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www.mghcme.org First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program

First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Page 1: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

First-episode psychosis and schizophrenia

Oliver Freudenreich, MD, FACLP

Co-Director,

MGH Schizophrenia Program

Page 2: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

Disclosures

I have the following relevant financial relationship with a commercial interest to disclose (recipient SELF; content SCHIZOPHRENIA):

• Alkermes – Consultant honoraria (Advisory Board)• Avanir – Research grant (to institution)• Janssen – Research grant (to institution), consultant honoraria (Advisory Board)• Neurocrine – Consultant honoraria (Advisory Board)• Novartis – Consultant honoraria• Otsuka – Research grant (to institution)• Roche – Consultant honoraria• Saladax – Research grant (to institution)• Elsevier – Honoraria (medical editing)• Global Medical Education – Honoraria (CME speaker and content developer)• Medscape – Honoraria (CME speaker)• Wolters-Kluwer – Royalties (content developer)• UpToDate – Royalties, honoraria (content developer and editor)

Page 3: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

Erich Lindemann Mental Health Center

Erich Lindemann1900-1974Chief of Psychiatry MGH 1955-1965

Page 4: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Learning objectives

At the completion of this talk, participants will be able to

– Discuss which three broad treatment principles are critical for the optimal treatment of schizophrenia

– Give examples for stage-based treatment goals in schizophrenia– Select patients who should be offered long-acting injectable

antipsychotics

Erich Lindemann Mental Health Center

Erich Lindemann – Chief of Psychiatry at MGH 1955-1965

Page 5: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Outline

A. Background: a brief history of psychiatryB. Broad treatment principles

• Recovery orientation• Prevention principles• High-quality medical care

C. New FDA drug approvalsD. New stage-based insights

• Prodromal phase• Acute psychosis• Post-psychotic/chronic phase

E. Summary: psychiatric jeopardy

Page 6: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Fleishman M. Psychiatr Serv. 2003;54:142.

Page 7: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

Myth of “natural history”

• TB as social disease

• Holy grail of modern medicine: molecular basis of disease

• “Desocialization” of scientific inquiry

• “Structural violence”

– Structural – built-in

– Violence – causing injury

• Health disparities

Farmer PE et al., PLoS Medicine 2006;3(10):e449.

Social interventions have greater impact

on outcomes than molecular advances.

Page 8: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Broad treatment principles

• Recovery orientation– Patient-centered care*– Patient/peer involvement in disease management– Holistic care (mens sana in corpore sano; no medical health

without psychiatric health)• Prevention orientation

– Timely care*– Staging– Medical prevention part of psychiatric care

• High-quality medical care– Effective care*– Safe care*– Integrated medical-psychiatric care

*Based on Institute of Medicine’s 6 Aims (2001)

Page 9: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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REVOVERYORIENTATION

Page 10: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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SOHO* – positive psychiatry

60.3

45.4

57

28.1

0 10 20 30 40 50 60 70

Symptoms

Function

Subjective Well-

being

Combined

remission

Percent

Lambert M et al., Acta Psychiatr Scand. 2008;118:220.MacBeth A et al. Early Interv Psychiatry. 2015;9:53.*Schennach R et al. Schizophr Res. 2019 [Epub ahead of print].**Dong M et al. Psychiatr Q. 2019 [Epub ahead of print]. [WHOQOL-BREF]

*N=392 never-treated patients

SOHO = Schizophrenia Outpatients Health Outcomes study

QoL**

Asymptomatic*18%

Page 11: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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RAISE trial

• Goal– Develop early-intervention system in real world of fragmented US

healthcare system

• NAVIGATE– Cluster randomization of 34 clinics in 21 states of NAVIGATE versus

community care (CC)– Core services: family education, resilience training, supported

employment/education, medications1

– N=404

• Results– Team-based, multi-component NAVIGATE improved primary outcome

variable (QoL) more than CC2

– Effects were better for those with shorter DUP (median 74 weeks)3

– Improved QOL if more perceived autonomy support4

1Mueser KT et al. Psychiatr Serv. 2015;66(7):680-90.2Kane JM et al. Am J Psychiatry. 2016;173(4):362-72.3Addington J et al. Psychiatr Serv. 2015;66(7):753-6.4Browne J et al. Psychiatr Serv. 2017;68(9):916-922.

RAISE = Recovery After an Initial Schizophrenia Episode

QoL = Quality of Life

Page 12: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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PREVENTIONPRINCIPLES

Page 13: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Prevention in psychiatry

• Medical prevention in schizophrenia• Primary prevention

– Universal prevention• Whole population

– Selective prevention• More susceptible subgroup, still symptom free

• Secondary prevention – “early intervention”– Indicated prevention

• Already showing signs of illness

• Tertiary prevention – minimize disability– Relapse prevention

1Gates J et al. Lancet Psychiatry. 2015;2(8):726-42.

