cochrane review: selective serotonin reuptake inhibitors (ssris) for depressive disorders in...

Selective serotonin reuptake inhibitors (SSRIs) for autism

spectrum disorders (ASD) (Review)

Williams K Wheeler DM Silove N Hazell P

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010 Issue 9

httpwwwthecochranelibrarycom

Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) (Review)

Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

6RESULTS

Figure 1 8

15DISCUSSION

16AUTHORSrsquo CONCLUSIONS

16ACKNOWLEDGEMENTS

17REFERENCES

19CHARACTERISTICS OF STUDIES

26DATA AND ANALYSES

26APPENDICES

31WHATrsquoS NEW

31HISTORY

32CONTRIBUTIONS OF AUTHORS

32DECLARATIONS OF INTEREST

32SOURCES OF SUPPORT

32DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iSelective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) (Review)


[Intervention Review]

Selective serotonin reuptake inhibitors (SSRIs) for autismspectrum disorders (ASD)

Katrina Williams1 Danielle M Wheeler2 Natalie Silove3 Philip Hazell4

1School of Womenrsquos and Childrenrsquos Health University of New South Wales amp Sydney Childrenrsquos Hospital Sydney Australia 2co

Cochrane Developmental Psychosocial and Learning Problems Group Belfast UK 3Child Development Unit The Childrenrsquos Hospital

at Westmead Westmead Australia 4Department of Psychiatry Concord Clinical School Sydney Medical School Sydney Australia

Contact address Katrina Williams School of Womenrsquos and Childrenrsquos Health University of New South Wales amp Sydney Chil-

drenrsquos Hospital Sydney Childrenrsquos Community Health Centre Cnr Avoc amp Barker Street Randwick Sydney NSW 2031 Australia

KatrinaWilliamsSESIAHSHEALTHNSWGOVAU

Editorial group Cochrane Developmental Psychosocial and Learning Problems Group

Publication status and date Edited (no change to conclusions) published in Issue 9 2010

Review content assessed as up-to-date 30 May 2010

Citation Williams K Wheeler DM Silove N Hazell P Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders

(ASD) Cochrane Database of Systematic Reviews 2010 Issue 8 Art No CD004677 DOI 10100214651858CD004677pub2


A B S T R A C T

Background

Autism spectrum disorders (ASD) are characterised by abnormalities in social interaction and communication skills as well as stereotypic

behaviours and restricted activities and interests Selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of co-

morbidity associated with ASD such as depression anxiety and obsessive-compulsive behaviours

Objectives

To determine if treatment with an SSRI

1 improves the core features of autism (social interaction communication and behavioural problems)

2 improves other non-core aspects of behaviour or function such as self-injurious behaviour

3 improves the quality of life of children and their carers

4 has short and long term effects on outcome

5 causes harms

Search strategy

We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2009 Issue 4) MEDLINE ( December 2009)

EMBASE (December 2009) CINAHL (December 2009) PsycINFO (December 2009) and ERIC (December 2009) without language

restrictions

Selection criteria

Randomised controlled trials (RCTs) of any dose of oral SSRI compared with placebo in participants with autism spectrum disorders

Trials must have included at least one standardised outcome measure

1Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) (Review)


Data collection and analysis

Two authors independently selected and appraised studies for inclusion and risk of bias All data were continuous Meta-analysis where

possible used a random-effects model

Main results

Seven RCTs with a total of 271 participants were included Four SSRIs were evaluated fluoxetine (two studies) fluvoxamine (two

studies) fenfluramine (two studies) and citalopram (one study) Five studies included only children and two studies included only adults

Varying inclusion criteria were used with regard to diagnostic criteria and intelligence of participants Seventeen different outcome

measures were reported Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive

behaviour (OCB) different tool types or components of these outcomes were used in each study As such data were unsuitable for

meta-analysis One large high quality study in children showed no evidence of positive effect of citalopram Two small studies in adults

showed positive outcomes for CGI and OCB one study showed improvements in aggression and another in anxiety

Authorsrsquo conclusions

There is no evidence of effect of SSRIs in children and emerging evidence of harm There is limited evidence of the effectiveness of

SSRIs in adults from small studies in which risk of bias is unclear

P L A I N L A N G U A G E S U M M A R Y

Selective serotonin reuptake inhibitors for the treatment of autism spectrum disorders

Autism spectrum disorders (ASD) are characterised by problems with social interaction and communication as well as repetitive

behaviours and limited activities and interests Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants which are

sometimes given to help anxiety or obsessive compulsive behaviours We found seven trials which evaluated four SSRIs fluoxetine

fluvoxamine fenfluramine and citalopram Five studies included only children and two studies included only adults One trial enrolled

149 children but all other trials were small We found no trials which evaluated sertraline paroxetine or escitalopram There is no

evidence to support the use of SSRIs to treat autism in children There is limited evidence which is not yet sufficiently robust to

suggest effectiveness of SSRIs in adults with autism Treatment with an SSRI may cause side effects Decisions about the use of SSRIs

for established clinical indications that may co-occur with autism such as obsessive compulsive disorder and depression in adults or

