Research Update: Early Intervention: The RAISE Early Treatment Program

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Research Update Early Intervention The RAISE
Early Treatment Program

• John M. Kane, M.D.Chairman, Dept. of
  PsychiatryThe Zucker Hillside HospitalExecutive
  VP for Behavioral Health ServicesThe North
  ShoreLong Island Jewish Health SystemProfessor
  and ChairmanDepartment of PsychiatryHofstra
  North Shore LIJSchool of Medicine

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Disclosure 2014 John M. Kane
Company Consultant/ Advisory Board Speakers bureau Shareholder Grants/Research support
Alkermes X      
Bristol-Meyers Squibb X X    
Eli Lilly X X    
EnVivo Pharmaceuticals X
Forest Laboratories X
Genentech X
H. Lundbeck A/S X      
Intracellular Therapeutics X      
Janssen Pharmaceutica X X    
Johnson and Johnson X      
MedAvante X  
Otsuka Pharmaceutical X X  
Reviva X
Roche X      
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Evolution of Psychosis
Fusar-Poli P. et al. JAMA Psychiatry.
201370(1)107-120.
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Clinical characteristics of first-episode
psychosis

• Typically adolescent or young adult
• Have lived with severe untreated psychotic
  symptoms
• On average, for at least a year
• Compared to peers
• Cognitively impaired
• Poorer psychosocial functioning
• More likely to smoke
• More likely to abuse substances
• Families are typically actively engaged
• Goals are to return to mainstream functioning

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Reported mean duration of untreated psychosis

• Presented by Diana O. Perkins, MD, MPH.
  University of North Carolina at Chapel Hill, 26th
  Sept 2003 (available at www.medscape.org/viewart
  icle/460974)

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Duration of Untreated Psychosis RAISE ETP n404

• Median DUP74 weeks (mean193.5262.2 weeks)
• 68 of participants had DUP gt6 months
• Correlates of longer DUP included
• earlier age of first psychotic symptoms
• substance use
• positive and general symptom severity
• poorer functioning
• referral from outpatient treatment settings

Addington J et al. Submitted for publication
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Table 1 Characteristics of RAISE-ETP
participants and associated Duration of Untreated
Psychosis (DUP N404) plt.05, plt.01, plt.001
Participant Characteristics Participant Characteristics N Weeks of DUP (MeanSD)
Gender Female Male 111 293 27 73 636.5 537
Racial background White Black or African-American American Indian Asian/Pacific Islander 218 151 22 13 54 37 5 3 496.5 637 521 554.5
Ethnicity Hispanic or Latino Not Hispanic or Latino 73 331 18 82 448 586.5
Prior Psychiatric Hospitalization Yes No 316 88 78 22 407 1564
Diagnosis at study entry Schizophrenia Schizophreniform disorder Schizoaffective disorder Brief psychotic disorder Psychotic disorder NOS 214 67 81 2 40 53 17 20 lt1 10 994.5 54 1385 21.5 267
Substance use Yes No 161 237 40 60 746.5 487
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Table 1 continued Characteristics of RAISE-ETP
participants and associated Duration of Untreated
Psychosis (DUP N404) plt.05, plt.01, plt.001
Participant Characteristics Participant Characteristics N Weeks of DUP (MeanSD)
Mental Health treatment status at study entry Outpatient Inpatient/partial hospital Unknown/other 230 120 54 57 30 13 667 377 625.5
Geographic region where receiving treatment North South Mid-West West 69 89 154 92 17 22 38 23 266.5 798 636 407
Community population density Rural Urban Suburban 102 198 103 25 50 25 737 487 576.5
Insurance coverage Private or private public Public only No insurance Insurance status unknown 82 127 173 19 20 32 43 5 376 737 577 587.5
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Implications of delayed treatment

• Greater decrease in functioning
• Loss of educational opportunities
• Impaired psychosocial and vocational development
• Personal suffering/family burdens
• Potential poorer response once treatment is
  provided
• Greater costs

