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Managing First Episode Psychosis

Abigail Donovan, M.D. Assistant Professor of Psychiatry, Harvard Medical School

Director, First Episode and Early Psychosis Program MGH Schizophrenia Program

Massachusetts General Hospital

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Disclosures

Neither I nor my spouse has a relevant financial relationship with a commercial interest to

disclose.

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Learning Objectives

• Recognize prodromal schizophrenia and understand options for intervention

• Understand key treatment goals for each phase of treatment of schizophrenia

• Understand interventions for comorbid health problems

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Mental illnesses are the chronic diseases of the young

Insel and Fenton, Arch Gen Psych 2005

Why do we care about schizophrenia anyway?

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Epidemiology of Schizophrenia

• Found in all cultures

• Lifetime prevalence of 1%

– Approx 72 million people affected worldwide

• Lifetime risk lower in females1

– Risk ratio males:females 1.42:1

• Average age of onset 16-25 years old

– Earlier in men, later in women

1. Aleman A et al. Arch Gen Psychiatry 2003;565

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Psychosis in Boston

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Definitions

Childhood Onset (COS)

• Onset before age 13

• Rare: <1% of all patients

• Very poor prognosis

• Cognitive delays are common1

• 25% co-morbid ASD2

• High rate of false positives2

– 25% re-diagnosed as bipolar

Adolescent/Early Onset (EOS)

• Onset before age 18

• ~ 30% of all FEP pts

• Compared to adult onset:

– Worse premorbid functioning

– Longer duration of untreated psychosis (DUP)

– More depression and SI

– Worse prognosis

1. Frangou, Front Hum Neurosci, 2010;79. 2. Stayer C et al. JAACAP 2004:1026.

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Genetics

• Overall heritability is 65-80%

• Many different genes implicated (>100 loci)1:

– COMT: catecholamine degradation, 22Q11DS

– MHC: immune and neurodevelopmental pathways

– NRXN1: regulation of neurotransmitters

• Key factor: advanced paternal age

– >45 yo: offspring have 2x risk for schizophrenia

– >50 yo: offspring have 3x risk for schizophrenia

1. PCG Nature 2014;421-427.

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Environmental Factors

• Genetic vulnerability PLUS additional social and environmental factors lead to schizophrenia

• Environmental Factors

– Inflammation during gestation (viral exposure)1

– Starvation in prenatal period (Dutch Hunger Winter)

• Social Factors2 – Immigration – Sexual trauma – Bullying – Major social stressors: losses, transitions

1. Canetta et al. Am J Psychiatry 2014;960-968 2. McGrath et al. Am J Psychiatry 2011;168;1235

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Brain Changes

• MRI findings1: – Increased ventricular volume

– Decreased hippocampal volume

– Decreased medial temporal lobe volume

– Decreased whole brain volume

• Brain abnormalities are present in drug naïve FEP patients2 and to a lesser extent in prodromal patients3

• Antipsychotics may also cause mild volume loss4,5

1.Guret al. Schizophr Bull, 2007;921-931 2. Ren . Am J Psychiatry 2013;1308-1316 3. Cerletti et al, Schizophr Bull 2012;1170-1179 4. Ho et al. Arch Gen Psych 2011;128-137 5. Lesh JAMA Psychiatry 2015;226-234

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Prodromal Period Post-Psychotic Period

Initiation of Antipsychotic

Psychosis

Positive Sx

Negative Sx

Based on Häfner, ABC Schizophreniestudie

1-5 years 1-2 years*

*DUP

Phases of illness

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Phases of treatment

GOALS KEY QUESTION

Prodromal

Phase

Prevent schizophrenia Treat with antipsychotic?

Acute

Psychosis

Keep DUP short

Achieve early remission of symptoms

Which antipsychotic?

What dose?

When to switch?

Post-psychotic

Phase

Achieve sustained remission

Recovery and QOL

Prevent morbidity

Treat for how long?

Courtesy of O. Freudenreich

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Prodrome: Case example

• 15 year old boy, high school student, normal development

• In the past year, – Grades have slipped from As to Cs – He has not been seeing friends as much – Not motivated to practice piano or basketball

• Mentioned to Mom that someone was following him

• MSE: engaged and cooperative, a little flat, +PI with insight

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Prodrome

• Early prodrome symptoms are non-specific, thus frequently recognized retrospectively – Social withdrawal

– Reduced concentration and attention: mimic ADHD

– Reduced drive and motivation

– Depression/Anxiety

– Poor hygiene

– Sleep disturbances

• Many teenagers will have these symptoms and not develop psychosis

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What is the risk of conversion?