children and anxiety in adults should be made on a case by case basis

B A C K G R O U N D

Description of the condition

Autism spectrum disorders (ASD) are characterised by qualita-

tive impairment in social interaction and communication skills as

well as stereotypic behaviours and limited activities and interests

While ASD is a commonly used term in clinical practice it is not

recognised by current mainstream disease classification systems

such as the Diagnostic and Statistical Manual of Mental Disorders

fourth edition or fourth edition text revision (DSM-IV DSM-

IV-TR) (APA 1994 APA 2000) and International Classification

of Diseases (ICD-10) (WHO 1993) ASD is generally considered

to include autism defined in Diagnostic and Statistical Manual

of Mental Disorders third edition (DSM-III) (APA 1980) as In-

fantile Autism and the third edition revised (DSM-IIIR) (APA

1987) and DSM-IV (APA 1994) as Autistic Disorder and in ICD-

10 (WHO 1993) as Classical Autism Also included in the term

ASD are the diagnoses Pervasive Developmental Disorder - Not

Otherwise Specified (PDD-NOS) rsquoother pervasive developmen-

tal disordersrsquo rsquopervasive developmental disorder unspecifiedrsquo As-

perger syndrome or Asperger disorder and atypical autism

Estimates of the prevalence of autism using the DSM-III DSM-

IIIR DSM-IV or ICD-10 diagnostic classification systems from

published literature up to April 2004 vary between 1 and 40 per

10000 and for any ASD between 3 and 82 per 10000 (Williams

2006) Publications from 2006 have estimated the prevalence of

any ASD between 22 and 116 per 10000 (Baird 2006 Fombonne



2006 Gillberg 2006 Guillem 2006 Williams 2008) however

lower rates have also been reported (Atladottir 2007 Chen 2007)

Males are affected about four times more frequently than females

Problems usually present in early childhood and continue through-

out life Autism places a considerable burden of care on the family

and society Follow-up studies have found that only 3-10 of peo-

ple with autism are able to live independently as adults (Billstedt

2005 Howlin 2004)

Description of the intervention

Therapies for autism spectrum disorders (ASD)

The heterogeneous nature of problems seen within the autism

spectrum means that it is often difficult to be sure which indi-

viduals will benefit from the many available therapies It is also

likely that different timing of therapy in relation to age and onset

of problems will change outcomes Many therapies are invasive

time consuming andor expensive and little is known about their

potential to cause harm Pharmacological treatments have been

used most commonly as adjuncts to behavioural intervention to

target specific symptoms and behaviours These treatments have

been associated with reductions in sleep disturbance mood dis-

order poor attentionconcentration and self-harm or aggression

towards others (Gringras 2000)

Selective serotonin reuptake inhibitors (SSRIs)

Antidepressants (most of which are likely to be SSRIs) are the

most commonly prescribed psychotropic medications for ASD

and the class of medication for which there has been the greatest

increase in prescribing (Aman 2005) The prescribing of SSRI

drugs to children and adolescents for any indication has however

been curtailed since the Committee on Safety in Medicines (UK)

and the Food and Drugs Administration (USA) released safety

warnings in 2003 and 2004 respectively concerning an increased

risk of suicide-related behaviours associated with these medications

(Murray 2005 Nemeroff 2007)

How the intervention might work

Increased rates of platelet serotonin transport and levels of whole

blood and platelet serotonin (5-hydroxytryptamine 5-HT) have

been reported in people with ASD (Cook 1996) Serotonin is

linked to the mediation of several psychological processes many

of which are altered in ASD including mood social interaction

sleep obsessive compulsive behaviours and aggression (Saxena

1995) It is therefore plausible that inhibition of serotonin reup-

take will result in improvement of ASD symptoms

Why it is important to do this review

Several studies have reported improvements following adminis-

tration of SSRIs However the subject numbers are small espe-

cially for paediatric patients and serious side effects including in-

creases in maladaptive behaviours urinary retention and seizures

are reported (Branford 1998) A recent larger study of children has

shown no improvement (King 2009) To our knowledge no drug

authority has specifically approved the use of SSRIs for autism

The prescribing of SSRIs for autism is therefore either rsquooff-labelrsquo

or is directed to an associated indicated disorder such as obsessive

compulsive disorder (OCD) or depression

Regarding indications and prescribing for children there are be-

tween-country variations The FDA has approved (allowed the

marketing of ) sertraline in children six years and older fluoxetine

in children seven years and older and fluvoxamine in children

eight years and older for the treatment of OCD The FDA has

approved fluoxetine in children eight years and older and escitalo-

pram in adolescents 12 to 17 years for the treatment of depression

In the UK the Commission on Human Medicines (formerly the

Committee on Safety of Medicines) contraindicates all antidepres-

sants other than fluoxetine for the treatment of depression in chil-

dren and adolescents In Australia fluvoxamine has been given a

specific indication of OCD in children eight years and over while

prescribers are urged to exercise caution in prescribing other SSRIs

for children under the age of 18 years

A systematic review of SSRIs is required to assess the evidence of

efficacy and harms when used to treat ASD

O B J E C T I V E S

To determine if treatment with SSRIs

1 improves the core features of ASD (social interaction commu-

nication and behavioural problems)

2 improves other non-core aspects of behaviour or function such

as self-injurious behaviour

3 improves the quality of life of adults or children and their carers


5 causes harms

M E T H O D S

Criteria for considering studies for this review

Types of studies



Trials were eligible for inclusion in the review if the assignment of

study participants to intervention or control group was random

Types of participants

Inclusion was limited to individuals with a diagnosis of an ASD de-

fined using DSM-IV or ICD-10 or equivalent as a Pervasive Devel-

opmental Disorder excluding Rett syndrome and Childhood Dis-

integrative Disorder Diagnosis must have been made using a stan-

dardised diagnostic instrument (Childhood Autism Rating Scale

(CARS) Autism Diagnostic Interview-Revised (ADI-R) Autism

Diagnostic Observation Schedule (ADOS) Diagnostic Interview

for Social and Communication Disorders (DISCO)) or by using

established diagnostic criteria (ICD-10 DSM-IV) No age limits

were applied

Types of interventions

Oral SSRIs regardless of dosage used or frequency of administra-

tion The control group must be a placebo group

Types of outcome measures

Types of outcomes

1 Core features of ASD ie social interaction

communication and behavioural problems including stereotypy

or restricted repetitive patterns of behaviour interests or

activities

2 Non-core aspects of behaviour and function such as sleep

disturbance self-mutilation aggression attention and

concentration problems and gastrointestinal function

3 Global assessment of health and function

4 Quality of life for the individual or their family

5 Adverse events

No outcome has been identified as primary because there is insuf-

ficient information at present to prioritise these outcomes We in-

tended to examine short (up to 3 months) medium (3-12 months)

and long term (greater than 12 months) outcomes if data were

available

Types of measures

1 Standardised diagnostic assessment instruments (CARS

ADI-R ADOS DISCO)