Mental healthstarts with

physical health1

Page 14: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Omega-3 fatty acids for indicated prevention

STUDY DESIGN• Ultra-high risk patients• Intervention: omega-3 PUFA x 6

months• All participants received Cognitive

Behavioral Case ManagementRESULTS• N=304 randomized• ¼ lost to follow-up• 6-month transition rates (CAARMS):

– Placebo 5.1% (=15)– PUFA 6.7% (=17)

• 12-month transition rates:– Placebo 11.2%– PUFA 11.5%

• No effect of adherence (40%!)

NEURAPRO = ?

McGorry PD et al. JAMA Psychiatry. 2017;74(1):19-27.Editorial: Kane JM and Correll CU. JAMA Psychiatry. 2017;74(1):11-2.

1.4 g omega-3 FA (840 mg EPA/560 mg DHA

Page 15: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Staging model of treatment

• Rational for staging– Avoid progression to disease stages where only

amelioration is possible– Better response to treatments in early stages– Earlier treatments are less aggressive

• Principles– Early intervention to treat patients as early as possible in

the disease course– Phase-specific care that tailors the interventions to the

patient’s needs– Stepped care that adjusts treatment intensity based on

response

Page 16: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Clinical staging in psychiatry

STAGE Definition Clinical features

0 Asymptomatic subjects Not help seekingNo symptoms but risk

1a “Help-seeking” subjects with symptoms

Non-specific anxiety/depressionMild-to-moderate severity

1b “Attenuated syndromes” More specific syndromes incl. mixedAt least moderate severity

2 Discrete disorders Discrete depr/manic/psych/mixed syModerate-to-severe symptoms

3 Recurrent or persistent disorder

Incomplete remissionRecurrent episodes

4 Severe, persistent and unremitting illness

Chronic deterioratingNo remission for 2 years

Hickie IB et al. Early Interv Psychiatry 2013;7:31.

Page 17: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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HIGH-QUALITYMEDICAL CARE

Page 18: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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“However beautiful the strategy*, you should occasionally look at the results.**”

-Sir Winston Churchill

* = what your clinic does

** = how your patient is doing Haas LF. JNNP 1996;61:465.

Page 19: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

RAISE – baseline cardiovascular risk

• N= 394

• Age

– Mean age 24 (15 to 40)

• Diagnosis

– FES spectrum

• Treatment history

– Mean 46 days

48%

51%

57%

40%

10%

13%

15%

3%

Overweight

Smoking

Dyslipidemia

Prehypertension

Hypertension

Metabolic syndrome

Prediabetes*

Diabetes*

Prevalence

Prevalence

Correll CU et al. JAMA Psychiatry. 2014;71(12):1350-63.*HbA1c based

Page 20: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Schizophrenia and diabetes

• Diabetes risk– Increased at illness onset1

– Risk increases once antipsychotics introduced2,3

– Insulin sensitivity decreases rapidly after second-generation antipsychotics are started4

– Subtype of schizophrenia5

• “Inherent” diabetes risk versus social determinants of health debate

• Maybe should focus on screening …6

1Pillinger T et al. JAMA Psychiatry. 2017;74(3):261-9. 2Rajkumar AP et al. Am J Psychiatry. 2017;174(7):686-94.3Andreassen OA. Am J Psychiatry. 2017;174(7):616-7. [Editorial] 4Nicole GE et al. JAMA Psychiatry. 2018;75(8):788-796.5Tomasik J et al. JAMA Psychiatry. 2019 [Epub ahead of print]. 6Mangurian C et al. JAMA Psychiatry. 2017;74(7);761-2. [Letter]

Diabetes is a disease that often shows itself in families in which insanity prevails.

- Sir Henry Maudsley, 1879

Page 21: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Safe medical care: screening

Pringsheim T et al. J Can Acad Child Adolesc Psychiatry. 2011;20(3):218-33.Morrato EH et al. JAMA Psychiatry. 2016;73(7):721-30.Vanderlip ER et al. Am J Psychiatry 2016; 173(7):658-63.See Taking Issue: Mangurian C. Psych Serv. 2017;68(3):213.