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Strategies to Reduce the Duration of Untreated
Psychosis

• Anonymous E-surveys of high school and college
  students, linkages to psycho-ed website and
  referral to specialty program
• Interviews of early phase patients (and families)
  to understand pathways to care and internet
  social media utilization and how it was effected
  by incipient psychosis

Asking for access to social media communications
for further examination using word
count/linguistic analysis Working with teenagers
to develop social media strategies to educate and
respond
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Key concepts for optimal first-episode medication
treatment

• Response rates for positive symptoms are very
  high
• No antipsychotic has demonstrated superior
  efficacy for the treatment of the initial
  psychotic episode. Tolerability is key
• Effective antipsychotic doses are usually lower
  than those needed for multi-episode patients
• Despite low antipsychotic doses, rates of side
  effects are high
• Relapse is frequent and the most important factor
  driving relapse is medication non-adherence
• There is often an overwhelming drive by patients
  and their families to stop treatment

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The risk for psychotic relapse is high
Year Relapse rate () 95 CI 95 CI Patients still at risk at end of year, n
Year Relapse rate () Lower limit Upper limit Patients still at risk at end of year, n
1 16.2 8.9 23.4 80
2 53.7 43.4 64.0 39
3 63.1 52.7 73.4 22
4 74.7 64.2 85.2 9
5 81.9 70.6 93.2 4

• n104 first-episode schizophrenia patients
  year(s) after recovery from the previous
  episode CIconfidence interval

• Robinson et al. Arch Gen Psychiatry
  199956241247

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Stopping medication is the most powerful
predictor of relapse

• Survival analysis risk of a first or second
  relapse when not taking medication is 5 times
  greater than when taking it

Hazard ratio for the first and second relapse

• n104

• Robinson et al. Arch Gen Psychiatry
  199956(3)241247

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Relapse fuels the progression of illness

• With each relapse
• Recovery can be slower and less complete
• More frequent admissions to hospital
• Illness can become more resistant to treatment
• Increased risk of self-harm and homelessness
• Regaining previous level of functioning is harder
• Patient has a loss of self-esteem and social and
  vocational disruption
• Greater use of healthcare resources
• Increased burden on families and caregivers

• Kane. J Clin Psychiatry 200768(Suppl 14)2730

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Consequences of a first and second relapse in
early phase illness

• After a first episode a young person might go
  back to school or work
• What happens if they relapse, will they be able
  to return a second time, or a third time?
• How do close friends or lovers react to a
  psychotic episode, and then a relapse?
• Many of lifes opportunities, and a persons
  potential, can be eroded by a small number of
  relapses early in the illness

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UCLA recovery criteria

• Recovery criteria must be met in each of 4
  domains
• Improvement in each domain must be sustained
  concurrently for ?2 years
• Level of recovery in these 4 domains is measured
  by symptom remission, appropriate role function,
  ability to perform day-to-day living tasks
  without supervision, and social interactions

• Liberman et al. Int Rev Psychiatry 200214256272

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Cumulative recovery rates by year in study
Year Cumulativerecovery rate () 95 CI 95 CI
Year Cumulativerecovery rate () Lowerlimit Upperlimit
3 9.7 3.7 15.8
4 12.3 5.4 19.1
5 13.7 6.4 20.9

• CIconfidence interval

• Robinson et al. Am J Psychiatry
  2004161(3)473479

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A systematic review and meta-analysis of recovery
in schizophrenia
Conclusions Based on the best available data,
approximately, 1 in 7 individuals with
schizophrenia met our criteria for recovery.
Despite major changes in treatment options in
recent decades, the proportion of recovered cases
has not increased

• Jääskeläinen et al. Schizophr Bull
  201339(6)12961306

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A nationwide cohort study of oral and depot
antipsychotics after first hospitalisation for
schizophrenia

• Tiihonen et al. Am J Psychiatry 2011168603609

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Is there a case for earlier use of LAI
antipsychotics?