• PACE 4001

• N=416 UHR patients followed for 15 years

• Highest rate of conversion in first 2 years: 20%

• Total conversion rate: 34.9% (comparable to other studies)

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Yearly Transition Rate

1. Nelson et al. JAMA Psychiatry 2013;793-802

PACE=Personal Assessment and Crisis Evaluation

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Prevention?

• 3 RCT: Risperidone + CBT1, CBT alone2, Olanzapine3

• All interventions delayed onset of psychosis during treatment period, but did not prevent psychosis during follow up

• As soon as patients stopped treatment, they developed psychosis at equal rates

• No indication to use antipsychotic medication

1.McGorry et al. Arch Gen Psychiatry 2002;921-928 2.Morrison et al. Schizophr Bull 2007;682-7. 3.McGlashan et al. Am J Psychiatry 2006;790-9.

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Omega 3

• 1.2 g/d of omega-3 or placebo for 12 weeks, then 40 weeks of monitoring

• During active tx, sig. fewer conversions in omega-3 group

• After monitoring: – Only 1 add’l omega-3 pt

converted

– Overall transition rate:

5% vs. 28%

Omega 3

Placebo

5%

28%

1. Amminger et al. Arch Gen Psychiatry 2010;146-154.

P=0.007

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• Long term follow up

• Median 6.7 years

• Transition rate:

9.8% vs. 40%

• Protective effects of Omega 3 intervention were sustained long term

Omega 3 o.

Omega 3

Placebo

9.8%

40%

P=0.002

1. Amminger et al. Nature Comms 2015;1-7.

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How do we treat the prodome?

• Omega 3 may be beneficial and have little downside

– Results need to be replicated

• Psychosocial treatments may be beneficial and have little to no adverse effects

• We can also modify risk factors for progression

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Cannabis

• Individual level: earlier age at onset

– Age at onset is 1.81-2.72 years earlier in cannabis users

• Population level

– Frequent cannabis use in adolescents doubles risk of schizophrenia3

• Actively discourage cannabis use in youth

1. Dekker et al. Psychol Med 2012;1903-1911. 2. Large et al. Arch Gen Psychiatry 2011;555-561 3. Moore et al. Lancet 2007;319-328.

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Acute Psychosis: Case Example

• 18 yo, freshman in college, no formal psych history

• Stopped attending class due to poor concentration, grades now Ds

• Smoking cannabis daily

• Not socializing at all, rarely leaves dorm room

• Told parents he was hearing voices

• MSE: disheveled and malodorous, guarded, not engaged, self dialoging but denies hallucinations

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DSM 5: Schizophrenia

• Two Criterion A symptoms for one month: – Delusions

– Hallucinations

– Disorganized speech

– Disorganized behavior

– Negative symptoms

• One must be a “core symptom”

• Functional decline

• Total duration of symptoms: 6 months

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Cognition

• Cognitive performance is 1-2 SD below age matched controls1

• Affected areas include: attention, executive fxn, memory, processing speed, social cognition2

• Cognitive decline is nearly universal, present before the onset of psychosis, and worsens during the illness3

• Chronic impairment is specific to schizophrenia- not seen in bipolar disorder or depression4

1. Keefe et al. Schizophr Bull 2007;912-920. 2. Nuechterlein KH et al. Schizophr Res 2004;29-39. 3. Kahn et al. JAMA Psych 2013;1107-1112. 4. Meier et al. Am J Psychiatry 2014;91-101.

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• Antipsychotic treatment leads to very small improvements in cognitive subtests1

• Cognitive function is a critical determinant of global functional outcome2

Cognition

1.Frazier et al. JAACAP 2012;496-505 2.Kahn et al. JAMA Psychiatry 2013;1107-1112

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Medical Work Up

• Labs: – Chem 10 – CBC – LFTs – TSH – B12/Folate – ESR – ANA – Anti-treponemal antibodies/HIV – Ceruloplasmin – Toxicology screens

• Additional labs/testing as indicated by presentation

• Diagnostic testing: – MRI – EEG

• Good neuro exam

Courtesy of O. Freudenreich

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Anti-NMDAR Encephalitis

• Auto-antibodies are produced against the NMDA receptor, causing neurologic and psychiatric symptoms, including psychosis

• Definitive diagnosis is made by testing CSF for anti-NMDAR antibodies1

– testing CSF: 100% sensitive

– testing serum: 85% sensitive

• 55% of pts have prodromal flu-like symptoms2

1. Gresa-Arribas et al. Lancet 2014;167-177. 2.Armangue et al. J Pediatr 2013;850-856.

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Anti-NMDAR Encephalitis

• Subsequent symptoms include:

– Movement disorders: dyskinesias, choreoathetosis (84% of children1)

– Seizures (77% of children1)

– Decreased level of consciousness

– Autonomic instability (86% of children1)

– Psych sx’s: mood symptoms, agitation, bizarre behavior, AH/VH, delusions

1.Jones et al. Neuroimag Clin N Am 2013;309-320.

