metabolic activity propagates and leads to atrophy What is the pathophysiological basis of limbic hyperactivity?

28 Metabotropic Glutamate Receptors (mglur2) Stimulation Reduces Glutamate Hyperactivity mglur2 NMDA Glutamate AMPA mglur mglur2 agonists reduce glutamate release and synaptic concentrations Moghaddam B, et al. Science. 1998;281(5381): ; Krystal JH, et al. Psychopharmacology (Berl). 2005;179(1):

29 Human CBV Phenotype Replicated in Rodent Model Humans Mice Schobel SA, et al. Arch Gen Psychiatry. 2009;66(9):

30 Natural History of Schizophrenia Rationale for Early Detection and Intervention Stages of Illness Healthy Worsening Severity of Signs and Symptoms Premorbid Abnormal Brain Development No Sxs Onset/Progression Prodrome First Break Early Sx Puberty Chronic/Residual End-Stage Deterioration Prevention of Progression Neurochemcal Dysregulation Psychotic Sxs Neurodegeneration Psychotic Sxs Negative Sxs Cognitive Sxs Gestation/Birth Years Lieberman JA, et al. Biol Psychiatry. 2001;50(11):

31 Call to Action Proactively address the duration of untreated psychosis in individuals with schizophrenia Discuss the available biomarkers that can help in the diagnosis of schizophrenia

32 #CHAIR2016 Questions Answers &