2 Standardised communication assessments

3 Quality of life questionnaires

4 Rating scales of emotions and behaviour including

depression anxiety aggression obsessive compulsive behaviour

5 Global impression rating scales

6 Other health outcome rating scales

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Tri-

als (CENTRAL) (The Cochrane Library issue 4 2009) and the

following biomedical science databases MEDLINE (December

2009) EMBASE (2009 Week 49) CINAHL (December 2009)

and PsycINFO (December 2009) We also searched the social sci-

ence and education databases Sociological Abstracts (December

2009) and ERIC (December 2009)

Search terms were modified to meet the requirements of indi-

vidual databases The optimally sensitive search strategy for ran-

domised controlled trials developed for the Cochrane Collabora-

tion (Clarke 2003) was combined with medical subject headings

and text words specific for autism and pervasive development dis-

orders as developed by the Cochrane Developmental Psychoso-

cial and Learning Problems Group Search terms were modified

to meet the requirements of individual databases regarding differ-

ences in fields and syntax The aim of the search strategy was for

high precision and recall There were no language restrictions

See Appendix 1 to Appendix 7 for details of search terms for each

database

Searching other resources

We also searched bibliographies of articles identified through the

search strategy and contacted known experts in the field


Selection of studies

Titles and abstracts from the searches were screened by two au-

thors in 2004 2006 and 2008 (DW KW) and December 2009

(KW NS) Disagreement was resolved by consensus and articles

that did not fulfil the inclusion criteria were discarded Potentially

relevant articles were retrieved for full-text assessment and data

extraction

Data extraction and management

Data were organised using Review Manager Data extraction forms

were developed a priori and included information regarding meth-

ods participant details dose and frequency of SSRI administra-

tion and outcomes Data were extracted by two independent re-

viewers (KW and DW or NS) No disagreements arose



Assessment of risk of bias in included studies

Two authors (KW and NS or DW) independently assessed each

included study using the risk of bias criteria outlined in chapter

8 of the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2008) without blinding to authorship or source The

assessments were compared for inconsistencies and differences in

interpretation were resolved by discussion and consensus Risk of

bias was assessed according to the following five domains with rat-

ings of rsquoYesrsquo (low risk of bias) rsquoNorsquo (high risk of bias) and rsquoUnclearrsquo

(uncertain risk of bias)

1 Sequence generation

Was the allocation sequence adequately generated

ldquoYesrdquo (computer generated random numbers table of random

numbers coin-tossing or similar) ldquoNordquo (day of week evenodd

clinic record number clinician judgment participant preference

laboratory test result such as haemoglobin value or similar) or

ldquoUnclearrdquo (insufficient information about the sequence generation

process to permit judgment)

2 Allocation concealment

Was allocation adequately concealed

ldquoYesrdquo (central independent unit sequentially numbered drug con-

tainers or sealed envelopes of identical appearance or similar)

ldquoNordquo (alternation or rotation date of birth non-opaque envelopes

open table of random numbers or similar) or ldquoUnclearrdquo (randomi-

sation stated but no information on method used is available)

3 Blinding

Was knowledge of the allocated intervention adequately prevented

during the study

ldquoYesrdquo (identical placebo medication or similar) ldquoNordquo (tablets ver-

sus liquid or similar) or ldquoUnclearrdquo (blinding stated but no infor-

mation on method used is available)

4 Incomplete outcome data

Were incomplete data dealt with adequately by the researchers

ldquoYesrdquo (no missing outcome data missing outcome data balanced

in numbers across intervention groups and reasons for dropouts

and withdrawals described or similar) ldquoNordquo (reason for missing

outcome data likely to be related to true outcome or similar) or

ldquoUnclearrdquo (number or reasons for dropouts and withdrawals not

described)

5 Selective outcome reporting

Are reports of the study free of suggestion of selective outcome

reporting

ldquoYesrdquo (study protocol is available published reports include all ex-

pected outcomes or similar) ldquoNordquo (not all of the studyrsquos pre-spec-

ified primary outcomes have been reported one or more reported

primary outcomes were not pre-specified or similar) or ldquoUnclearrdquo

(insufficient information to permit judgement of rsquoadequatersquo or rsquoin-

adequatersquo)

Any other potential sources of bias such as stopping the study

early or extreme baseline imbalance were also explored

Measures of treatment effect

Binary data

If two or more studies presented outcomes from either standard-

ised instruments or diagnostic evaluations as proportions the rela-

tive risk and risk difference with 95 confidence intervals would

have been calculated from meta-analysis Number needed to treat

would also have been calculated where appropriate However only

one study presented categorical outcomes

Continuous data

Where standardised assessment tools generated a score as the out-

come measure comparisons were made between the means of

these scores We calculated mean difference (MD) where possible

and calculated standard error (SE) using data available from the

same study or imputed it from another study in the same meta-

analysis as described in Chapters 7 9 and 16 of the CochraneHandbook for Systematic Reviews of Interventions (Higgins 2008)