PossibleBENCHMARK

80% glucose monitoring(40% lipid monitoring)

Page 22: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

New FDA drug approvals

• 2017: Valbenazine1

– Approved for tardive dyskinesia (TD)– VMAT-2 inhibitor

• 2017: Deutetrabenazine2

– Approved for Huntington’s disease and TD– VMAT-2 inhibitor

• 2017: Proteus sensor for aripiprazole• 2017: Aripiprazole lauroxil long-acting injectable

– 2-month dosage

• 2018: Aripiprazole lauroxil long-acting injectable– New initiation regimen

• 2018: SC risperidone long-acting injectable• 2019: NONE

– Perhaps lumateperone – PDUFA date September 27, 2019

1Freudenreich O and Remington G. Clin Schizophr Relat Psychoses. 2017;11(2):113-119.2Anderson KE et al. Lancet Psychiatry. 2017;4(8):595-604.

Page 23: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Long-acting injectable antipsychotics

Drug Dose strengths Dose (IM) & Frequency Notes

Haloperidol decanoate[HALDOL DECANOATE]

Vials 50mg/mlVials 100mg/ml

50 - 200 mg monthlyOther dose intervals are possible

Initiation: overlap with oral antipsychoticLoading dose strategy possibleMaintenance dose equals 20 x oral dose

Fluphenazine decanoate[PROLIXIN DECANOATE]

Vials 25mg/ml 6.25 - 25 mg every 2 weeksOther dose intervals are possible

Initiation: overlap with oral antipsychotic

Risperidone microspheres[RISPERDAL CONSTA]

12.5mg, 25 mg, 37.5 mg, 50 mg

12.5-50 mg every 2 weeks Initiation: 3 week overlap with oral antipsychoticMain release of drug occurs 3 weeks after injection50 mg every two weeks corresponds to 4 mg/d oral (50 mg is highest IM dose]

Risperidone long-acting suspension[PERSERIS]

90 mg, 120 mg 90 or 120 mg monthlysubcutaneously

For subcuaneous use90 mg corresponds to 3 mg/d oral120 mg corresponds to 4 mg/d oral

Paliperidone palmitate[INVEGA SUSTENNA]

[INVEGA TRINZA]

39 mg, 78 mg, 117 mg, 156 mg, 234 mg

273 mg, 410 mg, 546 mg, 819 mg

39-234 mg monthly

273-819 mg every 3 months

Loading dose of 234 mg [deltoid!] to initiate (no oral overlap needed), 2nd

dose one week later, the monthly156 mg monthly corresponds to 9 mg/d oralEvery 3 months dose can be used after 4 months of monthly injections546 mg corresponds to 9 mg/d oral

Olanzapine pamoate[ZYPREXA RELVPEVV]

150 mg, 210 mg, 300 mg, 405 mg

150 or 300 mg every 2 weeks405 mg monthly

No overlap with oral antipsychotic (higher initiation doses)Monitor for 3 hours of observation for post-injection delirium/sedation syndrome (PDSS)*300 mg monthly corresponds to 10 mg/d oral

Aripiprazole monohydrate[ABILIFY MAINTENA]

Vials 200 mg/ml 160mg- 400mg monthly Initiation: 2 week overlap with oral antipsychotic300 mg corresponds to 10 mg/d oral; 400 mg to 15 mg/d

Aripiprazole lauroxil[ARISTADA]

441 mg, 662 mg, 882 mg, 1064 mg

441,662,882 mg every 4 weeks882 mg every 6 weeks1064 mg every 2 months

Initiation: 3 week overlap with oral antipsychotic or with initiation regimenInject rapidly due to non-Newtonian fluid characteristicsOnly lowest dose of 441 mg dose can be given in deltoid441 mg monthly corresponds to 10 mg/d oral 662 mg monthly or 1064 mg every two months corresponds to 15 mg/d oral882 mg monthly corresponds to 20 mg/d oral (highest IM dose)

Oral test dose required for all antipsychotic if patient has never been exposed to IM antipsychotic*See REMS website for olanzapine pamoate

Page 24: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

Prodrome

Pre-psychotic phase Critical phase Chronic phase

First episode

Stable disability

Partial recovery

Full recovery

Second episode

Sym

pto

ms,

fu

nct

ion

, dis

abili

ty

Typical course of schizophrenia

Page 25: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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New stage-based insights

GOALS KEY QUESTION

ProdromalPhase

Prevent psychosisPrevent schizophrenia?

Treat with antipsychotic?

