The treatment of ASD in The treatment of ASD in young adults. young adults.

Declan Murphy, Professor of Psychiatry and Brain Maturation,Declan Murphy, Professor of Psychiatry and Brain Maturation,Institute of Psychiatry, London, UKInstitute of Psychiatry, London, UK

Work Funded by the MRC U.K. A.I.M.S network, the Wellcome Trust, National Institutes of Health (USA), Cure Autism Now, Autism Speaks, Dept of Health (NIHR program UK), SLAM.

Take Home Message(s)Take Home Message(s)1.1. Most people with ASD do not need a psychiatrist.Most people with ASD do not need a psychiatrist.2.2. But, many young adults with ASD do have significant co-But, many young adults with ASD do have significant co-

morbidity in mental health. That needs to be treated.morbidity in mental health. That needs to be treated.3.3. The (RCT) evidence base for treatments The (RCT) evidence base for treatments specificallyspecifically in in

young adults is missing.young adults is missing.4.4. Avoid the use of antipsychotics for ‘challenging behaviour’ Avoid the use of antipsychotics for ‘challenging behaviour’

if at all possible.if at all possible.5.5. Use clinical ‘best practice’ and treat co-morbidity as in any Use clinical ‘best practice’ and treat co-morbidity as in any

other person, but take ASD into account.other person, but take ASD into account.6.6. ASD has life-long consequences. You need close working ASD has life-long consequences. You need close working

with colleagues in CAMHS and other services. with colleagues in CAMHS and other services. 7.7. There is Increasing understanding of the neurobiology.There is Increasing understanding of the neurobiology.8.8. Glutamate/Glutamine and 5-HT may be especially Glutamate/Glutamine and 5-HT may be especially

implicated.implicated.

Autistic DisordersAutistic Disorders

AutismAutism H.F.A. H.F.A. AspergersAspergers

Difficulties with reciprocal interaction & behaviour

Learning disability

Ritualistic & stereotyped behaviour

Language delay

Services for adults with ASD.Services for adults with ASD.

1.1. Very few that cover whole IQ/age spectrum.Very few that cover whole IQ/age spectrum.

2.2. National. Approximately 3 outpatient services. National. Approximately 3 outpatient services. Approx 3 private inpatient services opened in Approx 3 private inpatient services opened in the last year. Mainly for CBs. Many out-of-area the last year. Mainly for CBs. Many out-of-area care homes opening.care homes opening.

3.3. Services addressing life-long problems. Nil.Services addressing life-long problems. Nil.

4.4. Formal handover of child-to-adult. Often nil Formal handover of child-to-adult. Often nil when no LD.when no LD.

Co-MorbidCo-MorbidCommonly presentCommonly present

1. Depression.1. Depression.2. ADHD.2. ADHD.3. Anxiety, social phobia, agoraphobia.3. Anxiety, social phobia, agoraphobia.4. OCD (?).4. OCD (?).5. Psychosis ?5. Psychosis ?

Don’t forgetDon’t forget..6. Modifies symptom presentation of other disorders (e.g. 6. Modifies symptom presentation of other disorders (e.g.

Schizophrenia and OCD).Schizophrenia and OCD).

Always think of ASD in those who are not ‘getting better’Always think of ASD in those who are not ‘getting better’8. Social Phobia +/- OCD.8. Social Phobia +/- OCD.9. Schizophrenia. 9. Schizophrenia.

Assessment – takes one day. Assessment – takes one day. Approx 120 with ASD seen last Approx 120 with ASD seen last

year.year.

Family/clinical Interview Formal rating scales

Social and Biological measures – neuropsych, EEG, ECG, sMRI/MRS, karyotyping

Person with disorder

Eventual DiagnosisEventual Diagnosis

0

5

10

15

20

25

30

35

40

45

Person Profile

no ASD and no needfor ANY MH serviceASD

Other

Co-morbid diagnosis within ASD Co-morbid diagnosis within ASD (%)(%)

0

5

10

15

20

25

30

35

40

Diagnostic groups

'Only ASD'+ OCD+ anxiety disorder+ depression+ Psychosis+ PD'Risk to others'

NB – the screening out of ‘nothing needing Murphy’ and ‘only ASD’ removes a significant burden of care. Social Phobia and Drugs and alcohol increased across all groups.

0

10

20

30

40

50

60

70

80

90

wait assessment feeback treatment

Not satisfiedSatisfiedVery Satisfied

User/Carer Satisfaction

HOW DO I TREAT ?HOW DO I TREAT ?

CO-MORBIDITYCO-MORBIDITY As if it were the primary disorder, but As if it were the primary disorder, but

modify explanation and approach.modify explanation and approach. Core disorderCore disorder

Depending upon severity. Mostly Depending upon severity. Mostly behavioural/social/education/advice, behavioural/social/education/advice, occasional pharmacological occasional pharmacological (risperidone, and/or SSRIs).(risperidone, and/or SSRIs).