Where studies did not use sufficiently similar instruments to mea-

sure an outcome we conducted meta-analysis using standardised

mean difference

Unit of analysis issues

No unit of analysis errors were identified In all included studies

randomisation reporting and analysis were per individual partic-

ipant

Dealing with missing data

Where possible missing data and dropouts were assessed for each

included study and reported Reasons for missing data were pro-

vided when reported in trials Where insufficient data were re-

ported we contacted the trial authors for further information No

replies were received Where data could not be included in meta-

analysis we have included a summary in the text of the review

Assessment of heterogeneity

Consistency of results was assessed visually and by examining I2 (Higgins 2002) a quantity which describes approximately the

proportion of variation in point estimates that is due to hetero-

geneity rather than sampling error

Assessment of reporting biases

Insufficient studies were found to allow for the use of funnel plots

to investigate any relationship between effect size and study pre-

cision (closely related to sample size)



Data synthesis

Where possible when two or more studies were found that were

suitable for inclusion we planned to perform a meta-analysis on

the results using a random-effects model

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was not possible because of a lack of data for

meta-analysis Anticipated clinical differences included

- age of participants adult versus paediatric preschool versus

school age

- diagnostic classification

- dose of medication

Sensitivity analysis

Sensitivity analysis was planned to assess the impact of risk of bias

on the results of meta-analyses However we could not conduct

this analysis because there were too few data available for meta-

analysis for the same drug therapy age group and clinical outcome

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies

Seven studies are included in the review Five of the studies were

carried out in the USA 1 in France and 1 in Japan Participants

were children in five of the studies and adults in the other two

Results of the search

Electronic literature searches were conducted in December 2004

and yielded 46 titles Thirty-eight studies were excluded because

they were not randomised controlled trials (RCTs) or were not

about ASD Following full paper review four RCTs were identi-

fied The search was repeated in September 2006 and two further

trials were identified The search was repeated in December 2008

No new trials were found The search was repeated in December

2009 and one new trial was found Thus a total of seven RCTs

with 271 participants were included in this review

Of note fenfluramine was not searched for directly and is not

registered for use as an antidepressant but was identified as an

SSRI in electronic searches We debated its inclusion and chose

to retain the two trials to provide a complete clinical picture The

tricyclic antidepressant clomipramine was also identified using this

search method and is known to have serotonin uptake inhibitor

actions but was excluded because unlike fenfluramine it will be

included in a systematic review of tricyclic antidepressants and

ASD (currently in progress)

Different versions of assessment tools were used to measure sim-

ilar outcomes For example for CGI the Clinical Global Im-

pression - Severity scale (CGI-S) the Clinical Global Impression

- Improvement scale (CGI-I) and the Clinical Global Improve-

ment Scale Adapted to Global Autism (CGI-AD) were used and

sometimes the tool used was uncertain (CGI) (Guy 1976) Simi-

larly to measure Obsessive Compulsive Behaviour the Childrenrsquos

Yale-Brown Obsessive Compulsive Scales modified for pervasive

developmental disorders (CY-BOCS-PDD) (Scahill 2006) the

Childrenrsquos Yale-Brown Obsessive Compulsive scale (CY-BOCS)

(McKay 2003) and the Yale-Brown Obsessive-Compulsion Scale

(Goodman 1989Goodman 1989b) and a modified version of it

were used

Included studies

Five studies were conducted in children aged 3-17 years us-

ing fenfluramine (Barthelemy 1989 Leventhal 1993) fluoxe-

tine (Hollander 2005) fluvoxamine (Sugie 2005) and citalopram

(King 2009) Two studies were conducted in adults aged 18-

53 years using fluoxetine (Buchsbaum 2001) and fluvoxamine

(McDougle 1996)

Of the five trials in children two used DSM-IV-TR diagnoses of

Autistic Disorder Asperger Disorder or PDD-NOS (Hollander

2005 King 2009) One study (King 2009) also required at least

moderate severity on the CGI illness severity scale and a moderate

or greater score for compulsive behaviour items of the Childrenrsquos


developmental disorders (CY-BOCS-PDD) Both of these studies

included children with intelligence in the normal range with one

having an IQ range of 30-132 (Hollander 2005) and the other

reporting 61 of children with a non-verbal IQ over 70 (King

2009) One study included children ldquodiagnosed with autismrdquo using

DSM-IV but did not specify how criteria were applied or provide

information about intelligence (Sugie 2005) Two studies used

DSM-III criteria for a diagnosis of autism and included children

with intellectual impairment with IQ ranges of 16-63 (Leventhal

1993) and 30-75 (Barthelemy 1989)

Of the two adult studies one (Buchsbaum 2001) included adults

diagnosed using DSM-IV with autism or Asperger Disorders and

all patients were verbal with an IQ score range of 53 to 119

The other study included adults diagnosed with autism using the

DSM-III-R and ICD-10 criteria and individuals included were at

least ldquomoderaterdquo in severity using the CGI global severity of illness

rating Both intellectually able and disabled adults were included

(McDougle 1996)

One study (Leventhal 1993) included participants who had pre-

viously been treated with an SSRI Trial authors participated in a

multicentre non-randomised trial of 30 weeks duration and then

extended this trial with a 32 week cross-over RCT Thus there was



potential for carry-over effects from initial treatment which could

result in an underestimate of treatment effect

Treatment duration ranged from five to twelve weeks (see

Characteristics of included studies table) One study (Barthelemy

1989) used a shortened placebo period where participants re-

ceived placebo for only one month and active treatment for three

months The trial authors adopted this method because of parent

concerns with a lengthy non-treatment phase In all studies fol-

low-up was short term (12 weeks or less)

Excluded studies

Seven studies were excluded after full paper review Two studies

(Gordon 1993 Remington 2001) were trials of clomipramine a

tricyclic antidepressant which has SSRI characteristics but is not

classed as such Four studies were not randomised controlled trials

(Doyle 2001 McDougle 1996 Peral 1999 Sanchez 1996) One

of these studies (Doyle 2001) was a cost analysis of a treatment

not classed as an SSRI A further study did not use participants

with ASD (Humble 2001)