AcutePsychosis

Keep DUP shortAchieve initial response and

early positive symptoms remission

Which antipsychotic?Problem: early non-response

(positive Sx)

Post-psychoticPhase

Achieve sustained remissionRecovery and QOLPrevent morbidity

Treat for how long?Problems: early relapse and residual Sx (adherence); risk-

benefit

Page 26: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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PRODROMAL PHASE

Page 27: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Prodromal schizophrenia

• Prodrome can only be diagnosed in retrospect

• Transition risk for putatively prodromal patients not 100%1

• 18% after 6 months

• 22% after 1 year

• 29% after 2 years

• 36% after 3 years

• Majority will not convert (“false-positive”)

• “Probably at risk, but certainly ill”

• Help-seeking and not well2

1Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.2Lin A et al. Am J Psychiatry 2015;172:249.

PLEIOTROPIC

REVIEWS:Klosterkoetter et al. Dtsch Arztebl Int 2008;105:532.Fusar-Poli et al. JAMA Psychiatry 2013;70:107.Fusar-Poli et al. Psychol Med. 2014;44:17.

BROAD SYNDROME OF MENTAL DISTRESS

Page 28: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Transition risk prediction

• Challenge of identifying high-risk patients for selective or indicated prevention– Well-established in medicine (e.g., Framingham risk score)

• Two risk predictors:– NAPLS-2 sample1: http://riskcalc.org:3838/napls/

• Need neurocognitive data and data from SIPS interview

– South London and Maudsley NHS Foundation Trust2: http://www.psychosis-risk.net

• Limits of clinical approach in routine care– Low positive predictive value of positive symptoms (less then

2%)3

– Risk predictors are only for patients identified for being at risk– Risk predictors are not for routine screening

NAPLS = North American Prodrome Longitudinal Study1Cannon TR et al. Am J Psychiatry. 2016;173(10):980-8.2Fusar-Poli R et al. JAMA Psychiatry. 2017;74(5):493-500.3Livny A et al. Am J Psychiatry. 2018;175(4):351-358.

Page 29: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

www.mghcme.org

Early intervention CHR guidance

• Assess and treat syndromes (anxiety, depression)• Benign interventions to delay conversion1,2

• CBT should be first-line treatment• Integrated psychological interventions (EDIPPP)3

• Omega-3 fatty acids ineffective;4 NAC?; minocycline?

• Use of antipsychotics• Low-dose second-generation antipsychotic• If severe symptomatology• Not long-term for primarily preventive purpose

• Note: do not treat for pseudo-ADD with stimulants5,6,7

IEPA=International Early Psychosis Association1

EPA = European Psychiatric Association2

1Br J Psychiatry Suppl. 2005 Aug;48:s120.2Schmidt SC et al. Eur Psychiatry 2015;30:388.3McFarlane et al. Schizophr Bull 2015;41:30.

4McGorry PD et al. JAMA Psychiatry. 2017;74(1):19-27.5Freudenreich O et al. Am J Psychiatry 2006;163:2019.6MacKenzie LA et al. Pediatrics 2016;137:1.7Moran LV et al. NEJM. 2019;380(12):1128-38.

Page 30: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Cannabis guidance

• Clear down-sides– Component risk factor for 12% of schizophrenia1

– Increasingly potent THC products– Destabilizes early course schizophrenia via reduced

adherence2

– Effects on cognition

• CBD oil (brand name Epidiolex) (Schedule V)– 2018 FDA-approved for Lennox-Gastaut and Dravet

syndrome– Off-label prescribing– Minimal research regarding CBD

Pierre JM. Curr Psychiatry. 2019;18(5):13-20.Brunette MF et al. Psychiatr Serv. 2018;69(11):1181-3.1Di Forti M et al. Lancet Psychiatry. 2019;6(5):427-36.2Schoeler T et al. Lancet Psychiatry. 2017;4(8):627-33.

Page 31: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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“Der Ball ist rund und das Spiel dauert 90 Minuten.”

- Sepp Herberger

ACUTE PSYCHOSIS

Page 32: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Suicide prevention

• Mortality risk in early course schizophrenia– 12-month mortality rate comparable to being age 701

– High-risk period for suicide– Substance-related deaths contribute significantly2

• Participation in early psychosis programs reduces risk of premature death from suicide– PEPP program in greater London, Ontario3

• 75% reduced mortality risk in those in program compared to those who are not

• Higher hospitalization rate for those in program

– EASY program in Hong Kong4

• Reduced suicide risk in 12-year follow-up for those in program

PEPP = Prevention and Early Intervention Program for PsychosesEASY = Early Assessment Service for Young People with Psychosis1Schoenbaum M et al. Schizophr Bull. 2017 Oct 21;43(6):1262-72.2Reininghaus U et al. Schizophr Bull. 2015 May; 41(3): 664–73. [AESOP cohort]3Anderson KK et al. Am J Psychiatry. 2018;175(5):443-52. 4Chan SKW et al. JAMA Psychiatry. 2018;75(5):458-64.