• The percentage of time spent experiencing
  psychotic symptoms in the first 2 years is the
  strongest predictor of long-term symptoms and
  disability1
• With subsequent exacerbations, patients may
  experience a decrease in their treatment
  response2
• Neuropathological brain changes often progress
  with subsequent clinical episodes3
• LAI antipsychotics allow for swift identification
  of overt non-adherence and elimination of covert
  nonadherence4

• LAIlong-acting injectable

• 1. Harrison et al. Br J Psychiatry
  2001178(6)506517 2. Lieberman et al.
  Neuropsychopharmacology 19961413S21S 3.
  Lieberman et al. Psychiatr Serv
  200859(5)487496 4. Fenton et al. Schizophr
  Bull 199723(4)637651

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Impact of initiating LAI atypical antipsychotics
early in the disease course

• Patients initiated on an atypical LAI within 5
  years of onset of illness (24.2) were compared
  with those on an atypical LAI gt5 years after the
  onset of illness (75.8)

Longer median time to discontinuation (p0.003)
Greater improvement in PANSS scores (plt0.01)
Higher remission rates (plt0.001)
Longer time to relapse (p0.018)
Greater improvements in BPRS scores (plt0.01)

• n1,879 BPRSBrief Psychiatric Rating Scale
  LAIlong-acting injectable PANSSPositive and
  Negative Syndrome Scale

• Detke et al. Poster presented at the 52nd Annual
  New Clinical Drug Evaluation Unit (NCDEU)
  meeting 29th May1st June, 2012 Phoenix, AZ

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Relapse risk despite RIS-LAI adherence

• Stepwise Cox proportional predictors Canada vs
  US HR2.8 illness duration ?10 years vs 5
  years HR2.3 previous AP gt4 vs 4 mg/day
  HR1.8

• n323 post-hoc analysis of a 1-year relapse
  prevention study of R-LAI 25 mg vs 50 mg/2 weeks
  18.3 relapsed RIS-LAIrisperidone long-acting
  injectable APantipsychotic HRhazard ratio

• Nasrallah et al. Poster presented at the 52nd
  Annual New Clinical Drug Evaluation Unit (NCDEU)
  meeting29th May1st June, 2012 Phoenix, AZ

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Bartzokis et al. Sch Res 2012
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RAISE-ETP Executive Committee
John Kane Principle Investigator The Zucker Hillside Hospital (ZHH)
Delbert Robinson ZHH
Nina Schooler SUNY Downstate
Jean Addington University of Calgary
Sue Estroff UNC
Christoph Correll ZHH
Kim Mueser Boston University
David Penn UNC
Robert Rosenheck Yale University
Patricia Marcy ZHH Project Director

• ETPearly treatment program

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Principal NIMH Collaborators

• Robert Heinssen
• Susan Azrin
• Amy Goldstein

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Specified aims of RAISE

• Develop a comprehensive and integrated
  intervention to
• Promote symptomatic recovery
• Minimise disability
• Maximise social, academic, and vocational
  functioning
• Be capable of being delivered in real-world
  settings utilising current funding mechanisms
• Assess the overall clinical impact and
  cost-effectiveness of the intervention as
  compared to currently prevailing treatment
  approaches
• Conduct the comparison in non-academic,
  real-world community treatment settings in the
  United States

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RAISE ETP Site Distribution 34 sites in 21
states
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RAISE Trial Methods

• Sites are randomly assigned to administer either
  the RAISE Intervention or their current treatment
  program
• A central team of raters conducts structured
  diagnostic interviews and assesses subjects via
  live, two-way video interviews
• Assessors are masked to treatment condition
• Compatible with the site randomization model
• Expert assessors available to all sites
• Central rater team allows ongoing maintenance of
  high reliability of assessment
• Subjects are assessed for a minimum of 2 years

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RAISE Trial Design Subjects

• Sample size 404
• Age 15-40
• The following diagnoses are included in the
  differential
• schizophreniform disorder
• schizophrenia
• schizoaffective disorder
• psychotic disorder NOS
• brief psychotic disorder
• Less than six months of treatment with
  antipsychotic medications