Risk of bias in included studies

Study design

Two studies used a parallel design (King 2009 McDougle

1996) Four studies used a cross-over design (Barthelemy 1989

Buchsbaum 2001Hollander 2005Sugie 2005) No data were

available prior to the second phase One study had two treatment

phases four weeks placebo 16 weeks fenfluramine eight weeks

placebo followed by randomisation of 15 children to a cross-over

phase (Leventhal 1993) One study of fluoxetine observed a wash-

out period of four weeks (Hollander 2005) and another study of

fluvoxamine for two weeks (Sugie 2005) Different SSRIs have

different recommended wash-out periods ranging from 15 hours

(fluvoxamine) to 7-9 days (fluoxetine) Of the five studies that

reported using crossover methods for at least part of the study no

data was extracted from one (Sugie 2005) two studies used paired

t test analyses (Buchsbaum 2001 Leventhal 1993) and one also

used ANOVA analyses (Leventhal 1993) Two studies reported

comparative analyses using ANOVA (Hollander 2005 Barthelemy

1989) and one of these also used mixed regression models for com-

parative analyses (Barthelemy 1989) Figure 1 provides a summary

of the risk of bias of included studies



Figure 1 Risk of bias summary review authorsrsquo judgements about each risk of bias item for each included

study



Sequence generation

Sequence generation was adequate in two studies (King 2009

Sugie 2005 ) and unclear in the remaining five

Allocation

Allocation concealment was adequate in two studies (King 2009

Sugie 2005) Adequacy of allocation concealment was unclear in

five studies (Barthelemy 1989 Buchsbaum 2001 Hollander 2005

Leventhal 1993 McDougle 1996) No further unpublished infor-

mation about allocation concealment was forthcoming from trial

authors

Blinding

Outcome assessors were reported as being blind to treatment al-

location in three studies (Hollander 2005 King 2009 McDougle

1996) In the remaining four studies it was not possible to ascertain

if outcome assessors were blinded Of these four studies two stud-

ies stated that participants and treating physicians were blinded but

did not report blinding of outcome assessors (Barthelemy 1989

Buchsbaum 2001) and two studies used the term ldquodouble blindrdquo

to refer to all blinding (Leventhal 1993 Sugie 2005) Given that

the outcome measures used rely on subjective observation and as-

sessment there is potential for bias where outcome assessors were

not adequately blinded to treatment allocation

Incomplete outcome data

Three studies reported no loss to follow-up (Barthelemy 1989

Buchsbaum 2001 McDougle 1996 ) One study (King 2009)

reported that 13 of 76 withdrew from the placebo arm and 13

of 73 withdrew from the treatment arm of the trial Reasons for

withdrawal included adverse events (one serious in the treatment

group) protocol violation and consent withdrawal One study

(Leventhal 1993) reported one withdrawal prior to the randomised

phase and reported no data from this participant One study (Sugie

2005) excluded one participant due to non-compliance One study

(Hollander 2005) reported that of 62 patients who consented

18 were excluded for non-eligibility or non-compliance and 44

were randomised Of these 39 participants were included and

completed outcome data were published three were excluded due

to non-compliance one due to lack of efficacy and one was lost

from analysis due to lost records The exclusion of a participant

due to lack of efficacy creates a risk of bias as does exclusion of

those who were not compliant with therapy

Three studies reported not using or were assessed as not using

an intention-to-treat analysis (Hollander 2005 Leventhal 1993

Sugie 2005) Four studies reported the use of intention-to-treat

analysis or did not require any statistical adjustments as they had no

losses to follow up or changes in treatment allocation (Barthelemy

1989 Buchsbaum 2001 King 2009 McDougle 1996)

Selective reporting

The likelihood of selective reporting that is reporting only those

outcomes which showed evidence of treatment effect was lowest

for the most recent publication (King 2009) which was registered

at the commencement of the trial No other trial reported being

registered prior to commencement Five trials reported negative

outcomes (Barthelemy 1989 Buchsbaum 2001 Hollander 2005

King 2009 Leventhal 1993) one reported only positive outcomes

(McDougle 1996) and one study only reported effectiveness for

genetic subgroups (Sugie 2005) All studies reported at least one

relevant clinical outcome

Other potential sources of bias

We are unaware of any further potential sources of bias in the

included studies

Effects of interventions

Seventeen different standardised outcome measures were used in

the seven included trials (Table 1) Use of a single outcome mea-

sure by more than one study was uncommon but occurred for

the CGI and the Childrsquos Yale-Brown Obsessive Compulsive (CY-

BOCS) scales albeit using different scales and subsections of exist-

ing scales allowing meta-analysis for these two outcome measures

using standardised mean difference Results are presented below

by age (children or adults) and compound

Table 1 Outcome measures used in included trials

Outcome

measure

Barthelemy King Buchsbaum Hollander Leventhal McDougle Sugie

Core features

of autism



Table 1 Outcome measures used in included trials (Continued)

1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x

Core features (child data only)

Citalopram

In the study of citalopram in children the parent-rated Repetitive

Behavior Scale-Revised (RBS-R) (Bodfish 1999) was used and

there were no significant differences in any of the 6 subscale scores

at 12 weeks (P gt 036 for all) (King 2009)

