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First-episode psychosis and schizophrenia

Oliver Freudenreich, MD, FAPM

Co-Director,

MGH Schizophrenia Program

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Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial interest to

disclose:

Avanir (Research grant for PI)

Janssen (Honoraria for Consultant)

BeaconHealth Strategies (Honoraria for Consultant)

Up-To-Date (Honoraria/Royalties for editing/writing)

Wolters-Kluwer (Royalties for writing)

Global Medical Education (Honoraria for CME speaker)

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Erich Lindemann Mental Health Center

Erich Lindemann 1900-1974 Chief of Psychiatry MGH 1955-1965

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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 prevention 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

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Overview

A. Background: a brief history of psychiatry B. Broad treatment principles

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

C. New FDA drug approvals D. New clinical trials

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

E. Summary: psychiatric jeopardy

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

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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;3:1686.

Social interventions have greater impact

on outcomes than molecular advances.

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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)

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REVOVERY ORIENTATION

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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. Compare: Tohen M et al. J Clin Psychiatry 2016;77:781. Read: Alessandrini M et al. Schizophr Res 2016;171:27.

*N=392 never-treated patients

SOHO = Schizophrenia Outpatients Health Outcomes study

QoL

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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

1Mueser KT et al. Psychiatr Serv 2015;66:680. 2Kane JM et al. Am J Psychiatry 2016;173:362. 3Addington J et al. Psychiatr Serv 2015;66:753.

RAISE = Recovery After an Initial Schizophrenia Episode

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Neuroleptic strategy study (NeSSy)

• Effectiveness study – Double randomization*

– Six pairs of SGA-FGA

• Outcome variable – Generic patient-rated quality of life scale (SF-36)

– Area under the curve analysis*

• Results – SGA 85.1 points versus FGA 79.9 points (p=0.01)

– No difference in Clinical Global Impression scale

*Novel design

Gruender G et al. JAMA Psychiatry. 2016;3:717-729. Editorial: Leucht S and Davis JM. JAMA Psychiatry. 2016;3:694-695.

Effect size 0.34

Haloperidol Flupentixol Aripiprazole Olanzapine Quetiapine

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Open dialogue

• What is it? – A Finnish treatment approach

– Network meetings

– Old wine in new bottles?

• Does it work in the US? – Gordon feasibility study

• N=16 patients

• Can I use it with my patients? – Collaborative atmosphere

– Judicious use of antipsychotics

Gordon C et al. Psychiatric Services. 2016 (in press).

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PREVENTION PRINCIPLES

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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 • Omega-3 fatty acids

• Tertiary prevention – minimize disability – Relapse prevention

• Antipsychotics clear effective

Brown AS and McGrath JJ. Schizophr Bull 2011;37:257. 1Gates J et al. Lancet Psychiatry 2015;2:726. 2McGlashan TH. Schizophr Bull 2012;38:902.

Treatment TIMING2

Mental health starts with

physical health1

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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

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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;71:1350. *HbA1c based

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Smoking cessation myths

• Tobacco use is self-medication

• Patients with schizophrenia are not interested in quitting

• Quitting destabilizes patients psychiatrically

• Smoking cessation is a lower priority problem

Schroeder SA. World Psychiatry. 2016;15:175.

Do you know what to do if a patient with schizophrenia wants to quit smoking? Do you know what to prescribe?

Do you think Chantix is safe?

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HIGH-QUALITY MEDICAL CARE

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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.

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Premature mortality in schizophrenia

• US national cohort 2001 to 2007 • N=1,138,853 • Results

– All-cause SMR 3.7 (95% CI, 3.7-3.7) – Cardiovascular disease

• Highest mortality rate • 403.2/100,000 person-years • SMR 3.6 (95% CI, 3.5-3.6)

– Cancer mortality • Lung cancer had highest mortality rate • 74.8/100,000 person-years • SMR 2.4 (95% CI, 2.4-2.5)

– Particularly elevated SMR COPD (9.9) and influenza/pneumonia (7.0) – Accidental deaths twice as common as suicides – Notable cause of death was alcohol and other drug (nonsuicidal):

95.2/100,000 person-years

Olfson M et al. JAMA Psychiatry 2015 (in press). *Brown S et al. Br J Psychiatry 2010;196:116.

Most of excess mortality in schizophrenia is due to natural causes.*

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Safe medical care

Pringsheim T et al. J Can Acad Child Adolesc Psychiatry. 2011;20:218. Morrato EH et al. JAMA Psychiatry. 2016;73:721-730.

