Long term outcomes in First Episode Psychosis – results from the OPUS cohort

Stephen F. Austin Psychiatric Center North ZealandCopenhagen University, Denmark

TOP Conference 18-19th November 2015

Overview of presentation

• Description of OPUS trial

• 3 studies on long term outcomes in OPUS cohort1. Rates and predictors of recovery

2. Development of symptoms over time- trajectories

3. Consequences of persistent negative symptoms

• Study limitations

• Clinical implications and future research

OPUS Trial (1998-2000)

• OPUS trial (1998-2000) RCT -578 people with First Episode Psychosis (ICD10 F20-28)- effect of assertive intensive treatment vs standard treatment (Petersen 2005, Bertelsen 2008)

• OPUS Cohort- systematic follow-up (1 yr, 2yrs, 5yrs & 10yrs)

Domain Measure

Diagnosis Schedules for Clinical Assessment in Neuropsychiatry

Symptoms Schedule for Assessment of positive and negative symptoms (SAPS/SANS)

Functioning GAF: Global Assessment of Functioning (GAF) Personal and Social Function Scale (PSP)

Course of illness Life Chart Schedule

Psychiatric admissions Danish Psychiatric Central Research Register

Accommodation Supported accommodation register

Study 1: Recovery

Long term recovery in FEP

• Traditional view of schizophrenia as deteriorating, chronic condition- but many methodological problems (sampling, high dropout, no consensus in defining & measuring outcomes).

• Evidence base- need for FEP cohorts to be followed up systematically over several years (EPPIC, AESOP, TIPS)

• Recognized criteria for symptom remission (Andreasson 2005)

functioning (vocation, social living skills) – Recovery

AIM: Examine rates and baseline predictors of recovery at 10 year follow-up

Symptom remission & recovery

• Symptom remission rates range from 26-52% (Robinson 2004, Henry 2009, Bertelsen 2009, Hegelstad 2013, Morgan 2014)

• Functional remission rates range from 10-33% (Harrow 2005, Robinson 2004, Lambert 2006, Bobes 2007, Henry 2009, Wolff 2009)

• Recovery rates range from 10-25% (Harrow 2005, Lambert 2006, Bobes 2007, Wunderink 2009, Bertelsen 2009)

• Predictors of recovery- DUP, premorbid functioning, negative/positive symptoms, onset of illness, diagnosis, cognition, depression and work/education status

Definitions remission & recovery

• Symptom remission- minimal to mild symptoms across three dimensions (negative disorganisation and psychoticism) for a minimum of 6 months (Andreasson 2005)

• Recovery- symptom remission, no psychiatric admissions or supported accommodation over 2 years, GAF 60+, working or engaged study (Based on Liberman 2002)

Flow of participants at 10 yr follow-up

Included in OPUS (1998-2000) (n=578)

Removed from analysis (n=82)Schizotypal Diagnosis

Lost to follow up (n=192)Deceased (n=33)Emigrated (n=18)Declined (n=137)Unable to locate (n=2)Too ill to consent (n=1)

Participated in 10 year follow-up (n=304) -61%(Age-36 years, 55%- men, 25% -substance abuse)

• No significant differences between participators and non-participators (baseline symptoms, diagnosis, DUP, pre-morbid functioning or sex or age).

•Participators slightly higher baseline functioning GAF 41 versus 37, p<0.01)

Rates of remission & recovery

1 3 1 3 7

4 8 4 2 5 4

2 2 2 9 2 5

1 7 1 6 1 4

2 years 5 years 1 0 years

Recovery

Symptom Remission

Positive and/or Negative

Symptoms

Institutionalised

• Rates of symptom remission & recovery similar to other FEP studies*

• Across 10 years rates of recovery similar within OPUS cohort but they

are not the same people (2yrs to 5yrs 35%, 5yrs to 10yrs45%)

Functioning of participants (n=304)

Characteristic of functioning Participants meeting criteria

Functioning (GAF-F -60 +) 33% (n=99)

Currently working or studying 25% (n=76)

Not living in supported accommodation (last 2 yrs) 82% (n=250)

Adequate functioning in socially useful activities (PSP-A)(work, education, household chores, parenting)

38% n=115

Adequate social functioning (PSP-B) 69% (n=211)

Adequate self-care (PSP-C) 78% (n=236)

No aggressive/disruptive behaviour (PSP-D) 95% (n=289)

Receiving disability pension 64% (n=195)

Many people functioning well despite not meeting full recovery criteria

Baseline predictors for recovery

BaselineCharacteristics

Sex

Age included in trial

Schizoaffective Diag.