Fenfluramine

One study (Barthelemy 1989) measured core features of autism

using the Behavior Summarized Evaluation scale (BSE) This is a

25 item scale of which 11 items deal directly with autistic symp-

toms Average scores over four successive one-week periods were

used in analysis No significant change from baseline or significant

difference between treatment and placebo groups was found No

order effect was found in the cross-over study

Fluvoxamine

One study (Sugie 2005) measured core features of autism using

the Behavior Assessment Scale (BAS) a tool designed by the in-

vestigators and provided in the text of the paper The tool is re-

ported to have a correlation with the CARS (P lt 00001) How-

ever the primary focus of the paper is the correlation between

genetic polymorphisms and response to fluvoxamine BAS scores

were reported for participants based on subgroups as assessed by

their genotype and it was not possible to determine overall values

for treatment and control groups The authors report that 10 of

18 participants ldquorespondedrdquo to treatment

Three studies used measures that included some of the core features

of autism as an outcome No studies reported improvement in core

features of autism Meta-analysis of core features of autism was

not possible because of the differences in core features measured

and the tools used by the three studies

Composite measures of CGI and OCB (child data

only)

One study (King 2009) used a composite measure of the CGI im-

provement scale (CGI-I) and the CY-BOCS-PDD In this study

a CGI-I score of 1 or 2 and a 25 reduction on the CY-BOCS-

PDD were required as evidence of improvement The authors of

this study reported that the use of the composite score was a way

of ldquoincreasing the threshold for positive responserdquo Comparative

analysis showed no difference between treatment groups for the

composite score at 12 weeks (206 for citalopram versus 132

for placebo P = 028)

One study (Hollander 2005) used a composite score that included

the CGI-AD and a measure of change of repetitive behaviour

based on the CY-BOCS The authors created a composite score by

creating ldquoa change score by subtracting the pre-test CY-BOCS

from the post-test CY-BOCS Negative values on this measure

indicate a reduction in repetitive behaviors at post-test whereas

positive scores indicate an increase This raw change measure was

then added to the CGI-AD measure to augment the overall change

in autism severityrdquo Results of the mixed regression analysis in-

dicated a trend towards reduction in this global autism composite

improvement measure for subjects on fluoxetine as compared to

placebo (z = 1907 SE = 0703 P = 0056)

Composite scores used were different and were presented as cate-

gorical data in one study and continuous data in the other there-

fore meta-analysis was not possible

Clinical impression

Children

Citalopram

At 12 weeks there was no significant difference in the proportion

of CGI-I scale responders between the citalopram treated group

(329) and the placebo group (342) (relative risk 096 95

confidence interval 061 to 151 P = 099) (King 2009) Further

analysis in this study used the generalized estimating equation

method and found there was no significant difference in the rate

of improvement on the CGI-I scale between the groups (P = 094)

although both groups improved over time Since no other study



reported percentage improvement for CGI-I scale these data could

not be included in a meta-analysis

Fluoxetine

One study (Hollander 2005) used the Clinical Global Impression

Scale Global Autism Score (CGIS-GAS) There was no significant

benefit from fluoxetine treatment for this score

Fluvoxamine

One study (Sugie 2005) of fluvoxamine used the CGI scale to assess

improvements in behaviour However the results were presented

for different genotypes and it was not possible to assess the overall

outcome score for treatment and control groups

Variation instruments analysis approach and availability of data

meant that meta-analysis was not possible for this outcome for

children

Adults

Fluoxetine

One study (Buchsbaum 2001) used the CGI-GAS to measure

changes in behaviour Three of six participants showed improve-

ment Continuous outcomes were compared using paired t-tests

and reported for rsquobaselinersquo and fluoxetine with no significant

change (mean difference -100 SD 126) However it is uncertain

whether rsquobaselinersquo represents the control phase so these data were

unsuitable for inclusion in a meta-analysis

Fluvoxamine

One study (McDougle 1996) reported statistically significant im-

provements in behaviour following treatment with fluvoxamine

as assessed using the CGI scale improvement item at 4 8 and 12

weeks When presented as a proportion who had shown improve-

ment 53 of participants in the treatment arm were reported to

have improved on the CGI improvement item while no partici-

pants in the placebo arm had improved

Non core features of behaviour

Obsessive compulsive behaviour

Although stereotypy or restricted repetitive patterns of behaviour

interests or activities are core features of autism and may mani-

fest in similar ways to obsessive-compulsive behaviour obsessive

compulsive behaviour per se is not a core feature of autism and is

therefore reported here under non-core features of behaviour

Children

Citalopram (combined obsession and compulsion score only)

Using CY-BOCS-PDD (Scahill 2006) there was no significant

difference between the groups in score reduction over time from

baseline (mean (SD) minus20 (34) points for the citalopram group

and minus19 (25) points for the placebo group P = 085) (King

2009) Results for obsessions and compulsions were not reported

separately

Fluoxetine (compulsion score only)

One study (Hollander 2005) used the compulsions questions of

the CY-BOCS as their participants were aged 5-16 years and re-

ported no statistically significant difference between groups (effect

size changes were mean of -13 for phase 1 and -06 for phase 2)

Although both studies in children report no statistically significant

change on the CY-BOCS presentation of different components of

the scales (obsession and compulsion as one score or compulsion

score only) meant that available data were not suitable for meta-

analyses

Adults

Fluoxetine

This study used the full adult version of the tool reporting a sta-

tistically significant improvement in obsessions (P = 003) but not

compulsions (P = 086) and a 4 point difference favouring treat-

ment groups that was not statically significant for the overall score

(P = 006) (Buchsbaum 2001) As reported for the CGI outcome

uncertainty about whether rsquobaselinersquo represents the control phase

meant that available data were unsuitable for inclusion in a meta-

analysis

Fluvoxamine

One study of fluvoxamine (McDougle 1996) used a modified ver-

sion of the Yale-Brown Obsessive-Compulsion Scale There was

no significant difference in baseline scores between treatment and

control groups Fluvoxamine was reported to show a treatment

benefit compared with placebo (mean difference -82 95 CI -

1392 to -248) Sample size was small (N = 30) Statistically signif-

icant improvements in both obsession (P lt 002) and compulsion

(P lt 002) scores were reported at 8 weeks and also at 12 weeks

(obsession P lt 002 compulsion P lt 0001)