Possible BENCHMARK

80% glucose monitoring (40% lipid monitoring)

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New clinical trials

GOALS KEY QUESTION

Prodromal Phase

Prevent psychosis Prevent schizophrenia?

Treat with antipsychotic?

Acute Psychosis

Keep DUP short Achieve initial response and

early positive symptoms remission

Which antipsychotic? Problem: early non-response

(positive Sx)

Post-psychotic Phase

Achieve sustained remission Recovery and QOL Prevent morbidity

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

benefit

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PRODROMAL PHASE

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DSM-5 Attenuated Psychosis Syndrome*

A. Characteristic symptoms

Attenuated positive symptoms

with insight

B. Frequency/currency

Once per week in past month

C. Progression

D. Distress/disability/treatment seeking

E. Symptoms not better explained by

Depression, mania, substance use, ADD, …

F. Never had frank psychosis www.dsm5.org

Carpenter WT and van Os J. Am J Psychiatry 2011;168:460. Fleischhacker WW and DeLisi L. Curr Opin Psychiatry 2012;25:327.

*Section III

Putatively prodromal Clinical high-risk (HR) state for psychosis At-risk mental state (ARMS) Ultra-high-risk state (UHR)

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Early warning signs of psychosis

http://www.nimh.nih.gov/health/publications/raise-fact-sheet-early-warning-signs-of-psychosis-om-16-4305/index.shtml

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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

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Indicated prevention trial: follow-up

ω-3 FA

Placebo

12 weeks fish oil 700 mg EPA 480 mg DHA 10%

40% N=71 6.7 years Axis I disorder: PUFA 52.9% Placebo 82.9%

Amminger GP et al. Nature Communications 2015;6:7934.

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Early intervention guidance

• Treat syndromes (e.g., depression)1

• Benign interventions to delay conversion2

• Omega-3 fatty acids (requires replication); NAC? • Integrated psychological interventions (EDIPPP)3

• Antipsychotics only if DSM-IV diagnosis or special circumstances1

• Rapid deterioration

• Severe risk of suicide

• Aggression • Note: do not treat for pseudo-ADD with stimulants4

IEPA=International Early Psychosis Association

1Br J Psychiatry Suppl. 2005 Aug;48:s120. 2van der Gaag et al. Schizophr Res 2013;149:56. 3McFarlane et al. Schizophr Bull 2015;41:30. 4Freudenreich O et al. Am J Psychiatry 2006;163:2019.

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Early psychosis field – lessons learned

• Need for subtyping of CHR subjects – Clinical subtyping to reduce heterogeneity1

• Brief limited psychotic symptoms (BLIPS): higher risk • Attenuated psychotic symptoms (APS)

– 19% transition risk over 2 years

• Genetic risk and deterioration (GRD): very low risk • Deconstruct CHR back into original components2

– Need for biological markers3

– Need for transdiagnostic approach

• Need for population health systems4

– Complex rather than complicated responses

• IEPA is looking beyond psychosis – Early Intervention in Mental Health

IEPA = International Early Psychosis Association 1Fusar-Poli P et al. JAMA Psychiatry. 2016;73:113-120. 2Cornblatt BA and Carrion RE. JAMA Psychiatry. 2016;73:105-106. 3Bedi G et al. npj Schizophrenia 2015 (online) 4Srihari V et al. JAMA Psychiatry;73:101-102.

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

- Sepp Herberger

ACUTE PSYCHOSIS

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Etiology and pathophysiology

• Cannabis – Cannabis as component cause1

• Population-attributable fraction from skunk: 24%

– Complex gene-environment interaction2

– Adolescent cannabis use predicts psychosis3

• Symptoms are subclinical • No evidence for reverse causation

• Celiac disease4

• Autoantibodies – NMDA: false positive findings in schizophrenia5

– Autoimmune encephalitis in postpartum psychosis6

– Antibodies to surface dopamine-2 receptors7

1Di Forti M et al. Lancet Psychiatry 2015; 2:233-8. 2Volkow ND et al. JAMA Psychiatry 2016; 73:292-7. 3Bechtold J et al. Am J Psychiatry 2016;173:781-9 4Delichatsios HK et al. NEJM 2016;374:1875-83.

5de Witte LD et al. JAMA Psychiatry 201572:731-3. 6Bergink V et al. Am J Psychiatry 2015; 172:901-8. 7Pathmanandavel K et al. Biol Psychiatry 2015;77:537-47.