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RAISE Trial Outcomes

• Primary outcome measure Quality of Life scale
• Primary hypothesis
• RAISE intervention compared to community care
  will improve Quality of Life
• Other measured outcomes
• Service utilization
• Cost
• Consumer perception
• Prevention of relapse
• Enhanced recovery

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Navigate

• Team based
• Shared decision-making
• Strength resiliency focus
• Psychoeducational teaching skills
• Motivational enhancement teaching skills
• Collaboration with natural supports
• Four components
• Psychopharmacology COMPASS
• Individual Resiliency Training (IRT)
• Family psychoeducation
• Supported employment/education

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Individual Resiliency Training (IRT)

• Strength and Goal oriented
• Skill based
• Recovery emphasis
• Motivational techniques utilized throughout
• Connecting skills and information to goals
• Reframing events in positive light
• Promoting hope and positive expectations
• Tailored for first-episode clients
• Clinicians have at least Bachelors level
  education and prior clinical experience
• Most have Masters level degrees
• Modular and sequenced
• But sequence can be modified to address clients
  needs

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IRT Modules

• Standard
• Orientation
• Assessment
• Resiliency training
• Wellness management
• Psychoeducation/processing the illness
• Goal setting
• Relapse prevention
• Advanced
• Managing distress and grief
• Coping with depression and other symptoms
• Reducing substance abuse/dependence
• Improving social relationships

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Family Psychoeducation

• Begins soon after initial contact
• Includes client, relatives, other significant
  persons
• Basic and Advanced modules
• Coordinated with Individual Resiliency Training
• Assessment and identification of client and
  family goals
• Education about disorder and treatment
• Opportunity to process experience of psychotic
  episode and reduce stigmatizing beliefs about
  mental illness
• Strategies for improving quality of communication
  and problem solving

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Supported Education / Employment

• Established principles of supported employment in
  chronic populations modified for first episode
• Focus on return to school or work as soon as
  possible after symptom stabilization
• Goals determined by client preferences
• Supports provided to
• enroll/re-enroll in school
• re-enter or obtain work
• Ongoing supports provided to maintain school/work
  
• Coordination with clinical treatment and team
• Benefits counseling

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The Value of Measurement

• Contribution to diagnostic process
• Establishing baseline severity
• Providing targets and treatment goals
• Evaluating the efficacy of treatment
• Evaluating tolerability and adverse effects
• Influencing level of care
• Medical record documentation

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Obstacles to Measurement

• Inadequate appreciation of benefit
• Perceived value of global judgment
• Time constraints
• Lack of appropriate instruments
• Inadequate training
• Reimbursement concerns

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Computerized Decision Support System Longitudinal
Symptom Assessment
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Desired Characteristics of a Decision Support
System

• Ease of use
• Web-based available for desk tops, lap top, I
  Pad
• Incorporating patient self-report
• Interactive (results are constantly modified
  based on patient and prescriber input)
• Grade school level reading for self-report
• Validated assessment tools
• Incorporates psychiatric and medical data
• Substance abuse
• Nicotine use
• Adherence (including assessment of attitudes
  towards medication)
• Comprehensive side effect assessment
• Senior national experts involved in designing
• Extensive prescriber feedback

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Patient Self Report Form
Little red boxes indicate items not yet addressed
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Clinician Rated Form Includes Information From
Patient Self-Rated Form On Corresponding Items
And Adjusts The Prompt Questions Accordingly
This item includes prompt question for a patient
who did not endorse depressed mood on the
Self-Report Form
Prompt question for patient who did endorse
anxious mood
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Referral Source of Participants

• 335 (79) came from the usual referral sources
  for the agency (e.g. an inpatient unit, ER)
• 88 (21) came from community outreach activities

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Diagnoses at Enrollment
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Prior Psychiatric Hospitalizations

• 316 (78) had a prior psychiatric hospitalization
• 88 (22) had no prior psychiatric hospitalizations

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Demographic Characteristics

• 293 (73) men and 111 (27) women
• 340 (84) were between the ages of 18 and 30
  years old
• Mean age is 23.1 years modal age is 19.