Both studies reported improvement in obsessions as scored us-

ing the Yale-Brown Obsessive-Compulsion Scale One study

(McDougle 1996) also reported improvement in compulsions and

the combined obsession-compulsion score



Behaviour (child data only)

Citalopram

Of the five subscales of the Aberrant Behavior Checklist-Com-

munity version only the irritability scale achieved statistical sig-

nificance (without any correction for multiple comparisons) from

baseline to week 12 and the difference in change scores was small

(227 points favouring the citalopram group)

Fenfluramine

One study (Leventhal 1993) used the Ritvo-Freeman Real Life

Rating Scale to assess possible improvements in behaviour The

complex arrangement of placebo and treatment phases including

two cross-overs made the data from this trial difficult to inter-

pret To ensure that there was no carry-over effect or learning of

responses from repeat administration of the outcome measures

outcome data from the first phase only were used Overall there

was no significant improvement in behaviour (mean fenfluramine

073 SD 011 mean placebo 080 SD 015) There was a signifi-

cant improvement reported in motor abnormalities and on parent

reports of hyperactivity (P values not reported)

Anxiety (adult data only)

Fluoxetine

One study (Buchsbaum 2001) used the Hamilton Rating Scale for

Anxiety and reported significant improvement in the treatment

group compared with the control group after eight weeks treat-

ment (mean difference 450 SD 351 P = 003) Sample size was

very small (N = 6)

Depression (adult data only)

Fluoxetine


Depression There was no significant benefit seen in the treatment

group compared with the control group (mean difference 383

SD 387 P = 006)

Aggression (adult data only)

Fluvoxamine

One study (McDougle 1996) reported using the Brown Aggression

Scale as an outcome measure Fluvoxamine was significantly better

than placebo at reducing aggression (F = 457 P lt 003)

No other non-core behaviour outcomes such as sleep or self mu-

tilation were reported

Adverse effects

Children

Citalopram

Significantly more children in the citalopram-treated group had

one or more emergent adverse events compared to placebo (973

versus 868 P = 003) with adverse events recorded at each bi-

weekly visit using the Safety Monitoring Uniform Report Form

a semi-structured review of body systems (Greenhill 2004) One

child who had not previously suffered seizures experienced a pro-

longed seizure with loss of consciousness and required emergency

hospitalization Although citalopram treatment was ceased after

withdrawal from the trial the child continued to have frequent

seizures

Fenfluramine

One study (Barthelemy 1989) reported that one week after treat-

ment at 15 mgkg the dosage had to be reduced due to adverse ef-

fects in four children There were two cases of increased withdrawal

and sadness and two cases of increased stereotypies Dosage was

increased after one month in all but one child with no recurrence

of adverse symptoms Four children experienced poor appetite in

the first two weeks of treatment and four children displayed irri-

tability in the second month Mean weight significantly decreased

in the treatment group (P lt 002) in the first month of treatment

but stabilised by the second month and returned to normal one

month post-treatment

One study (Leventhal 1993) reported similar weight loss in the

first treatment phase with resolution by the second period of fen-

fluramine administration No further assessment of adverse effects

was reported

Fluoxetine

One study (Hollander 2005) used a side effects symptom check-

list There were no significant differences recorded in frequency

or severity of adverse effects between children in the treatment

or control groups There was no significant difference between

treatment and control groups on the suicide subscale of the Overt

Aggression Scale Six of 37 subjects had their dosage reduced due

to agitation and two of 36 had a ldquodosage reductionrdquo while on

placebo



Fluvoxamine

One study (Sugie 2005) used only blood biochemistry to evaluate

adverse effects No significant differences were reported between

treatment and control groups

Three of the studies in children provided detailed reporting of ad-

verse events and one reported a serious adverse event and statisti-

cally significant differences between occurrence of adverse events

in treatment and placebo groups (King 2009)

Adults

Fluoxetine

One study (Buchsbaum 2001) did not report assessment of any

adverse effects This small study of six adults was primarily focused

on cerebral metabolism

Fluvoxamine

One study (McDougle 1996) of adult participants reported that

fluvoxamine was well tolerated Three participants in the treat-

ment group and one in the control group reported nausea Two

participants in the treatment group and one in the control group

reported moderate sedation All adverse effects were recorded in

the first two weeks of treatment There were no recorded anti-

cholinergic adverse effects no significant changes in pulse blood

pressure or electrocardiographic changes No seizures or dyskine-

sias were reported

Quality of life

No study used any standardised measure of quality of life

Long term outcomes

No study recorded outcome beyond the length of the trial du-

ration with the exception of Barthelemy 1989 who monitored

weight loss (see adverse effects)

D I S C U S S I O N

People with ASD are a heterogeneous group Studies included

in this review included children and adults covering a wide age

range diagnosed using different classification systems and assess-

ment procedures and with different severity of problems and in-

tellectual ability Despite these differences there is consistency of

findings for the studies conducted in children and for those con-

ducted in adults There is no evidence of benefit for children from

one large study of citalopram with low risk of bias and from four

smaller studies In adults only evidence from small studies with

unclear risk of bias is available to date which report significant

improvements in clinical global impression (fluvoxamine and flu-

oxetine) obsessive-compulsive behaviours (fluvoxamine) anxiety

(fluoxetine) and aggression (fluvoxamine)