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New FDA drug approvals

• Cariprazine1

– 3rd Partial D2/3 agonist

• Pimavanserin2

– Approved for psychosis in Parkinson’s disease

– 5-HT2A inverse receptor agonist (not D2 blocker)

• Of interest – ITI-007 (Intra-Cellular Therapies) published phase

II trial3

– Encenicline (Forum) failed phase III trial

1Citrome L. Clin Schizophr Relat Psychoses 2016;10:109-19. 2Cummings J et al. Lancet 2014;383:533-40. 3Liebermann JA et al. Biol Psychiatry 2016;79:952-61.

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Post-Psychotic Phase Chronic phase

Nach dem Spiel ist vor dem Spiel. - Sepp Herberger

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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.

“The benefit of maintenance drug

treatment is relapse prevention, not

comprehensive treatment of schizophrenia.”

-William Carpenter 2001

“It suggests the disquieting conclusion that the benefits of active neuroleptics in reducing relapse may exact a price in occupational terms.” -Timothy Crow (1980s)

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LAI antipsychotics for FEP

Subotnik KL et al. JAMA Psychiatry 2015;72:822. Carpenter WT and Buchanan RW. JAMA Psychiatry 2015;72:745 [editorial].

Offer routinely as first-line maintenance

choice

LAI make non-adherence transparent and

reduce family burden.

oral

LAI

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Antipsychotic discontinuation

• Spanish cohort study (PAFIP) – Naturalistic, with 3-year follow-up

• Eligibility – Stable symptomatic and functional recovery after first episode of

psychosis

• Results – Discontinuation group: 31/46 = 68%

• Mean time to relapse: 209 days (most in first 6 months) • Signs of relapse: unreliable (too abrupt = within one month) • Possible predictors: DUP, psychosis, family history, living with family

– Control group: 7/22 = 32% • Fairly high relapse rate

• Conclusion – High relapse rate in good-prognosis cases that is reduced with

treatment PAFIP = Programa Asistencial de Fases Iniciales de Psicosis Mayoral-van Son J et al. J Clin Psychiatry. 2016;77:492-500. See also: Landolt K et al. Schizophr Res .2016;172:145-51. See also: Thompson A et al. Early Interv Psychiatry. 2016;10:355-361.

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Treatment for refractory psychosis

• Standard should be a clozapine monotherapy trial – Early use of clozapine1

– For limited response to clozapine you are “skating on thin ice”2

• Clozapine plus amisulpride or quetiapine

• Clozapine plus valproate or lithium

• ECT augmentation3

• Antipsychotic combination treatment – Probably very limited if any benefit for most – Clozapine is preferred over polypharmacy4

– Polypharmacy can often be reduced5

• ECT alone as maintenance treatment? 1Agid O et al. J Clin Psychiatry 2011;72:1439. 2Tracy DK et al. BMC Psychiatry 2015;15:174. 3Petrides G et al. Am J Psychiatry 2015;172:52. 4Velligan DI et al. Psychiatr Serv 2015;66:127. 5Essock SM et al. Am J Psychiatry 2011;168:702.

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Clozapine news

• Effectiveness – Meta-analyses differ1,2

– Best outcome variable3

• Safety – Diabetes, hyperlipidemia, intestinal obstruction4

– Safe for benign ethnic neutropenia5

• Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program6

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

1Siskind D et al. Br J Psychiatry. 2016 (in press). 2Samara MT et al. JAMA Psychiatry. 2016;73:199-210. 3McEvoy JP. JAMA Psychiatry. 2016 (in press) . 4Stroup TS et al. Am J Psychiatry. 2016;173:166-173. 5Manu P et al. J Clin Psychiatry. 2016;77:e909. 6https://www.clozapinerems.com/CpmgClozapineUI/home.u

DARC = Duffy antigen/receptor chemokine gene

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

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Antipsychotic safety

• Antipsychotics1

– Swedish database study – About 20,000 patients with schizophrenia in Sweden – Decreases mortality

• HR 0.59; 95% CI, 0.49-0.70 (moderate exposure) • HR 0.75; 95% CI, 0.63-0.89 (high exposure)

• Concomitant benzodiazepine2

– Retrospective Medicaid database study – Almost 20,000 patients with schizophrenia – 20% were prescribed a benzodiazepine – Increased mortality

• HR = 1.48; 95% CI, 1.15-1.91 • HR = 3.08; 95% CI, 2.63-3.61 (if no antipsychotic)

1Tiihonen J et al. Am J Psychiatry. 2016;173:600-606. 2Fontanella CA et al. J Clin Psychiatry. 2016;77:661-667