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404 subjects entered the RAISE-ETP study

• We examined their medication prescriptions at the
  time of study entry before any influence of
  treatment by study guidelines or procedures
• We identified 159 (39.4) subjects who might have
  benefitted from one or more changes in their
  psychotropic prescriptions

• ETPearly treatment program

• Robinson et al. In Press Amer J Psych

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Of these 159 subjects

• 14 (8.8) were prescribed recommended
  antipsychotics at higher than recommended doses
• 51 (32.1) were prescribed olanzapine (often at
  high doses)
• 37 (23.3) were prescribed more than one
  antipsychotic
• 58 (36.5) were prescribed an antipsychotic, but,
  also an antidepressant, without a clear
  indication
• 16 (10.1) were prescribed psychotropic
  medications without an antipsychotic
• 5 (1.2) were prescribed stimulants

• Robinson et al. In press Amer J Psych

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RAISE smoking, lipid abnormalities, hypertension
diabetes metabolic syndrome with related drug
treatment
Prevalence / lack of intervention ()
Smoking
LowHDL-C
High totalcholesterol
HighLDL-C
Hightriglyceride
HighBP
Pre-diabetesmellitus(HbA1C)
Diabetes
Metabolicsyndrome
Dys-lipidemia

• After 47 days average lifetime antipsychotic
  treatment, olanzapine and quetiapine were related
  to higher metabolic values dyslipidemia TC 200
  mg/dL or TG 150 mg/dL, or low HDL TCtotal
  cholesterol TGtriglyceride HDLhigh-density
  lipoprotein LDLlow-density lipoprotein

• Correll et al. In press JAMA Psych

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Smoking at study entry

• 51.2 of subjects reported smoking cigarettes at
  the time of study entry
• No subject was being prescribed nicotine
  replacement or varenicline
• Only 11 subjects (7 currently smoking) were
  prescribed bupropion (indication for bupropion
  not recorded)

• Robinson et al. Unpublished data

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E-Health Potential to Address Problem Areas of
In-Person Services

• Severe mental illness treatment is insufficient
• gt50 do not receive specialty mental health
  services (Mojtabai et al, 09),
• 4-15 receive minimally adequate treatment (far
  short of standards for care) (Wang et al, 02)
• 15-25 years for EBPs to reach routine care (IOM,
  01)
• Lack of expertise in community treatment settings
• High cost of setting up maintaining an EBP
• Too few clients for economy of scale in clinics,
  or geographic areas
• Once reach routine care EBPs often lack fidelity
  (Drake et al, 01)
• Travel adds burden
• Families/supporters left out of treatment
• Healthcare is poorly understood--regardless of
  education level
• Chronic illness management occurs at home

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The Improving Care Reducing Cost (ICRC) Program
Translates toThe Health Technology Program (HTP)

• John Kane , Delbert Robinson, Nina Schooler, Mary
  Brunette, Kim Mueser, Dror Ben-Zeev, Jennifer
  Gottlieb, Armondo Rotundi, Christoph Correll,
  Susan Gingrich, James Robinson, Bob Rosenheck,
  Patricia Marcy

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Program Overview

• Goal
• To reduce ER visits and hospital days while
  providing better care, better health and
  increased patient satisfaction. This will be
  done by fostering innovation in the use of
  technology and by training and deploying a new
  cadre of personnel in the behavioral health
  field Mental Health/Health Technology (MH/HT)
  Case Managers.