PsychoticDisorganizedNegative Symptoms

GAF Functioning

High school finished

Social contact

DUP

PAS social

PAS academic

Univariate

Odds Ratio (C.I. 95%) p value

0.73 (0.38-1.40) 0.35

0.93 (0.88-0.99) 0.03

5.02 (1.49-16.32) 0.009

1.08 (0.84-1.38)0.99 (0.99-1.00)0.56 (0.41-0.76)

0.570.380.001

1.02 (1.00-1.05) 0.051

2.68 (1.38-5.21) 0.003

9.57 (1.28-71.25) 0.028

0.99 (0.98-1.00) 0.377

0.08 (0.01-0.55) 0.01

0.84 (0.01-0.58) 0.012

Multivariate

Odds Ratio (C.I. 95%) p value

- -

0.92 (0.86-0.99) 0.039

3.71 (0.78-17.81) 0.101

--0.51 (0.34-0.75)

--0.001

- -

2.13 (0.94-4.87) 0.072

4.85 (0.58-40.24) 0.144

- -

0.77 (0.06-8.56) 0.788

0.31 (0.03-3.76) 0.363

GAF-Global Assessment of Functioning DUP-Duration of untreated psychosis PAS- Pre-morbid adjustment scale

Age included & Negative symptoms

Negative symptoms OR 0.51 (C.I. 95% 0.34-0.75)

For each increase of 1 pt on negative symptom scale (0-5) risk of recovery decreases by approx. 49% (+2pts 74% )

Age included OR 0.92 (C.I 95% 0.86-0.99)

For each year diagnosis/treatment is later, risk of recovery decreases by approx. 8% (3yrs+ 22%)

Negative symptoms at 1 year independently contributed to recovery after controlling for baseline symptoms (OR 0.49 C:I 95% 0.25-0-98)

Study 2: Trajectories

Symptom Trajectories I

• Traditionally long term studies in FEP are based on cross sectional data (recovered vs not recovered).

• These studies do not capture how the illness manifests over time- symptom trajectories.

• Analysis of data using dichotomous outcomes may be inefficient (Royston 2006)

• Newer statistical techniques (Latent Class Analysis (LCA)

identify patterns of outcome in large data sets.

Symptom Trajectories II

• Studies- identified 4-5 positive symptom trajectories (reduction and stabilization) but used proxy for symptoms- hospitalization (Levine 2011, Rabinowitz 2007).

• Studies using clinical data (4-trajectories) but based on three month follow-up (Schennach et al 2012)

• No studies have examined long term trajectories for negative symptoms (Case 2010)

AIM: Identify positive and negative symptom trajectories and baseline predictors

Positive symptom trajectories

0

1

2

3

4

5

0 1 2 3 4 5 6 7 8 9 10

Positiv

e S

ym

pto

ms (

SAPS)

Years

Response 47%

Delayed 12%

Episodic 13%

Relapse 15%

No response 13%

Positive symptoms- pattern of reduction and stabilization over time (70%)

Negative symptom trajectories

0

1

2

3

4

5

0 1 2 3 4 5 6 7 8 9 10

Negative S

ym

pto

ms (

SAN

S)

Years

Response 28%

Delayed 19%

Relapse 26%

No response 27%

Negative symptoms- relatively little change over time (80%)

Predictors for positive symptom trajectories

Baseline characteristics Relapse Delayed Episodic No response

Odds ratio (OR)(95% C.I.)

Odds ratio (OR)(95% C.I.)

Odds ratio (OR)(95% C.I.)

Odds ratio (OR)(95% C.I.)

Duration of untreated psychosis

1.47**(1.21-1.80)

1.27**(1.07-1.52)

1.32**(1.04-1.68)

1.34**(1.12-1.61)

Functioning (GAF-F) 0.99(0.53-1.82)

1.23(0.92-1.65)

0.62(0.35-1.11)

0.68*(0.47)

Substance abuse 5.9**(1.1.81-19.2)

2.33(0.89-6.12)

1.64(0.45-6.00)

3.47**(1.39-8.65)

Schizophrenia diagnosis(F20)

2.24(0.69-7.27)

7.09(1.34-37.5)

1.9(0.60-6.04)

2.20(0.67-7.21)

Response trajectory reference group C.I.- 95% confidence interval * p<0.05, ** p<0.01, *** p<0.001OR reflects a one year increase in DUP, OR reflects 10 point increase in functioning on GAF- F

Predictors for negative symptom trajectories

Baseline characteristics Relapse Delayed No response

Odds ratio (OR)(95% C.I.)

Odds ratio (OR)(95% C.I.)

Odds ratio (OR)(95% C.I.)