Page 33: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Substance-induced psychosis

• Danish population-based registry study1,2

– 20-year follow-up– N=6,778– Majority alcohol, cannabis, amphetamines– 32.2% of patients converted to schizophrenia or bipolar disorder

• Substantial differences in conversion rates between substances– Almost 50% if cannabis-induced psychosis

• Half converted within 3 years to schizophrenia• The younger the patient, the higher the conversion risk

• Implications– 50% of cannabis induced psychosis will become schizophrenia– Longer-term follow-up and treatment needed to prevent

schizophrenia?– Are we looking at increased incidence rates of schizophrenia?

• “…drug-precipitated disorder in highly vulnerable individuals”3,4

1Starzer MSK et al. Am J Psychiatry. 2018;175(4):343-50.2Ghose S. Am J Psychiatry. 2018;175(4):303-4. [Editorial]3Kendler KS et al. Am J Psychiatry. 2019;176(9):711-9.4Tandon R and Shariff SM. Am J Psychiatry. 2019;176(9);683-4. [Editorial]

Page 34: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Antipsychotic choice

• Efficacy1,2

– Antipsychotics not equivalent• Clozapine ES 0.88• Olanzapine ES 0.59• Risperidone ES 0.56

– Overall efficacy for rest• ES 0.33 to 0.50

• Avoid haloperidol in first-episode patients3

• Partial agonist antipsychotics– No higher risk for psychiatric hospitalization when

switching to aripiprazole4

1Smith RC et al. Psychopharmacology. 2019;236(2):545-59.2Leucht S et al. Lancet. 2013;382(9896):951-62.3Zhu Y et al. Lancet Psychiatry. 2017;4(9):649-705. [network meta-analysis]4Montastruc F et al. JAMA Psychiatry. 2019;76(4):409-17.

Choose wisely

Page 35: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Should you switch antipsychotics?

• Good overall remission rate after 10 weeks of treatment

– 2/3 of patients

• 56% responded in four weeks to amisulpride

• No added benefit from switching to olanzapine

• Some benefit from switching to clozapine (25%) but not as good as responders

Amisulpride

Amisulpride

Clozapine

Olanzapine

Leucht, S et al. Schizophr Bull. 2015;41:549-58.Kahn RS et al. Lancet Psychiatry. 2018; 5(10):797-807.

DOUBLE BLIND

6 w

ks1

2 w

ks4

w

OPTiMiSE = Optimization of Treatment and Management of Schizophrenia in Europe

Page 36: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Post-Psychotic PhaseChronic phase

Nach dem Spiel ist vor dem Spiel.- Sepp Herberger

Page 37: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Premise

Schizophrenia is arelapsing-remitting illness

with accrued disability over time.

Page 38: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Cost of relapse in schizophrenia

• Relapse has psychosocial toxicity– Loss of job– Derailed education– Criminal problems– Suicide– Loss of reputation

• Relapse might be biologically harmful1

– Emergent treatment non-response in 16%

• Sustained remission is basis for accrued treatment benefits over time

1Emsley R et al. J Clin Psychopharmacol. 2013;33(1):80-3.

Page 39: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Prevention in psychiatry

• Primary prevention

• Secondary prevention – “early intervention”

• Tertiary prevention – minimize disability

Relapse prevention as key goalof schizophrenia care

Page 40: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Rationale for treatment

Treatment asprevention

Page 41: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Antipsychotic for relapse prevention

• 50 years of evidence1

• Meta-analysis of N=6493• Median follow-up 26 weeks

• Antipsychotics reduce 1-year relapse rate• Drug 27% versus placebo 64%• RR 0.40 [95% CI 0.33-0.49]• No effect of: number of episodes; length of stability; FGA

vs. SGA; abrupt vs. gradual withdrawal• Limitations

– Limited view of schizophrenia (recovery!)• Long-term cost-benefit (function)2

1Leucht S. Lancet. 2012;379(9831):2063.2Wunderink L et al. JAMA Psychiatry. 2013;70:913.See Goff DC et al. Am J Psychiatry. 2017;1;174(9):840-849.

“The benefit of maintenance drug

treatment is relapse prevention, not

comprehensive treatment of schizophrenia.”

-William Carpenter 2001

“It suggests the disquieting conclusion thatthe benefits of active neuroleptics in reducing relapse may exact a price in occupational terms.”