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In FEP, when to test?

• Psychotic symptoms, plus:

– Movement disorders

– Seizures

– Autonomic instability

– Altered consciousness

• Will any patients be missed?

– Cohort Study: only 0.9% of patients have a purely psychiatric presentation1

– All patients had an abnormal MRI and/or EEG

1. Kayser MS JAMA Neurol 2013;1133-1139.

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Acute Psychosis: Treatment Questions

• When do you start treatment?

• Which antipsychotic is first-line treatment?

• What dose do you use?

• How long do you treat before you switch?

• How long do you treat the first episode?

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Treat ASAP

• Minimize duration of untreated psychosis (DUP)

• Early intervention is associated with:

– Improved clinical outcomes at 2 years1 and 5 years2

– Higher GAF, improved social functioning, fewer symptoms at 20 years3

• Early intervention increases the chances of achieving initial remission4

1. Melle et al. Arch Gen Psych 2008;634-640 2. Larsen et al. Psychol Med 2011;1461-1469. 3. Cechnicki et al. Psych Res 2014;420-425. 4.Fraguas et al. Schizophr Res 2014;130-138.

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What antipsychotic to use?

• Café Trial1 SGAs only – Olanzapine, quetiapine and risperidone had comparable efficacy

• EUFEST2 FGAs and SGAs

– Haloperidol, quetiapine, ziprasidone, amisulpride, olanzapine had comparable efficacy

– SGA’s were more well tolerated: 33-53% vs 72% FGA discontinuation rate

• TEOSS3 FGAs and SGAs, children only – Molindone, olanzapine, risperidone had comparable efficacy

and comparable discontinuation

– Olanzapine had significant weight gain

1.McEvoy et al. Am J Psychiatry 2007;1050-1060. 2.Kahn et al. Lancet 2008;1085-1097. 3. Sikich et al. Am J Psychiatry 2008; 1420-1431

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• Paliperidone: 3-12 mg QD, approved 12-17 yo – Active metabolite of risperidone, similar SE profile

• Lurasidone: 40-160 mg QD, w/ food, not approved in children – Akathisia, less weight gain, more EPS?

• Asenapine: 2.5-10 mg BID SL, approved for bipolar only – Sedation, EPS, weight gain

• Iloperidone: 1-12 mg BID, not approved in children – Sedation, weight gain

• Brexpiprazole: 2-4mg QD, not approved in children – Partial D2 agonist, akathisia, weight gain

Newer Antipsychotic Medications

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Comparative Efficacy Meta-Analysis

• Meta-analysis, 15 antipsychotics: FGAs, SGAs, Clozapine1

• Clozapine was significantly more effective

• Olanzapine and risperidone were more effective than most (small effect size); all others had similar efficacy

• Haloperidol had highest all cause discontinuation

1.Leucht et al. Lancet, 2013;951-962

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Medication Efficacy

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• Because SGAs have similar efficacy, but are better tolerated than FGAs, start with an SGA

• Given that efficacy is generally similar between SGAs, consider different side effect profiles and individual patient vulnerabilities to make initial choice

Bottom Line

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What dose to use?

• First-episode patients are more responsive to medication

• FEP patients require lower doses of antipsychotics than multi-episode patients

• First-episode patients are more sensitive to side effects than multi-episode patients

1. Robinson et al. Schizophr Bull 2005;705-722.

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What dose to use?

• FEP patients respond to lower doses of antipsychotics1,2

Haloperidol 2.1 mg

Aripiprazole 10 mg

Olanzapine 11.7 mg

Risperidone 2.4mg

Quetiapine 500 mg

FEP Daily Target Dose

1. Lieberman, 2003 2.Schooler, 2005

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When to switch antipsychotics?

• Clinical improvement is slow – Positive symptoms take weeks to resolve – Negative symptoms take months/years (if they

resolve at all)

• AACAP Guidelines: After 6 weeks, if there are insufficient effects while using adequate dosages, consider switching

• Patients without even minimal improvement at week 2 are unlikely to have later response1

– 2 weeks of a therapeutic dose

1. Leucht et al. Am J Psychiatry, 2015;617-629.

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Clozapine

• 20% of FEP patients will not respond to FGAs or SGAs

• Patients with 2 failed trials should be offered clozapine

– The only antipsychotic agent for which there is established superiority over other agents

• For tx refractory schizophrenia, clozapine is more beneficial than haloperidol and high dose olanzapine (66% vs 33%)1

• Clozapine can be used in adolescents, but adolescents are more sensitive to its side effects, especially2:

akathesia (15% vs 3%) neutropenia (6% vs 1%)

1. Kumra, Biol Psychiatry 2008;524. 2. Sporn, et al. JAACAP 2007;1349-1356.

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How long to treat?