Disorganized symptoms (SAPS) 2.01*(1.09-3.71)

1.44(0.76-2.40)

2.38**(1.38-4.22)

Functioning (GAF-F) 0.79(0.55-1.12)

0.86(0.52-1.43)

0.52**(0.35-0.78)

Sex (male) 1.94(0.83-4.52)

1.31(0.47-2.74)

3.43***(1.45-8.13)

Schizophrenia diagnosis (F20) 5.70**(1.65-19.72)

3.32(0.86-12.84)

8.86***(2.75-28.53)

Inadequate social contact 3.13*(1.25-7.69)

3.44**(1.29-9.09)

5.55***(2.22-12.50)

Pre-morbid social function (PAS) 1.34**(1.08-1.67)

0.99(0.77-1.28)

1.33**(1.13-1.69)

Response trajectory reference group C.I.- 95% confidence interval * p<0.05, ** p<0.01, *** p<0.001OR reflects 1 point increase in disorganized symptoms, OR reflects 10 point increase in functioning , Inadequate social contact less than one contact a week with family or friend, OR reflects 0.1 point decrease in PAS scale (range 0.0-1.0)

Study 3: Persistent Negative Symptoms

Negative symptoms

• Primary negative symptoms as core pathology versus secondary negative symptoms as consequence of illness (Carpenter 1988)

• Current psychometric approaches- affective flattening, alogia, anhedonia, asociality, avolition. (New measures:

CAINS- Blanchard et al. , BNSS- Kirkpatrick et al.)

• Expressive deficits and avolition most common groupings in factor analysis (Messinger 2011, Carpenter 1988)

• Numerous studies have identified negative symptoms implicated with poor outcomes (Ho 1998, Milev 2005, Blanchard

2005, Austin, Nordentoft et al. 2013)

Persistent Negative symptoms (PNS)

• Persistent negative symptoms (PNS) – enduring and not secondary to psychotic symptoms or depression.

• Rates of PNS within FEP - 4%-30% dependent on definition and follow up (Malla 2004, Hovington 2012, Galderisi 2013)

• People with PNS – poorer outcomes and drop out from treatment (Edwards 1999, Malla 2004, Hovington 2012)

• Relatively little research on PNS prevelance and impact on outcomes (especially long term outocomes).

AIM: Identify prevelance, long term outcomes and predictors of persistent negative symptoms

Design • Study design is prospective- identify primary negative

symptoms present at 1 & 2 years.

• PNS- Significant scores on at least one negative symptom dimension (affective flattening, alogia, avolition, asociality,

anhedonia) for at least 6 months and not secondary to psychotic symptoms, depression or medication side effects (Buchanan 2007)

Domain Measure

Diagnosis Schedules for Clinical Assessment in Neuropsychiatry (SCAN)

Symptoms Schedule for Assessment of Positive and Negative symptoms (SAPS/SANS)

Functioning GAF: Global Assessment of Functioning (GAF)

Side effects UKU side effects rating scale

Characteristics Total

Age (mean) 26.96 years (S.D 6.24)

Sex (males) 205 (55.9%)

Schizophrenia (F20)Schizotypal (F21) Acute psychosis (F23) Delusional disorder Schizoaffective (F25)

241 (65.7%)63 (17.2%)27 (7.4%)18 (4.9%)12 (3.3%)

Substance Abuse Diagnosis 101 (27.5%)

Psychotic symptoms Negative symptomsGAF-S SymptomsGAF-F Function Duration of untreated psychosis (weeks)

2.67 (S.D 1.48)2.13 (S.D 1.15)34.24 (S:D 10.91)42.49 (S.D 13.63)96.74 (S.D 165.07)

Participant characteristics (n=367)

Prevalence of negative symptoms

• A total of 90 people (24%) were identified with PNS based on full follow-up data (n=369)

Negative symptom global subscales Prevalence of negative symptoms in

PNS group (n=90)

Anhedonia-Asociality 70%

Affective flattening 44%

Avolition/apathy 42%

Alogia 13%

Baseline predictors for PNS

BaselineCharacteristics

Men

Cannabis

High-school degree

Age

Not working or student

GAF-S (10 points)

GAF-F (10 Points)

DUP

Psydim

Negdim

Socinx baseline

Acadinx baseline

Univariate

Odds Ratio (C.I. 95%) p value

2.21 (1.32-3.69) p=0.002

1.69 (1.03-2.77) p=0.04

1.04 (0.64-1.70) p=0.86

0.99 (0.95-1.03) p=0.65

0.74 (0.42-1.30) p=0.30

1.00 (0.97-1.02)0.69 (0.56-0.85)

p=0.67p=0.001

1.00 (0.98-1.01) P=0.85

0.82 (0.69-0.96)1.56 (1.25-1.96)

p=0.02p<0.001

1.14 (1.01-1.27) p=0.03

1,11 (0,98-1,25) p=0.11

Multivariate

Odds Ratio (C.I. 95%) p value

1.58 (0.89-2.81) p=0.12

1.60 (0.92-2.80) P=0.10

0.70 (0.55-0.90) p=0.006

0.80 (0.64-1.01)1.41 (1.10-1.82)

p=0.06p=0.007

1.05 (0.92-1.20) p=0.45

Long term outcomes (PNS)