Obsessionality/Repetitive Obsessionality/Repetitive BehaviourBehaviour

Familial aggregation of OCD in Familial aggregation of OCD in ASD ASD

Motor tics, obsessive-compulsive (OCD) and affective Motor tics, obsessive-compulsive (OCD) and affective disorders significantly more common in relatives of disorders significantly more common in relatives of autistic probands.autistic probands.

Individuals with OCD more likely to exhibit autistic-Individuals with OCD more likely to exhibit autistic-like social and communication impairments. like social and communication impairments.

OCD may index an underlying liability to autism.OCD may index an underlying liability to autism.

Bolton PF et al Psychol Med. 1998 Mar;28(2):385-95.Bolton PF et al Psychol Med. 1998 Mar;28(2):385-95.

Micali N, Chakrabati S, Fombonne E. Autism. 2004 Mar;8(1):21-37.Micali N, Chakrabati S, Fombonne E. Autism. 2004 Mar;8(1):21-37.

Summary 1.Summary 1.

OCD is probably part of the genetic OCD is probably part of the genetic landscape for ASD.landscape for ASD.

BUT.BUT.Are the obsessional/repetitive behaviours Are the obsessional/repetitive behaviours

in ASD similar or different to OCD ?in ASD similar or different to OCD ?How common is OCD – and other How common is OCD – and other

symptoms ?.symptoms ?.

OCD vs Autism.OCD vs Autism.McDougle et al; Am. J. Psych. 1995McDougle et al; Am. J. Psych. 1995

OCDOCDAggressionAggression

SexSex

ReligionReligion

ContaminationContamination

SymmetrySymmetry

SomaticSomatic

AutismAutism

HoardingHoarding

Need to Need to knowknow

ObsessionsObsessions

OCDOCD

CleaningCleaningChecking Checking CountingCounting

AutismAutism

RepeatRepeatOrderOrderHoardHoardTouchTouchSelf damageSelf damage

Behaviours

Baron-Cohen & WheelwrightBaron-Cohen & WheelwrightBr. J. Psych. 1999Br. J. Psych. 1999

Folk PhysicsFolk Physics

Numerical informationNumerical information

DatesDates

TimetablesTimetables

DiariesDiaries

MathsMaths

Measuring & countingMeasuring & counting

High prevalence of obsessions and compulsions in Asperger’s High prevalence of obsessions and compulsions in Asperger’s

syndrome (Russell et al, Br J Psychiatry, 2005,186:525-8syndrome (Russell et al, Br J Psychiatry, 2005,186:525-8 ))

  

ASD Group (n=35)

 

OCD Group(n=38)

2

(df=1)p

Obsessions:        

Aggressive 17 (48.6) 22 (57.9) .636 ns

Contamination 21 (60) 25 (65.8) .262 ns

Sexual 10 (28.6) 11 (28.9) .001 ns

Hoarding 14 (40) 20 (52.6) 1.16 ns

Religious 10 (28.6) 10 (26.3) .047 ns

Symmetry 18 (51.4) 24 (63.2) 1.02 ns

Somatic 6 (17.1) 19 (50.0) 8.73 p=.003

Compulsions:        

Cleaning 20 (57.1) 25 (65.8) .576 ns

Checking 22 (62.9) 31 (81.6) 3.21 ns

Repeating 14 (40) 25 (65.8) 4.87 p=.024

Counting 3 (8.65) 9 (23.7) 3.02 ns

Arranging 8 (22.9) 14 (36.8) 1.69 ns

Hoarding 11 (31.4) 17 (44.7) 1.36 ns

Interference/Distress

38% at least 1-3 hours/day

56% at least moderate levels of interference

47% at least moderate anxiety if ritual prevented

Treatment. Evidence base for Treatment. Evidence base for SSRIsSSRIs

Few treatment studies of OCD in people with Autism Few treatment studies of OCD in people with Autism Spectrum Disorders, all have focused on Spectrum Disorders, all have focused on pharmacology targeting generic symptom pharmacology targeting generic symptom ‘classes’. ‘classes’.

Several studies of pharmacological interventions Several studies of pharmacological interventions have reported that repetitive thoughts and have reported that repetitive thoughts and behaviors in individuals with ASD are significantly behaviors in individuals with ASD are significantly reduced by treatment with a variety of serotonin reduced by treatment with a variety of serotonin reuptake inhibitors (Brodkin reuptake inhibitors (Brodkin et alet al, 1997; Hollander , 1997; Hollander et al,.et al,. 2005; McDougle 2005; McDougle et alet al, 1998), and , 1998), and risperidone (McDougle risperidone (McDougle et alet al, 2000, 2005), 2000, 2005)

Evidence base for CBTEvidence base for CBTSingle-case reports.

