Why it matters to detect and treat first episode psychosis

ALACRITY Training Series, May 26 2022

Marcela Horvitz-Lennon MD MPH

Associate Professor, Part-Time, Cambridge Health Alliance & Harvard Medical School

Senior Research Scientist, RAND Corporation

Outline

• Review of Psychosis and Schizophrenia
• Review of modifiable drivers of remission outcomes including duration of untreated psychosis
• Review of initiatives to reduce DUP
• Implications for clinicians and policymakers

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Psychosis

• Manifestations also observable in general population as subclinical psychotic experiences
• Only a fraction associated with distress and help-seeking 🡪 psychotic experiences with clinical relevance (clinical high-risk)
• Most are transient but for some, experiences may persist and lead to impairment 🡪 psychotic disorder
• Persistence and impairment predicted by environmental risks interacting with genetic risks

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Clinical high risk

• Signs may emerge months or years before diagnosis
• Difficulty concentrating/functioning at school or work
• Suspiciousness, unusual beliefs
• Perceptual disturbances, increased sensitivity to sights and sounds
• Decreased motivation, social withdrawal
• At 2-3 years follow-up:
• ~20-25% transition to psychotic disorder
• ~40% undergo remission
• ~1/3 remain at clinical high risk – better neurocognitive performance vs. those who develop full psychosis
• Transition to schizophrenia-spectrum disorders much more likely (>70%)
• ~1 in 10 transition to affective psychoses

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Nature and Nurture

Schizophrenia

• Onset early in life
• First episode of psychosis (FEP) typically in late teens, early 20’s
• Prevalence is low (<1%) but high burden of disease
• Reduced life expectancy – die 15-20 years younger
• Course – variable, frequently disabling but remission is possible
• Worse prognosis in the US relative to other industrialized countries
• Relapses leading to hospitalization or incarceration are common
• Overrepresented among homeless persons (CA, 1999-2000, ~1 in 5)
• More than 3 in 4 lack gainful employment & depend on income supports
• Illness is costly to US society
• In 2013, total costs = $155.7 billion (healthcare costs: 24%; unemployment: 38%)

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�Risk factors - shared by subclinical psychosis & schizophrenia �

• Sociodemographic
• age, sex, marital status, employment and educational status, race/ethnicity
• Non-genetic etiological factors
• Trauma & stressful life events, urbanicity,* cannabis and other substance abuse*
• Genetic etiological factors: familial clustering
• positive dimensions (e.g., disorganization, unusual experiences)
• negative dimensions (e.g., cognitive disorganization, introverted anhedonia)
• Cognitive deficits:
• Neurocognition: verbal memory, executive functioning
• Social cognition: deficits in mentalization (understanding misunderstanding) and j reasoning bias (jumping-to-conclusions)

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*urbanicity and cannabis- interaction with age/developmental stage

Remission in schizophrenia

• Most studies define as “better overall” (symptoms, functioning)
• Fewer: better quality of life, improved cognitive performance
• Remission statistics (at some point during f/u)
• FEP: 48%
• Multi-episode (chronic) Schizophrenia: 43%
• Roughly 3 in 4 are stable in their remission status
• Predictors of remission:
• Premorbid functioning
• Duration of untreated psychosis (DUP)
• Lower symptom burden

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Optimizing remission through focus on modifiable predictors

• Reducing DUP
• Reducing symptom burden – improving treatment response

Duration of Untreated Psychosis

• Cumulative time between onset of psychosis and symptom control
• Large body of research suggests association between longer DUP and clinical and functional outcomes
• Both in the short and long-term – 20 years after psychosis onset
• Association unique to the early stage of the illness - “critical period”
• Duration of the “critical period” not firmly established
• Evidence suggests a range of 2-5 years

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Duration of Untreated Psychosis, Cont’d

• Although strength and causal validity of evidence have been questioned…
• Multiple studies of varied methodology with similar results
• Recent large random-effects meta-analysis (129 studies, most prospective) confirmed evidence and concluded that DUP is an important prognostic factor that predicts clinically relevant outcomes over the course of the illness
• Reasons for prognostic significance of DUP not well elucidated
• Neurotoxic effects
• Disruption of normal progression at a critical time during human development – becoming a social and self-reliant member of society