OUTCOMES NO PNS PNS T-TEST /OR

GAF-S Symptoms N=217, 56.9 (16.4) N=58, 48.7 (15.3) T=3.44, p<0.001

GAF-F Function N=217, 58.3 (15.9) N=58, 46.6 (14,1) T=5.09, p<0.001

PSP overall N=217, 59.3 (15.6) N=58, 47.6 (14.8) T=5.15, p<0.001

Overall QOL N=212, 3.7 (0.9) N=51, 3.5 (1.0) T=1.73, p=0.09

Psychotic N=217, 1.0 (1.3) N=57, 1.2 (1.4) T=0.93, p=0.35

Negative N=213, 1.2 (1.0) N=57, 2.0 (1.1) T=5.24, p<0.001

Recovered -5yrs 34 (19.1 %) 6 (11.3 %)OR 1.85 (0.73-4.68),

p=0.19

Recovered** -

10yrs44 (20.4 %) 2 (3.3 %)

OR 7.42 (1.74-31.6),

p=0.007

*Results for 10 year follow-up **Recovery defined as symptom remission, no psychiatric admissions or supported accommodation over 2 years, GAF 60+, currently working or engaged study (Based on Liberman 2002)

Study limitations I

• Up to one third of data missing at 5 & 10 year follow up. Participators better -overestimate good outcomes

• Predictor analyses show association not causation

• No evaluation of cognitive functioning- link to recovery

• Analysis used RCT (different treatment impact on outcomes at 2 years)

No detailed information on treatment after 2 years

Study limitations II

• Recovery (Study 1) Baseline characteristics used as predictors, factors collected over 10 years not examined

• Trajectories (Study 2) Relatively small sample size and number of data points for this statistical procedure

• Infrequent and unevenly spaced follow-up may oversimplify variation in symptoms (changes 5 to 10 years)

• Persistent Negative Symptoms (Study 3) Few evaluations of psychopathology in first two years (optimal 6, 12, 18mths).

Clinical Implications I

• Low rate of recovery (14%), barriers to recovery (not

working). Need to improve access to workplace - Individual

Placement Support (IPS)- Preliminary studies up to twice as effective as traditional methods in maintaining employment (Bond 2008, Campbell 2011)

• Narrow definition of recovery (clinical recovery), increased focus on personal recovery (Anthony 1993).

• CHIME framework (Leamy 2011) investigate interaction clinical/personal recovery (Jorgensen 2014, Slade 2015).

• Symptom trajectories are heterogenous, change possible after many years (timing and duration of interventions).

Clinical Implications II

• Negative symptoms- associated with poor prognosis to and non-responsive over time

• Prevention- psychoeducation shorter DUP (Melle 2008),

• Pharmacological -anti-depressants, minocycline, glutamatergic agents,

alpha-7 nicotinic agents, first/second generation anti-psychotics.

Clinical Implications III

• Psychological - CBT (ES =0.44) (Wykes 2008) but treated secondary to psychotic symptoms (Baandrup, Austin…2015).

• Social Recovery Therapy (chronic negative symptoms) (Grant 2012)

• Motivation enhancement Training (MOVE- PNS)(Velligan 2015)

• Cognitive remediation -Meta-analysis (small effect)

(Pfammatter 2006) Klingberg (2012) -combination CR & CBT (?)

• Transmagnetic cranial stimulation (TMS) Meta-analysis (small effect- duration of effects?) (Dlabac de lange et al. 2010)

No evidence based treatments for negative symptoms !

The OPUS study

• Merete Nordentoft

• Pia Jeppesen

• Anne Thorup

• Lone Petersen

• Mette Bertelsen

• Britt Morthorst

• Marianne Melau

• Rikke Gry Secher

• Carsten R. Hjorthøj

• Nikolai Albert

• Lasse Randers

• Heidi Jensen

• Esben Budtz Jørgensen

• Ole Mors

• Per Jørgensen

• Torben Christensen

• Gertrud Krarup

• Phoung Le Quack

• Preben Mortensen

• Lars Morså

• Esben Budtz Jørgensen

Center for Psychitric Research , Risskov

Stephen.01.Austin@regionh.dk

Psychiatric Center Copenhagen

Thankyou for your attention !