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Treatment for negative symptoms

• Meta-analysis1

– No clinically significant improvement

• Rasagiline2

– MAO-B inhibitor approved for Parkinson’s disease

– Small RTC with benefit for avolition

• CBT for negative symptoms3

• Still waiting for glycine reuptake inhibitor

– Bitopertin story4

• Cariprazine5

1Fusar-Poli P et al. Schizophr Bull 2015;41:892. 2Buchanan RW et al. Schizophr Bull 2015;41:900. 3Perivoliotis D and Cather C. J Clin Psychol 2009:65:815. 4Goff DC. JAMA Psychiatry 2014;71:621. 528th European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.3.d.053. Presented August 31, 2015.

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Treatment for cognition

• Nicotinic system

– Alpha-7 nicotinic acetylcholine receptor agonists

– Encenicline positive phase II, FAILES phase III

– Nelonicline (ABT-126) positive phase II

• “Fell short of significance on the MCCB composite score”

• Significant treatment-by-smoking interaction

• Estrogen

– Selective estrogen receptor modulators MCCB = MATRICS Consensus Cognitive Battery Haig GM et al. Am J Psychiatry. 2016;173:827-835

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Raloxifene add-on in schizophrenia

• Women with schizophrenia1

• Raloxifene (brand name Evista) – Selective estrogen receptor modulator (SERM)2

– FDA-approved for breast cancer prevention and osteoporosis

– Possible pro-cognitive benefit in schizophrenia3

• Kulkarni trial4

– Women with refractory schizophrenia

– Broad efficacy across several domains

– No improvement in cognition

1Seeman MV. Womens Health. 2012;8:215-24. 2Mirkin S and Pickar JH. Maturitas. 2015;80:52-7. 3Weickert TW et al. Mol Psychiatry. 2015;20:685-94. 4Kulkarni J et al. JAMA Psychiatry. 2016 (in press).

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STRIDE study

• Stride = PREMIER lifestyle interventions with DASH diet

• Multi-site RCT in community settings and integrated health plan in Pacific Northwest

• 6 month weekly group intervention and 6 month monthly maintenance

• Inclusion criteria: – BMI had to be at least 27 – Had to take antipsychotic

• N=200 randomized – Mean age 47 – Mean BMI 38.3 – 72% female – 29% schizophrenia spectrum

• Intervention participants – Lost 4.4 kg more than controls in

first 6 months – Lost 2.6 kg more than controls over

12 months – Had lower fasting glucose after 12

months – Had fewer medical hospitalizations

(6.7% vs. 18.8%)

• Open questions – Implementation challenges – Best maintenance treatment

STRIDE = ?

Green CA et al. Am J Psychiatry 2015;172:71. Bartels SJ. Am J Psychiatry 2015;172:9. (editorial)

Weight loss is possible for patients with SMI

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CHANGE trial

• Randomized, pragmatic trial to reduce 10-year risk of cardiovascular disease

• Interventions – 12-month individual, manualized life-style coaching

– Care coordination

• Outcome – N=428

– No effects of either intervention compared to treatment as usual

• Do we need structural change?

CHANGE = ? Speyer H. et al. World Psychiatry. 2016;15:155-165.

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Acronym Jeopardy

Prodrome Cohorts Treatment

APS SOHO RAISE

IEPA STEP EUFEST

CHR PAFIP CHANGE

Berkwits M. Ann Intern Med 2000;133:755.

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The right treatment, at the right intensity, at the right time, in the right place

• Right treatment – Effective care = evidence-based*

• Comprehensive care – Medications – Psychological treatments and rehabilitation

– Safe care = integrated and population-based

• Right intensity – Stepped care

• Treatment intensity adjusted based on response

• Right time – Timely care = without delay* – Phase-specific care

• Right place – Patient-centered = humane care* – Continuum of care

• Includes asylum

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

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Sequential antipsychotic trials

• Select • Lowest-risk choice • Patient preference

• LAI acceptable? • Cost?* • Early ancillary medical prevention

• Behavioral interventions

• Adjunctive metformin

• Monitor • Clinical response • Follow antipsychotic monitoring guidelines

• Adjust • Switch antipsychotics

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

• Add psychological treatments and group behavioral interventions

• Treat medical morbidities

See editorial: Robinson D. Am J Psychiatry. 2016;173:554-555. *Rosenheck RA et al. Psychiatr Serv. 2016 (in press).

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The long view

You need to be “The man in the arena.”

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John Umstead Hospital, Butner, NC, ca. 1995

Thank you!