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Hospitalization and schizophrenia

• Schizophrenia is characterized by relapses
  (hospitalizations) and returns to the community
• Challenging for making progress toward recovery
• Hospital stays are a major cost driver
• Six month cost for newly discharged patients
• 16,300
• Re-hospitalization 11,900
• Medication 3,000
• Other 1,400
• Six month cost for other patients
• 8,200
• Risk for rehospitalization is greatest in the
  months immediately following discharge

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Health Technology Program

• Focuses on critical 6 months following hospital
  discharge
• Engages patient with a treatment team
• Uses innovative tech tools to provide treatment
• Outcome assessment and monitoring is integrated
  in treatment
• Treatment is tailored to patient needs and
  preferences
• Shared decision making

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The Health Technology Team

• Project director
• Identifies and enrolls patients at the critical
  time
• At or immediately following a hospitalization
• Leads the team
• Psychiatrist/prescriber
• Assesses symptoms, side effects and adherence
• Prescribes medication based on assessment and
  evidence-based treatment guidelines
• Mental Health/Health Technology Case Manager
• Provides case management services
• Guides the patient in use of new tech tools

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The Health Technology Program Components

• Relapse Prevention Plan
• In-person guidance to create My Relapse
  Prevention Plan
• Daily Support Website
• Web-based support for patients and families
• FOCUS
• smart phone app to cope with adherence, mood,
  sleep, social dysfunction and voices
• Coping with Voices and Paranoia
• Web-based computer CBT programs
• Prescriber Decision Assistant
• Web-based Medication Decision Support System

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Relapse Prevention Planning (RPP)

• Five in person sessions occurring in the first 2
  months of treatment
• Session 1 Orientation to Program and goals
• Session 2 Medication Strategies
• Session 3 Stress
• Session 4 Substance Use
• Session 5 Putting it All Together

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The Daily Support Website (DSW)

• Web-based support for patients and families
• Provide illness coping education material to
  patients and families
• Social networks with participants and family
  members
• Chat rooms for patients, families, and patients
  and families
• Help individuals and families with the illness
• Opportunity to interact with an online therapist
• Identify early warning signs and prevent relapse
• Option to identify early warning signs and
  receive daily text reminders
• Case managers alerted if early warning signs are
  present

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FOCUS A smart phone application

• 5 treatment targets Med adherence, voices,
  social functioning, mood and sleep
• Up to 3 targets can be selected at one time
• Patients can receive up to 3 push
  notifications/check-ins per day
• Each check-in 4 messages
• Case Managers work with patient to select
  appropriate targets
• Case managers have access to a real time report
  of patient responses
• Targets can be changed throughout the program

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Coping with Voices and Paranoia

• Interactive, game-based program that teaches CBT
  skills to persons with psychotic disorders
• Self-paced but forced exposure to all program
  components in order
• Cumulative building of skills, complexity
  increases somewhat over sessions
• Multi-Modality animated tutorials, readings,
  audio and video, interactive games, symptom
  reporting and tracking, social feed component,
  interactive quizzes

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PDA Decision Support System

• The PDA is a web-based decision support system
  that assists patient-provider communication and
  decision making
• Patients complete a self assessment prior to
  seeing the prescriber
• The prescriber interview is tailored based on the
  patients responses on the self assessment
• The HTP program uses evidence-based medication
  treatment to decrease patient risk of relapse
• The appropriate use of clozapine and efforts to
  promote medication adherence (e.g. long-acting
  injectable antipsychotics) are crucial for this
  goal

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Implementation

• Project Director Case Manager identify patient
• Patient consents to participate and receives
  baseline assessments
• Patient meets with case manager
• Goal to develop and implement a plan for
  preventing relapse and rehospitalization that
  incorporates appropriate tech tools
• Laptop computer, internet connection and Smart
  Phone are provided
• Patient meets with prescriber for assessment and
  medication management
• Treatment continues for SIX months

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Conclusions

• Early and effective intervention is key for
  achieving the best outcomes in schizophrenia
• Non-adherence remains a major challenge and is a
  frequent cause of relapse and re-hospitalisation
• Recovery rates remain disappointingly low
• A combination of pharmacotherapy and psychosocial
  treatments are critical to facilitate recovery