Simulated long-term impacts of reducing DUP

Reducing symptom burden in schizophrenia

• Pharmacological interventions (antipsychotic drugs) can effectively control positive psychotic symptoms and reduce hospitalizations
• Continuous antipsychotic drug treatment during the early stage of the illness lowers risk of death
• Problems: Inadequate antipsychotic prescribing practices and inadequate medication adherence, including in early schizophrenia
• Psychosocial interventions can improve social and occupational functioning and housing stability, and reduce hospitalizations
• Problems: Inadequate supply of well-trained clinicians, inadequate funding for complex interventions

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Evidence-based interventions for FEP

• Coordinated Specialty Care: team-based model, provides antipsychotic drug treatment, cognitive-behavioral therapy, supported employment and education, family education & support, and case management
• Shares features with assertive community treatment
• CSC has greater focus on education & employment and is more time-limited and office-based than ACT
• Other models: Early Psychosis Prevention and Intervention Center (EPPIC), Portland Identification and Early Referral (PIER), Prevention and Recovery in Early Psychosis (PREP), etc.

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Affordable Care Act and expanded parity laws facilitated access to care

• Option of Medicaid expansion
• Access to subsidized private insurance
• Adults 19–25 may remain enrolled as dependents of parents’ policies
• Elimination of exclusions for pre-existing conditions
• Inclusion of mental health and substance abuse benefits in the package of essential health benefits
• Extension of parity protections to marketplace plans and Medicaid managed care
• Enhancement of the optional Medicaid authority 1915(i) allowing states to provide home- and community-based services

Despite the evidence and some policy successes…

• People with schizophrenia in the US still lack adequate access to high-quality care, some more than others
• True regarding all stages of the illness
• Particularly consequential during FEP
• Urgent need for:
• Greater and equitable access to care
• Greater and equitable use of evidence-based practices
• Minimal/no use of practices lacking empirical support

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However, there has been progress in DUP front

• Broad recognition of DUP reduction as an opportunity for secondary prevention
• Several initiatives to promote early intervention services for FEP
• Improve detection & facilitate access to care
• Reduce DUP
• Improve outcomes

Federal and state efforts to reduce DUP

• “Recovery After an Initial Schizophrenia Episode” (RAISE) grant-making initiative by the NIMH (2008) to evaluate CSC effectiveness
• Mental Health Block Grant set-aside funds for FEP care
• Since FY 2014, SAMHSA has required states to set aside a growing portion of the MHBG funds for CSC-like models (5% - 10%)
• States can leverage funds through inclusion of services reimbursed by Medicaid or commercial insurance
• Policy has led to a large expansion of CSC-like services
• In 2020, 50 state MHBG-funded programs reported serving ~18,000 individuals
• MHBG set-aside funds were increased as part of the Coronavirus Aid, Relief, and Economic Security (CARES) act and the American Rescue Plan Act (ARPA)

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A large public investment on DUP reduction�

RAISE and set-aside initiatives

Efforts to reduce DUP, Cont’d: EPINET

• NIMH Funding Opportunity Announcements for EPINET (Practice-Based Research to Improve Treatment Outcome) - 2018
• EPINET launched in 2019 - https://nationalepinet.org/
• Significant federal investment

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EPINET Structure

• ENDCC – EPINET National Data Coordinating Center

EPINET Tools

Implications for Public Policy

• Invest in broadening access to all serious mental illness care including FEP
• Enforce and strengthen parity laws
• Provide resources and incentives for high-quality and equitable care
• Medicaid - not enough providers, insufficient budgets
• MHBG set-aside funds – insufficient
• Improve oversight – penalize abusive utilization review practices & network inadequacies
• Invest in educating and training the mental health workforce

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�Role for public policy not limited to health policy�

• Address non-genetic/modifiable risk factors through social policy
• Address stigma and other drivers of inadequate decisions by individuals, communities, clinicians, payers, and office-holders

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Implications for clinicians

• Maintaining people engaged in care, particularly those with FEP, is crucial
• Even for patients who refuse or adhere poorly to medication regimens
• Delivering treatments with empirical support is crucial
• Reduces time in uncontrolled psychosis
• Improves odds of remission
• For people with FEP, potential for greatly improved long term outcomes
• Conceptualizing our role beyond treating disease and delivering healthcare
• “Medicine is social science, and politics nothing but medicine on a grand scale” (Rudolf Virchow, 1821‒1902)

Thank you!