A child with Asperger Syndrome (Reaven and Hepburn, 2003).A child with Asperger Syndrome (Reaven and Hepburn, 2003).An adult with autism (Lindley An adult with autism (Lindley et al, et al, 1977). 1977).

RCTs

Nil specifically of OCD in ASD. Nil specifically of OCD in ASD.

However…….CBT intervention for anxiety disorders in children However…….CBT intervention for anxiety disorders in children with Asperger Syndrome which included young people with with Asperger Syndrome which included young people with OCD (Sofronoff, Atwood & Hinton (2005). Pediatric OCD OCD (Sofronoff, Atwood & Hinton (2005). Pediatric OCD cases in this study who were in the wait list control group cases in this study who were in the wait list control group did not improve on parental ratings; whereas those who did not improve on parental ratings; whereas those who received CBT did.received CBT did.

Preliminary results of CBT pilot study.Preliminary results of CBT pilot study.Proportions of improved/unimproved patients (>25% drop on Proportions of improved/unimproved patients (>25% drop on

the YBOCS) in the CBT (n=12) and no-treatment (n=7) groupsthe YBOCS) in the CBT (n=12) and no-treatment (n=7) groups..

0

20

40

60

80

100

Perc

entag

e

CBT (n=12) No-treatment (n=7)

Improved

Unimproved

Individual responsesIndividual responsesFigure 1: Plot of individual values of YBOCS total severity scores pre

and post treatment

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5

10

15

20

25

30

35

40

Time 1 Time 2

No CBT

CBT

OCD in ASDOCD in ASD

More common than we thought.More common than we thought.

Preliminary evidence for CBT, and SSRIs Preliminary evidence for CBT, and SSRIs as effective.as effective.

Why the increase in OCD/obsessional Why the increase in OCD/obsessional symptoms ?symptoms ?

Simplistic overview of theories for Simplistic overview of theories for obsessional symptoms/restricted obsessional symptoms/restricted

interestsinterests CognitiveCognitive

1.1. Executive Function.Executive Function.

2.2. Central coherence.Central coherence.

Anatomical/neurochemicalAnatomical/neurochemical3.3. Fronto-striatal circuits.Fronto-striatal circuits.4.4. Serotonergic systemSerotonergic system

VENTROMEDIAL CAUDATE

ORBITO –FRONTALCORTEX

MEDIAL DORSALTHALAMUS

GLOBUS PALLIDUSSUBSTANTIA NIGRA

GLOBUS PALLIDUS EXTERNA

SUBTHALAMIC NUCLEI

Fronto-striatal circuits Fronto-striatal circuits Implicated in OCDImplicated in OCD

McAlonan et al; 1) Brain, 2002, Vol 127, 1594-1606, and 2) Brain. 2005 Feb;128(Pt 2):268-76

Gray Matter

So…….pretty straightforwardSo…….pretty straightforward

Abnormalities in the function and Abnormalities in the function and anatomy of fronto-striatal circuits may anatomy of fronto-striatal circuits may help explain OCD in ASDhelp explain OCD in ASD

I Wish !I Wish !

1.1. Different parts of the circuit have Different parts of the circuit have different, and multiple, functions.different, and multiple, functions.

2.2. We also need to know HOW these We also need to know HOW these differences arise.differences arise.

3.3. We also need to understand the We also need to understand the neurochemistry.neurochemistry.

McAlonan et al; 1) Brain, 2002, Vol 127, 1594-1606, and 2) Brain. 2005 Feb;128(Pt 2):268-76

Gray Matter

Putamen vs caudate and Putamen vs caudate and repetitive behaviour in ASD repetitive behaviour in ASD

0.550.500.450.400.350.300.25

W_rput

15.00

12.50

10.00

7.50

5.00

2.50

0.00

Rep

etit

ive

beh

avio

rs o

n A

DI-

R

R Sq Linear = 0.09

6.004.00

right caudate

15.00

12.50

10.00

7.50

5.00

2.50

0.00R

epet

itiv

e b

ehav

iors

on

AD

I-R

R Sq Linear = 0.064

Magnetic Resonance Magnetic Resonance SpectroscopySpectroscopy

a)

b)

Medial prefrontal voxel Parietal voxel

Prefrontalmetabolite concentration mM

6

7

8

9

10

11

12

Cr+PCr

10

11

12

13

14

15

NAA

1

2

3

4

Cho

Parietalmetabolite concentration mM

10

11

12

13

14

15

NAA

6

7

8

9

10

11

12

Cr+PCr

1

2

3

4

Cho

autisticdisorder

controls

autisticdisorder

controls

autisticdisorder

controls

autisticdisorder

controls

autisticdisorder

controls

autisticdisorder

controls

Murphy et al;Arch Gen Psych2002.