-Timothy Crow (1980s)

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Antipsychotic discontinuation

• Finish cohort study1,2

– N=8,719 first-episode patients, followed for 20 years – Three main findings

• Antipsychotics reduce relapse risk• Risk of relapse increases with increased treatment duration• Lowest risk of death in continuously treated patients compared to

untreated or minimally treated patients

– Conclusion• Patients stabilized on antipsychotics for several years have a high

relapse risk if antipsychotics are discontinued

• Unclear that diagnosis can be improved by discontinuing antipsychotics3

– Clear risks: higher mortality, reduced responsiveness after relapse

1Tiihonen J et al. Am J Psychiatry. 2018;175(8):765-773.2Kahn RS. Am J Psychiatry. 2018;175(8):712-713. [Editorial]3Sommer I et al. Curr Opin Psychiatry. 2019;32(3):147-156.

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Deprescribing

• Classic study1

– Eliminating a second antipsychotic often possible– Successful switch in 2/3 of patients

• Recent meta-analysis2

– All-cause discontinuation favors staying: RR = 2.28, 95% CI = 1.50-3.46, P < 0.001)

• Prioritize– TD risk: reduce cumulative antipsychotic dose and limit FGA use– Metabolic risk: eliminate high-risk antipsychotics– Cognition: anticholinergics– May want to keep clozapine plus aripiprazole3

– May want to keep antidepressant4

1Essock SM et al. Am J Psychiatry. 2011; 168(7):702-8. 2Matsui K et al. Schizophr Res. 2019 [Epub ahead of print].3Tiihonen J et al. JAMA Psychiatry. 2019 [Epub ahead of print].4Stroup TS et al. JAMA Psychiatry. 2019 [Epub ahead of print].See also behavioral economics (nudging): Sacarny A et al. JAMA Psychiatry. 2018; 75(10):1003-11.

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Long-acting injectable antipsychotic medications

• Relapse risk 20 to 30% lower for LAI compared to oral1

• Shared decision-making should be based on facts– LAI gives real-time, accurate information about adherence

• Greatest benefit if started in hospital on patients who have relapsed because of non-compliance

• A reasonable strategy for patients experiencing a first psychotic episode2

– Avoids family conflict

• Best if employed as part of comprehensive care program– Maintaining frequent clinical contact may be a valid psychosocial

relapse prevention treatment3

• Can be life-saving4

– 30% lower risk LAI compared to oral antipsychotic

• Breakthrough symptoms (hospitalization) still high: 30% incidence5

1Tiihonen J et al. JAMA Psychiatry. 2017 Jul 1;74(7):686-693. 2Subotnik KL et al. JAMA Psychiatry. 2015(8);72:822-9. 3Buckley PF et al. Psychiatr Serv. 2016(12);67:1370-72. 4Taipale H et al. Schizophr Res. 2017 [Epub ahead of print]. 5Rubio JM et al. Psychol Med. 2019 [Epub ahead of print].https://www.thenationalcouncil.org/topics/long-acting-medications/

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Not everyone gets better with first-line antipsychotics

• Move to clozapine1

– Refractoriness

– Aggression and self-injury

• Risks of not prescribing clozapine

– Accruing psychosocial toxicity

– “End-stage” brain disease with poor function

– Polypharmacy

– Higher mortality41Warnez S and Alessi-Severini S. BMC Psychiatry. 2014;14:102.2Demjaha A et al. Psychol Med. 2017;47(11):1981-9.3Tiihonen J et al. JAMA Psychiatry. 2017;74(7):686-93.4Tiihonen J et al. Lancet. 2009;374(9690):620-7.

Clozapine has real-world effectiveness for relapse prevention.3

Over 80% of refractory patients are refractory from the start.2

Page 46: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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TDM – Potential benefits

• Informed decision regarding root causes of treatment complications– Poor response to antipsychotics (25% of patients)

• Pseudo-refractoriness (non-adherence) vs. refractoriness*

– Poor tolerability of antipsychotics (15% of patients)• Slow elimination vs. high drug sensitivity

• Identifies patients at higher relapse risk1

• Indications– Non-response at therapeutic doses– Uncertain drug adherence– Suboptimal tolerability– Pharmacokinetic drug-drug interactions

Predmore Z et al. Psychiatr Serv. 2018;69:12-4.1Melkote R et al. Schizophr Res. 2018; 201:324-328. [CATIE sample]*McCutcheon R et al. Acta Psychiatr Scand. 2018;137(1): 39–46.

*1 in 5 TRS patientsmay have non-detectable drug level.