�Howes et al. (2021). The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis. World Psychiatry, 20(1):75-95.�

• 13 meta-analyses - 129 studies - total sample size= ~26,000 patients.
• Due to potential violations of statistical assumptions in some meta-analyses, authors conducted random-effects meta-analysis of primary studies.
• Graded association between DUP and each outcome as convincing, highly suggestive, suggestive, weak, or non-significant.
• At presentation:
• suggestive evidence for relationship between longer DUP and more severe negative symptoms and previous self-harm
• At follow-up:
• highly suggestive evidence for relationship between longer DUP and more severe positive and negative symptoms and lower chance of remission.
• suggestive evidence for relationship between longer DUP and poorer overall functioning and more severe global psychopathology.
• Clinically meaningful effect sizes.
• DUP of 4 weeks predicted >20% more severe symptoms at follow-up vs. DUP of 1 week.

CAB domains

Bibliography

• Addington J, Heinssen RK, Robinson DG, et al. (2015). Duration of untreated psychosis in community treatment settings in the United States. Psychiatric Services, 66(7), 753-756.
• Ascher-Svanum H, Zhu B, Faries DE, et al. (2010). The cost of relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry, 10(1), 2.
• Ascher-Svanum H, Nyhuis AW, Faries DE, et al. (2010). Involvement in the US criminal justice system and cost implications for persons treated for schizophrenia. BMC psychiatry, 10(1):1.
• Behan C, Kennelly B, Roche E, et al. Early intervention in psychosis: health economic evaluation using the net benefit approach in a real-world setting. The British Journal of Psychiatry. 2020;217(3):484-490.
• Bilder S, & Mechanic D. (2003). Navigating the disability process: Persons with mental disorders applying for and receiving disability benefits. The Milbank Quarterly, 81(1), 75-106.
• Birchwood M, Todd P, & Jackson C. (1998). Early intervention in psychosis. The critical period hypothesis. British Journal of Psychiatry. Supplement, 172(33), 53-59.
• Boonstra N, Klaassen R, Sytema S, et al. (2012). Duration of untreated psychosis and negative symptoms—a systematic review and meta-analysis of individual patient data. Schizophrenia research, 142(1), 12-19.
• Charlson FJ, Ferrari AJ, Santomauro DF, et al. (2018). Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophrenia Bulletin, 44(6):1195-1203.

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Bibliography

• Cloutier M, Aigbogun MS, Guerin A, et al. (2016). The economic burden of schizophrenia in the United States in 2013. The Journal of Clinical Psychiatry, 77(6), 764-771.
• Correll CU, Galling B, Pawar A, et al. (2018). Comparison of Early Intervention Services vs Treatment as Usual for Early-Phase Psychosis: A Systematic Review, Meta-analysis, and Meta-regression. JAMA Psychiatry, 75(6):555-565.
• Emsley R, Rabinowitz J, Medori R. (2007). Remission in early psychosis: Rates, predictors, and clinical and functional outcome correlates. Schizophrenia Research, 89(1-3):129-139.
• Folsom DP, Hawthorne W, Lindamer L, et al. (2005) Prevalence and risk factors for homelessness and utilization of mental health services among 10,340 patients with serious mental illness in a large public mental health system. American Journal of Psychiatry, 162(2):370-376.
• Friis S, Melle I, Johannessen JO, et al. (2016). Early predictors of ten-year course in first-episode psychosis. Psychiatric Services, 67(4):438-443.
• Fusar-Poli P, Bechdolf A, Taylor MJ, et al. (2013) At risk for schizophrenic or affective psychoses? A meta-analysis of DSM/ICD diagnostic outcomes in individuals at high clinical risk. Schizophrenia Bulletin, 39(4):923-932.
• Fusar-Poli P, Salazar de Pablo G, Correll CU, et al. (2020). Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention. JAMA Psychiatry, 77(7):755-765.