a) b)

Prefrontal Cr+PCr concentration (mM)

1413121110987

Com

mun

icati

on

defi

cits

(A

DI-

C)

25

20

15

10

5

0

Prefrontal NAA concentration (mM)

161514131211

Ob

sess

ionalit

y (

Y-B

OC

S s

core

)

30

20

10

0

White Matter Association White Matter Association TractsTracts

Superior CP

P < 0.003

Inferior CPMiddle CP (commissural fibres)

Middle CP (cortical afferents)

Short Cerebellar Fibres P <0.0001

VIRTUAL IN VIVO DISSECTIONS OF THE CEREBELLAR WHITE MATTER FIBRES (RIGHT HEMISPHERE)

Social Berhaviour and Social Berhaviour and ‘challenging behaviour’‘challenging behaviour’

                  

 

Implicit gender discrimination task while viewing mild (25%) and intense (100%) expressions contrasted with neutral faces and a baseline condition in an erfRMI design. Individual facial stimulus presentation 2s, ISI 3 – 8s with average interval 4.9s, with fixation cross shown in the ISI

0 vs 25 vs 100% Emotion (disgust)

Controls Asperger Subjects

Magnetic Resonance Magnetic Resonance SpectroscopySpectroscopy

Amygdala-Hippocampal Amygdala-Hippocampal complexcomplex

NAA – Kids vs adultsNAA – Kids vs adults

4.4

4.6

4.8

5

5.2

5.4

5.6

NC ASP

Kids Adults

***

NS

Preliminary data. Replication required.

So what is causing neuronal So what is causing neuronal death to be different ?death to be different ?

Is it Glutamate ? Is it Glutamate ?

Hippo_Glu/Gln

PATIENT_

2.22.01.81.61.41.21.0.8

HIP

PO

_GL

18

16

14

12

10

8

Page et al. Am J Psychiatry. Jan 2007

Genetic variation in the serotonin Genetic variation in the serotonin transporter modulates system-wide transporter modulates system-wide

activation to emotionactivation to emotion

ll sl ssSubgroup

-0.05

0.00

0.05

0.10

0.15

0.20

BO

LD

% c

han

ge:

Mea

n +

/- 2

SE

VLPFC

IOG

MACC

Legend; VLPFC = Ventrolateral Prefrontal Cortex: IOG = Inferior Occipital

Gyrus: MACC = Dorsal/Middle Anterior Cingulate Cortex.

short allele of a polymorphism in the promoter region of the serotonin transporter gene, SLC6A4

5-HT 2 A receptor binding in 5-HT 2 A receptor binding in ASD.ASD.

1.0000 2.0000

cont=1 asp=2

0.0000

0.5000

1.0000

1.5000

2.0000

Me

an

cing_01

f_cor_01_l

f_cor_01_r

m_temp_cor_01_l

m_temp_cor_01_r

occ_cor_01

par_cor_01_l

par_cor_01_r

sup_temp_cor_01_l

sup_temp_cor_01_r

Murphy et al, Am J Psychiatry, 2005Murphy et al, Am J Psychiatry, 2005

Take Home Message(s)Take Home Message(s)1.1. Most people with ASD do not need a psychiatrist.Most people with ASD do not need a psychiatrist.2.2. But, many young adults with ASD do have significant co-But, many young adults with ASD do have significant co-

morbidity in mental health. That needs to be treated.morbidity in mental health. That needs to be treated.3.3. The (RCT) evidence base for treatments The (RCT) evidence base for treatments specificallyspecifically in in

young adults is missing.young adults is missing.4.4. Avoid the use of antipsychotics for ‘challenging behaviour’ Avoid the use of antipsychotics for ‘challenging behaviour’

if at all possible.if at all possible.5.5. In the meantime, use clinical common sense and treat co-In the meantime, use clinical common sense and treat co-

morbidity as in any other person, but take ASD into morbidity as in any other person, but take ASD into account.account.

6.6. ASD has life-long consequences. You need close working ASD has life-long consequences. You need close working with colleagues in CAMHS and other services. with colleagues in CAMHS and other services.

7.7. There is Increasing understanding of the neurobiology.There is Increasing understanding of the neurobiology.8.8. Glutamate/Glutamine and 5-HT may be especially Glutamate/Glutamine and 5-HT may be especially

implicated.implicated.

MRC MRC UK Autism Imaging Multicentre UK Autism Imaging Multicentre

StudyStudy(MRC: UK AIMS PROGRAM)(MRC: UK AIMS PROGRAM)

IOP

CAMBRIDGE

OXFORD