Page 47: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Clozapine news

• Effectiveness– Excellent for relapse prevention1

– Clozapine augmentation strategies are limited2

– Clozapine plus aripiprazole prevents hospitalizations3

– Best clinical efficacy (cohort studies)4

• Safety– Diabetes, hyperlipidemia, intestinal obstruction,5 aspiration pneumonia– Safe for benign ethnic neutropenia6

– Feasible to continue during chemotherapy7

• Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program8

– Goal was to increase clozapine use– Replaces multiple registries– Absolute neutrophil count only– Different cut-offs for benign ethnic neutropenia

1Tiihonen J et al. JAMA Psychiatry. 2017;74(7):686-93. 2Correll CU et al. JAMA Psychiatry. 2017;74(7):675-84.3Tiihonen J et al. JAMA Psychiatry. 2019 [Epub ahead of print]. 4Masuda T et al. JAMA Psychiatry. 2019 [Epub ahead of print].5Stroup TS et al. Am J Psychiatry. 2016;173:166-73. 6Manu P et al. J Clin Psychiatry. 2016;77:e909.

7Graininger BT et al. Eur J Haematol. 2019 [Epub ahead of print]. [Review] 8https://www.clozapinerems.com/CpmgClozapineUI/home.u

Page 48: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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Clozapine underutilization

• Clozapine underused in London community settings1

– Point-prevalence of TRS: 56%

– Never received clozapine: 52%

• NASMHDP report: Clozapine underutilization: addressing the barriers2,3

NASMHDP = National Association of State Mental Health Program Directors1Back K et al. J Psychopharmacol. 2019 [Epub ahead of print].2http://www.nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf3Kelly DL et al. Psychiatr Serv. 2018;69(2):224-227.

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www.mghcme.orgMarder SR. Am J Psychiatry 2016;173:103

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Treatment for negative symptoms

• SSRI antidepressant1

– Efficacy seen in DECIFER trial for citalopram2

– ES 0.32 (DUP <18 weeks) and 0.52 (DUP >18 weeks)

• Rasagiline3

– MAO-B inhibitor approved for Parkinson’s disease

– Small RTC with benefit for avolition

• CBT for negative symptoms4

• Cariprazine5

• L-methylfolate6 1Smith RC et al. Psychopharmacology. 2019;236(2):545-59.2Goff DC et al. Schizophr Res. 2019;208:331-337. 3Buchanan RW et al. Schizophr Bull. 2015;41(4):900-8.4Perivoliotis D and Cather C. J Clin Psychol. 2009:65(8):815-30.5Nemeth G et al. Lancet. 2017;389(10074):1103-13.6Roffman JL et al. Mol Psychiatry. 2018;23(2):316-22.

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Treatment for CIAS

• Avoid adding insult to injury– Reduce anticholinergic burden

• Short-term and long-term risks (10% of dementia cases)1

– Quit smoking!2

• Consider cognitive training if available3,4

• Psychopharmacology add-on strategies– Numerous pharmacological strategies including

enhancing glutamatergic activity, cholinesterase inhibitors, cannabidiol, alpha-7 nicotinic agonists have failed

– Missing: dopaminergic strategies (COMT inhibitors)5

1Coupland CAC et al. JAMA Intern Med. 2019 [Epub ahead of print]. 2Vermeulen JM et al. Am J Psychiatry. 2018;175(11):1121-8. 3Keshavan MS et al. Am J Psychiatry. 2014;171(5):510-22. Review4Best MW et al. Am J Psychiatry. 2019;176(4):297-306.5Sinkeviciute I et al. NPJ Schizophr. 2018;4:22.

CIAS = Cognitive Impairment Associated with Schizophrenia

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Beyond monitoring: need for action

• Physical health monitoring (screening) alone does not improve mortality

• Improving physical health through intervention1

– Psychiatric stability

– Dietary and exercise interventions

– Choice and duration of antipsychotic prescribing

– Pharmacological support for smoking cessation

– Screening for health conditions

• Correct (standard) medical treatment saves lives2

1Ilyas A et al. Br J Psychiatry. 2017;211:194-96.2Kugathasan P et al. JAMA Psychiatry. 2018;75:1234-40.Ward MC and Druss BG. JAMA Psychiatry. 2019;76(7):759-60. [JAMA Network Insights]

2018

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Keeping patients alive

• Iatrogenic morbidity1

• Example of med-psych integration RTC– HOME study2,3

– Improved quality of care (not clinical outcome…)

• Example of illness self-management RTC– TTIM study4

– Better diabetes control after 60-week intervention

• Example of screening– Screening, Testing, Immunization, Risk-Reduction, Integrated

Treatment (STIRR-IT)5

• Example of optimal cardiovascular care– Secondary prevention of myocardial infarction5

1Correll CU et al. World Psychiatry. 2015;14:119-136. 2Druss BG et al. Am J Psychiatry. 2017;174(3):246-55.3Chwastiak L and Fortney J. Am J Psychiatry. 2017;174(3):199-200. [editorial]4Sajatovic M et al. Psychiatr Serv. 2017 Sep 1;68(9):883-890. 5Arnold RM. Psychiatr Serv. 2018;69(11):1188-90.6Kugathasan P et al. JAMA Psychiatry. 2018; 75(12):1234-40.