Bibliography

• Hegelstad WT, Larsen TK, Auestad B, et al. (2012). Long-term follow-up of the TIPS early detection in psychosis study: effects on 10-year outcome. American Journal of Psychiatry, 169(4):374-380.
• Heinssen R.K. GAB, Azrin S. T. (2014). Evidence-Based Treatments for First Episode Psychosis: Components of Coordinated Specialty Care. Rockville, MD: National Institute of Mental Health.
• Horvitz-Lennon M, Donohue JM, Domino M, et al. (2009). Improving quality and diffusing best practices: The case of schizophrenia. Health Affairs, 28(3):701-12
• Horvitz-Lennon M, Breslau J, Scharf D, et al. (2015). Case Study: Early Assessment of the Mental Health Block Grant Set-Aside Program for Addressing First Episode Psychosis and other Early Serious Mental Illness. RAND Corporation.
• Horvitz-Lennon M, Predmore Z, Orr P, et al. (2019). Simulated long-term outcomes of early use of long-acting injectable antipsychotics in early schizophrenia. Early Intervention in Psychiatry, 13(6):1357-1365
• Horvitz-Lennon M, Predmore Z, Orr P, et al. (2020). The Predicted Long-Term Benefits of Ensuring Timely Treatment and Medication Adherence in Early Schizophrenia. Administration and Policy in Mental Health and Mental Health Services Research, 47(3):357-365.
• Horvitz-Lennon M. Evidence-Based Practices or Practice-Based Evidence: What is the Future? In: Goldman H, Frank R, and Morrissey J, editors. The Palgrave Handbook of American Mental Health Policy. Palgrave Macmillan, 2020.
• Howes OD, Whitehurst T, Shatalina E, et al. (2021). The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis. World Psychiatry, 20(1):75-95.

Bibliography

• Johnstone EC, Crow TJ, Johnson AL,et al. (1986). The Northwick Park study of first episodes of schizophrenia: I. Presentation of the illness and problems relating to admission. The British Journal of Psychiatry, 148(2):115-120.
• Kane JM, Robinson DG, Schooler NR, et al. (2016). Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. American Journal of Psychiatry, 173(4):362-372.
• Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nature Reviews Disease Primers. 2015;1:15067.
• Kotov R, Fochtmann L, Li K, et al. (2017). Declining clinical course of psychotic disorders over the two decades following first hospitalization: Evidence from the Suffolk County Mental Health Project. American Journal of Psychiatry, 174(11):1064-1074.
• McCutcheon RA, Reis Marques T, Howes OD. (2020). Schizophrenia—An Overview. JAMA Psychiatry, 77(2):201-210.
• McGorry PD. (2015). Early intervention in psychosis: obvious, effective, overdue. The Journal of Nervous and Mental Disease, 203(5):310.
• Malla A, McGorry P. (2019). Early Intervention in Psychosis in Young People: A Population and Public Health Perspective. American Journal of Public Health, 109(S3):S181-S184.

Bibliography

• Marshall M, Lewis S, Lockwood A, et al. (2005). Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Archives of General Psychiatry, 62(9):975-983.
• Melle I, Joa I, Larsen TK, et al. (2012). Shortening the duration of untreated psychosis: Experiences from the TIPS study. Early Intervention in Psychiatry, 6:5.
• Norman RM, Malla AK. (2001). Duration of untreated psychosis: a critical examination of the concept and its importance. Psychological Medicine, 31:381-400.
• O’Keeffe D, Kinsella A, Waddington JL, et al. (2022). 20-Year Prospective, Sequential Follow-Up Study of Heterogeneity in Associations of Duration of Untreated Psychosis With Symptoms, Functioning, and Quality of Life Following First-Episode Psychosis. American Journal of Psychiatry, 179(4):288-297.
• Oliver D, Davies C, Crossland G, et al. (2018). Can We Reduce the Duration of Untreated Psychosis? A Systematic Review and Meta-Analysis of Controlled Interventional Studies. Schizophrenia Bulletin, 44(6):1362-1372.
• Penttilä M, Jääskeläinen E, Hirvonen N, et al. (2014). Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. British Journal of Psychiatry, 205(2):88-94.
• Perkins DO, Gu H, Boteva K, et al. (2005). Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. American Journal of Psychiatry, 162(10):1785-1804.
• Robinson DG, Schooler NR, John M, et al. (2015). Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study. American Journal of Psychiatry, 172(3):237-248.

Bibliography

• Rosenheck R, Leslie D, Keefe R, et al. (2006). Barriers to employment for people with schizophrenia. American Journal of Psychiatry, 163(3), 411-417.
• Rosenheck RA, Estroff SE, Sint K, et al. (2017). Incomes and Outcomes: Social Security Disability Benefits in First-Episode Psychosis. American Journal of Psychiatry, 174(9):886-894.
• Tiihonen J, Tanskanen A, Taipale H. (2018). 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia. American Journal of Psychiatry, 175(8):765-773.
• Lange KW. (2021). Rudolf Virchow, poverty and global health: from “politics as medicine on a grand scale” to “health in all policies”. Global Health Journal, 5(3):149-154.