AACAP Guidelines 2013 • Most individuals need long term treatment and are

at significant risk of relapse if medication is discontinued

• Maintain medication at the lowest effective dose to minimize adverse events

• After prolonged remission, a small number of individuals may be able to discontinue medication

• Change from 2001 guidelines- emphasized intermittent treatment or discontinuation

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Relapse off Medication

• 3 year, open label trial1

• All FEP patients, stable for 2 years

• All patients underwent gradual medication taper

• Relapse rates:

– 79% at 1 year

– 97% at 3 years

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Recurrence Rate (%)

1. Emsley et al. J Clin Psychiatry, 2012;e541-e547

79%

94% 97%

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Maintenance Treatment

• Strongly encourage long term treatment at the lowest effective dose

• Most patients ask for a trial off medication – They will do it with or without you

• After 1-2 years of stability, after significant discussion of risks, consider gradual taper, with close monitoring

• Multi-episode patients will need indefinite maintenance treatment

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• RAISE Study • Comprehensive tx vs.

usual care • Comprehensive tx:

– Med management, individual therapy, family psycho-ed, supp employment/ed

• Outcomes: – Time in treatment,

functioning, QLS, PANSS, depression, hospitalizations

All about meds?

1. Kane et al. AJP in Advance 2015 doi:10.1176.

Quality of Life Score

P=0.015

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Prognosis

• Short-term prognosis: – Most (80%) achieve short term symptomatic remission1

• Long-term prognosis:

– Less than 40% maintain remission for >6 months2

– Relapse rate is very high (>82% during first 5 yrs)3

• Functional prognosis at 7 years4: – 36% of patients are employed

– 22% of patients are employed and socially connected

– 14% are employed, socially connected & symptomatically remitted

1. Lieberman et al. J Clin Psychiatry 1993;369-376. 2. Gaebel et al. Schizophr Res 2014;478-486. 3. Robinson et al. Arch Gen Psychiatry 1999;241-247. 4.Henry et al. J Clin Psych 2010;716-728.

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• Schizophrenia is associated with a 20 year decrease in life expectancy1 and a 4 fold increase in mortality2

• Premature mortality is due to cardiovascular dz, respiratory dz, infections and cancers3

• Even in FEP, cardiac and metabolic abnormalities are present early on4

• Related to underlying illness, unhealthy lifestyle, antipsychotic meds, inadequate medical care

Morbidity and Mortality

1. Druss et al. Med Care 2011;599-604. 2. Revier at al. J Nerv Ment Dis 2015;379-386. 3. Olfson et al. JAMA Psychiatry 2015;1172-1181. 4. Correll et al. JAMA Psychiatry 2014;1350-1363.

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Antipsychotics and Weight Gain

• Children may be particularly prone to weight gain

• Naturalistic study: At 12 weeks, antipsychotic naïve youth gained1:

– 4.4 kg on aripiprazole

– 5.3 kg on risperidone

– 6.1 kg on quetiapine

– 8.5 kg on olanzapine

1. Correll et al. JAMA 2009;1765-1773.

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Monitoring

• Baseline: – BMI

– Fasting glucose, lipids, BP

– Family history of obesity, DM, CVD, HTN

• BMI: check at 4, 8, 12 weeks, every 3 months after

• Fasting glucose, lipids, BP: check at 3 months, then annually if normal

• Intervene for abnormalities!

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Metformin

• N=148 patients with schizophrenia1

• Randomized to metformin 1,000 mg BID or placebo

• All patients received diet and exercise counseling

1. Jarksog et al. Am J Psychiatry, 2013;1032-1040

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Behavioral weight loss interventions

• 2 studies of behavioral weight loss interventions in patients with SMI1,2

• Diet and nutrition education, ind weight management, group exercise sessions

• Both studies demonstrated significant weight loss in intervention groups

1. Daumit et al. N Engl J Med, 2013;1594-1602. 2. Green et al. Am J Psychiatry 2015;71-81

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Summary

• Recognizing and intervening in the prodrome – Omega 3 fatty acids

• Key treatment goals for each phase of the first episode – Treat early with low doses of SGAs

– Encourage maintenance treatment for most patients

• Monitor and treat comorbid physical health conditions

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Acknowledgements

MGH Schizophrenia Program

Oliver Freudenreich, MD

Daphne Holt, MD, PhD

Cori Cather, PhD

John Tyson, MD

Hannah Brown, MD

Yosh Kaneko, MD

THANK YOU!