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Exercise for schizophrenia patients

• The challenge– Cardiovascular morbidity and mortality in SMI patients– Sedentary life-style associated with poor cognition1

• The simple solution– Exercise is “neuroprotective”– Exercise has broad effects on well-being2

• Improves global cognition3

• Key pathways: inflammatory pathways, BDNF (hippocampus)

• Challenges– Implementation: supported exercise– Maintaining gains: sustaining exercise– Mobile interventions starting to show promise4

1Hamer M et al. Psychol Med. 2009;39:3-11.2Noordsy DL et al. Am J Psychiatry. 2018;175(3):209-214.3Firth J et al. Schizophr Bull. 2017;43:546-556.4Ben-Zeev D et al. Psychiatr Serv. 2018;69(9):978-985.

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Smoking cessation

• Prevalence remains high– 62% in a sample of research patients1

– Smoking affects, among other things, quality of life2

• Address smoking in schizophrenia– Cardiovascular and cancer mortality3

– Cognitive benefits from quitting4

• Improved processing speed (digit symbol coding)

• Smoking cessation principles5

• Varenicline– Efficacy: EAGLES trial6

– Safety: removal of black box warning7

1Dickerson F et al. Psychiatr Serv. 2018;69:147-153. 2Vermeulen J et al. Lancet Psychiatry. 2019;6(1)23-34.3Olfson M et al. JAMA Psychiatry 2015;72(12):1172-81.4Vermeulen JM et al. Am J Psychiatry. 2018;. 175(11):1121-8. 5Cather C et al. CNS Drugs. 2017;31(6):471-81.6Anthenelli RM et al. Lancet. 2016;387(10037):2507-20. [EAGLES trial]7www.fda.gov/downloads/Drugs/DrugSafety/UCM532262.pdf

NeededOpt-out stanceMaintenance treatment

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Acronym Jeopardy

Prodrome Cohorts Treatment

NAPLS SOHO OPTiMiSE

IEPA RAISE EAGLES

CHR GROUP DECIFER

Berkwits M. Ann Intern Med 2000;133(9):755-62.

Capture! Shock! Excite! Clinical trial acronyms and the "branding" of clinical research.

Page 57: First-episode psychosis and schizophrenia · First-episode psychosis and schizophrenia Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Program. Disclosures I have the

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How do we avoid poor outcomes?

• Poor outcomes so commonly observed in schizophrenia are likely best explained by:– Poor access to treatment– Late engagement in care– Poor engagement in ongoing care/poor adherence– Cumulative negative impact of substance abuse, medical/psychiatric

comorbidities, and multiple social determinants of health

• Antipsychotic adherence to prevent relapse is a critical part of treatment– Increasing role of digital medicine unavoidable*

• Deficits must be realistically assessed and supported• Medical prevention must be part of psychiatric treatment

• 2018 WHO Guidelines for Management of physical health conditions in adults with severe mental disorders**

Zipursky RB. J Clin Psychiatry. 2014;75 Suppl 2:20-24.Fusar-Poli P et al. World Psychiatry. 2017;16(3):251-64.*Buck B et al. Schizophr Res. 2019;208:167-172.**https://www.who.int/mental_health/evidence/guidelines_physical_health_and_severe_mental_disorders/en/

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Sequential antipsychotic trials

• Select• Lowest-risk choice• Patient preference

• LAI acceptable?• Early ancillary medical prevention

• Behavioral interventions• Adjunctive metformin*

• Monitor• Clinical response• Follow antipsychotic monitoring guidelines**

• Step-up• Switch antipsychotics

• Early use of clozapine for refractory patients• Clozapine over polypharmacy

• Add psychological treatments• Treat medical morbidities

**Perfect is the enemy of good.

*Gerken AT et al. Curr Psychiatry. 2016;15(11):e1-2.**Vanderlip ER et al. Psychiatr Serv. 2014;65(5):573-6.

It is not the critic who counts […]. The credit belongs to the

man who is actually in the arena […].

President Theodore Roosevelt (1910)

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Rudolf Virchow

„Die Medizin ist eine soziale Wissenschaft, und die Politik ist nichts weiter als Medizin im Großen.“

- Rudolf Virchow, 1821-1902

Waitzkin H. Social Medicine. 2006;1:5-10.

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John Umstead Hospital, Butner, NC, ca. 1995

Thank you!