IMPRO

VIN

G TH

E DETEC

TION

OF YO

UTH

S AT RISK OF

PSYCH

OSIS IN

THE C

OM

MU

NITY: A

NEU

ROD

EVELO

PMEN

TAL

PERSPECTIV

E

PEPPNET W

ebinar

Monica E C

alkins, Ph.D. A

ssociate Professor of Psychology D

irector, Clinical Research A

ssessment

Associate D

irector, Penn Psychosis Evaluation and Recovery C

enter (PERC)

Neuropsychiatry Section, D

epartment of Psychiatry

Perelman School of M

edicine

University of Pennsylvania

Oct 17, 2018

Jerome Taylor, M

.D. C

hild, Adolescent &

Adult Psychiatrist

Children’s H

ospital of Philadelphia

Disclosures

¨ N

one

Background

¨ 

Subthreshold psychotic-like experiences

¤ 

Are relatively com

mon in the general population of children and adolescents.

¤ 

Develop into distressing and im

pairing psychotic disorders in a minority of youths.

¨ 

Increasing our ability to identify youth at risk of psychosis in the general public is a key step tow

ards an improved ability to prevent the disorder.

¨ 

Clinical challenges in screening/Identifying P

S sym

ptoms in children/

adolescents ¤ 

Little normative/base rate data – Is this just a “norm

al” experience? Is this just an “adaptive” response to circum

stances? n 

Related – child’s conflation of “norm

al” childhood experience with “abnorm

al”

¤ 

Com

orbidities - Is this just “due to/manifestation” of [other thing/disorder]?

¤ 

Ability/w

illingness to disclose ¤ 

Limited collateral inform

ant knowledge of subthreshold positive sym

ptoms

Background

¨ 

The Philadelphia N

eurodevelopmental C

ohort (PN

C) w

as founded to characterize clinical and neurobehavioral phenotypes of genotyped youths. ¤ A

llowed com

munity screening to identify the earliest em

ergence of psychosis spectrum

symptom

s in young people. ¤ C

omplem

entary to investigations of clinically help-seeking individuals.

¨ 

Through the PN

C, w

e aimed to prospectively investigate predictors and

trajectories of psychosis spectrum features in a com

munity sam

ple of U

.S. youths.

¤ Findings inform

understanding of significance of early subthreshold sym

ptoms

(2015) J Child Psychology and Psychiatry

• A

merican Recovery and

Reinvestment A

ct (ARRA

) Funded

• Available in the public dom

ain (dbG

ap) – 199 approved requests to date

• A

ge 8-21 • 

Mean age = 14.2 (s.d.=3.7)

• Fem

ale = 52 %; A

A/O

ther = 44%

• N

=9,498 • 

Time 1 recruitm

ent = 2009-2011 • 

In-home = 66%

PH

EN

OTY

PIN

G

(n=9,498)

Clinical A

ssessment

Neurocognitive

Testing N

euroimaging

(n=1,445)

CA

G

(50,293) E

MR

Center for A

pplied Genom

ics

T1: Psychosis Spectrum

Assessm

ent

• P

ositive Threshold P

sychosis: H

allucinations/ D

elusions (K-

SA

DS

) • 

Positive S

ub-threshold P

sychosis (PR

IME

S

creen, Miller et al.

2004)

• N

egative/ D

isorganized (6 S

cale of Prodrom

al S

ymptom

s items)

Younger children endorsed higher levels of subthreshold positive sym

ptoms – led to “norm

ing” the psychosis spectrum

Symptom

s

• Youngest and oldest males had higher total scores than fem

ales

• Minority youth endorsed m

ore symptom

s at all age bins (p’s <0.01)

• Calculated z-scores based on m

eans and standard deviations within each age year for

the total sample, m

ales, females, E

uropean-Am

erican and African-A

merican/O

ther

groups.

“Norm

ing” the psychosis spectrum Sym

ptoms

• O

nline look up table (in development):

https://pil.med.upenn.edu/prim

e

• Standard (T) score tables w

ere

generated for each reference

group, where T=50+10(z). T

scores have a mean of 50 and

a standard deviation of 10.

• Age, sex and race norm

ative

references for PS

-R can inform

interpretation of individual

responses in research, clinical

and comm

unity settings.

T-score<6060-6970-7980-8990-99100+

• A

mong m

edically healthy youth, age 11-21 (mean 15 y.o.):

• psychotic sym

ptoms: 3.7%

• sub-psychotic sym

ptoms: 12.3%

• only subthreshold negative sym

ptoms: 2.3%

• P

S sym

ptoms predicted by m

ale sex, younger age, non-EA race

• P

sychosis spectrum sym

ptoms associated w

ith • 

Reduced neurocognitive accuracy and global functioning

• Increased odds of depression, anxiety, behavioral disorders, substance use, suicidal ideation

“Validation” of the Psychosis Spectrum C

onstruct

“Validation” of the Psychosis Spectrum C

onstruct

Interviewer O

bservations

Global A

ssessment of Functioning (G

AF)

Family Interview

for Genetics S

tudies (FIG

S) – B

rief

Sem

i-Structured P

sychopathology A

ssessment

K-S

AD

S M

ood, AD

HD

, S

ubstance S

tructured Interview for

Prodrom

al Syndrom

es (S

IPS

)

Dem

ographics and Medical H

istory

Timeline

Interviewer O

bservations

Global A

ssessment of Functioning (G

AF)

Sem

i-Structured P

sychopathology A

ssessment

K-S

AD

S M

ood, AD

HD

, S

ubstance S

tructured Interview for

Prodrom

al Syndrom

es (S

IPS

)

Timeline

Adult P

roband (age 18-21) and C

ollateral Informant (of youths 9-17)

Middle P

roband (age 11-17)

• 2-year Follow

-up: Psychosis S

pectrum=249, N

on-Spectrum

=254 • 

Assessm

ents conducted blind to Time 1 risk status

At 2-year follow-up (m

ean 17 y.o.), PS symptom

s persisted or w

orsened in 51% of baseline PS, w

ith remaining classified as

”resilient”. PS symptom

s emerged in 16%

of baseline Non-PS.

Persistent group had increased concurrent comorbid

psychopathology in most dom

ains, and a higher rate of psychosis fam

ily history.

Symptom

persistence predicted by baseline higher severity of subclinical psychosis, low

er global functioning, and prior psychiatric medication

PNC$$

9,498$

Psychosis$Spectrum

$153$

Persist$$87$

(57%)$

Psycho=c$Disorder$

13$(8%

)$

SubApsychosis$$74$

(48%)$

Resilient$66$

(43%)$

NonAPsychosis$Spectrum

$$230$

Emerge$56$

(24%)$

Psycho=c$Disorder$

4$(2%

)$

SubApsychosis$52$

(22%)$

$$

Typically$Developing$$174$(76%

)$

Time 1

Time 3

Figure 1. .

At 4-year follow-up (n=383, m

ean 19 y.o.), using methods

identical to Time 2, psychosis spectrum

features persisted or w

orsened in 57% of youths classified as PS at baseline

Persistent Resilient

Emergent

Typically D

eveloping

N

87 66

56 212

Female (%

) 48.3

62.1 51.8

55.2

African-A

merican/

Other %

73.6

60.6 75.0

44.3

T1 PRIME-Screen – Revised Total (m

ean±

SD)

6.7 (5.1) 4.0 (4.0)

2.0 (2.5) 1.3 (1.7)

T1 PRIME-Screen

Revised, Age

Norm

ed (mean

±SD

)

1.3 (1.4) 1.0 (1.1)

-0.1 (0.8) -0.4 (0.5)

T1 SOPS N

egative/D

isorganized A

ge Norm

ed (m

ean±SD

)

1.4 (1.7) 0.5 (1.2)

-0.2 (0.8) -0.4 (0.6)

T1 Global A

ssessment

Scale (mean

±SD

)

68.3 (12.8) 76.4 (12.8)

77.5 (10.8) 84.8 (9.5) PN

C$$9,498$

Psychosis$Spectrum

$104$

Persist$$58$

(56%)$

Persist$42$

(41%)$

Remit$

16$(15%

)$

Remit$

46$(44%

)$

Re?occur$14$

(14%)$

Remit$

32$(31%

)$

Non?Psychosis$Spectrum

$$116$

Emerge$20$

(17%)$

Persist$12$

(10%)$

Remit$

8$(7%

)$$

Non?PS$$96$

(83%)$

Emerge$9$

(8%)$$

Non?PS$87$

(75%)$$$

Time 1

Time 2

Time 3

Figure 2.

Am

ong youths assessed at all three time-points (n=220),

56% show

ed temporal stability in presence or absence of

psychosis spectrum

sym

ptoms,

while

the rem

ainder exhibited

varying patterns

of sym

ptom

remission,

re-occurrence and em

ergence over time (see Figure 2).

Am

ong youths assessed at all three time-points (n=220),

56% show

ed temporal stability in presence or absence of

psychosis spectrum

sym

ptoms,

while

the rem

ainder exhibited

varying patterns

of sym

ptom

remission,

re-occurrence and em

ergence over time (see Figure 2).

In youth assessed at all three time-points (n=220),

59% (n=129) show

ed temporal stability in presence or

absence of psychosis spectrum sym

ptoms

Rem

ainder exhibited fluctuating patterns of symptom

rem

ission, re-occurrence and emergence over tim

e (“flux”).

Conclusions

¨ 

Varying courses of psychosis spectrum sym

ptoms are evident early in U

.S. youth

representative of the comm

unity. ¤ P

sychosis spectrum persistence, em

ergence, and resilience are dynamic

developmental processes.

¤ A

ge must be considered – both in interpretation of self-reported sym

ptoms and

because youth are still passing through risk period n To our know

ledge, first effort to provide normative, standardized reference scores for

a psychosis spectrum screening tool across age range.

n R

esults underscore the need to interpret endorsements of com

munity youths in the

context of age, sex and race. n S

tandard scores developed here can facilitate assessment of the “norm

alcy” of individual responses according to these dem

ographic parameters

n N

ow 6 year follow

-up (mean 21 y.o.) - concurrent validation via screening and S

IPS

¨ 

A majority (70-75%

) of youth with persistent P

S sym

ptoms reported speaking w

ith a professional about m

ental health concerns n R

eflects a

critically im

portant opportunity

for sim

ple screening

to identify

and intervene early w

here warranted.

PNC

Collaborators and Support

Raquel E

. Gur, M

D P

hD

Ruben C

. Gur, P

hD

Kathleen M

erikangas, PhD

Theodore S

atterthwaite, M

D

Daniel W

olf, MD

, PhD

Jam

es Yi, MD

, PhD

Tyler M

oore, PhD

K

osha Ruparel, M

S

Marcy B

urstein, PhD

D

avid Roalf, P

hD

Christian K

ohler, MD

B

ruce Turetsky, MD

H

akon Hakonarson, M

D

W

e thank the participants and their families. S

upported by RC

2MH

089983 (RE

G);

K08M

H079364 (M

EC

); K23M

H098130 (TD

S); D

owshen P

rogram for N

euroscience; and the Lifespan B

rain Institute M

onica E. Calkins, PhD

Jerom

e H. Taylor, M

D