This review again highlights problems with trial methods already

found in other systematic reviews of treatments for ASD (Jesner

2007 Sinha 2004 Williams 2005) Variations in the clinical pro-

file of ASD trial participants such as the age of participants their

IQ the severity of their problems and whether they have the prob-

lems that the treatment is suggested to ameliorate are likely to

lead to differences in treatment effectiveness It is not yet known

whether these factors influence the effectiveness of a treatment

under investigation independently or as inter-related factors It is

also possible that some measures are suitable for measuring change

in participants of some ages and not others or that they accurately

measure an outcome for individuals with one severity of ASD or

IQ but not for others This means that meaningful interpretation

of the variations in reported outcomes from the studies included

in this review is not straightforward

This review details the findings of seven randomised controlled

trials Two trials each evaluated the effectiveness of fluoxetine

fenfluramine and fluvoxamine and one trial looked at citalopram

In one multi-centre study the sample size was over 100 but the

next largest study recruited 39 participants Small sample sizes

increase the likelihood of type II error that is that no significant

change will be found where one exists Meta-analysis can address

this where sufficient studies use the same outcome measures but

only two meta-analyses were possible in this review

Exacerbating the above problem of small individual trial sample

size is the use of a variety of outcome measures Seventeen differ-

ent outcome measures were used in studies contributing to this

review and variations of measures generated for the same outcome

(different tool or different items from a given tool) also occurred

For this reason and because of important differences in the age of

the populations studied this review like others of treatments for

ASD (Sinha 2004 Williams 2005) found that meta-analyses were

not possible

A further concern with outcome measures is their sensitivity to

change and what magnitude of change individuals and families

would perceive as sufficient to warrant therapy Behavioural out-

comes such as sleep disturbance self-mutilation attention and

concentration problems and gastrointestinal function were not

assessed by any of the trials nor was quality of life Consumer

involvement in outcome measure selection is important to both

generate data that are meaningful to those who use them and to

facilitate practice change if clear evidence of effectiveness (or a lack

of effectiveness) is found

All studies reported outcomes until trial completion (maximum

duration 12 weeks) with the exception of weight loss which was

monitored for longer in one trial (Leventhal 1993) The lack of



medium and long-term follow-up remains a characteristic problem

of trials in ASD

Other SSRIs particularly sertraline are used in clinical practice

to treat problems associated with ASD Our review identified no

RCTs of sertraline nor RCTs of paroxetine and escitalopram

Treatment with SSRIs may cause various adverse effects One

study reported significantly more adverse events in children on

citalopram compared to placebo and one serious adverse event

a prolonged seizure (King 2009) Both studies of fenfluramine

reported adverse effects in children including withdrawal and

sadness which prompted dosage changes (Barthelemy 1989) and

weight loss (Barthelemy 1989 Leventhal 1993) With monitor-

ing dose adjustment and time all but one of these adverse effects

were resolved No significant differences were reported for side ef-

fects in children in the treatment or placebo group for fluoxetine

(Hollander 2005) and little information was available for side ef-

fects in children in the fluvoxamine study (Sugie 2005) The adult

studies (fluvoxamine and fluoxetine) both reported that treatment

was well tolerated

A U T H O R S rsquo C O N C L U S I O N SImplications for practice

There is no evidence that SSRIs are effective as a treatment for

children with autism In fact there is emerging evidence that they

are not effective and can cause harm As such SSRIs cannot be

recommended as a treatment for children with autism at this time

For adults small positive effects have been seen with fewer side

effects reported but the possible risk of bias and small sample size

of the trials make clear recommendations impossible at this time

Decisions about the use of SSRIs for established clinical indica-

tions that may co-occur with autism such as obsessive-compulsive

disorder and depression and anxiety (in the case of adults) should

be made on a case by case basis

Not all the SSRIs currently in use have been subjected to con-

trolled trials for ASD As ASD causes substantial impairment par-

ents of children with the condition are motivated to try treatments

regardless of the evidence Nevertheless it is important that pre-

scribing clinicians are explicit to parents and patients about the

limited evidence discuss the risks of treatment and discuss other

pharmacological and non-pharmacological interventions

Implications for research

The present review has highlighted the significant challenges in

researching outcomes in the pharmacological treatment of autism

However quality studies are feasible if adequately resourced as

demonstrated by the trial of citalopram reported in this review

and the trial of the unrelated compound risperidone (McCracken

2002) presented in another review (Jesner 2007)

In our opinion knowledge about the effectiveness and safety of

SSRIs for childhood autism would be best served in the first in-

stance by a replication of the citalopram study which will either

confirm or refute the absence of effect on core symptoms For

completeness an adequately powered RCT should be conducted

on at least one other SSRI We would recommend fluoxetine ow-

ing to its favourable safety profile We are aware of one such study

that reached primary study completion in 2009 (ClinicalTrialsgov

identifier NCT 00515320) and another scheduled to commence

in 2010 (Virasinghe personal communication) Sufficiently large

trials would permit the examination of subgroup differences in

responsiveness to SSRIs Comparisons of interest include pre-pu-

berty versus puberty and low IQ versus normal IQ

Knowledge about the effectiveness and safety of SSRIs for adult

autism would be best served by the conduct of at least one ad-

equately powered RCT of a commonly prescribed drug such as

fluoxetine

Comparison between trials in all age groups would be aided by

the use of a core battery of standard outcome measures As a mini-

mum we recommend a measure of global functioning (eg CGI)

a measure of repetitive and stereotyped behaviours (eg Repetitive

Behavior Scale - Revised) a measure of disruptive behaviour (eg

Aberrant Behavior Checklist) and a measure of obsessive compul-

sive symptoms (eg Yale-Brown Obsessive Compulsive Scale)

If short term benefit is established in acute trials in the future for

one or more key clinical outcomes then sustained benefit could

be explored through the use of a relapse prevention trial con-

ducted over 12-18 months This is relevant as treatments directed

to autism tend to be long term A relapse prevention trial also af-

fords the opportunity to obtain systematic adverse event data over

a longer period

A C K N O W L E D G E M E N T S

The authors would like to thank the Cochrane Developmental

Psychosocial and Learning Problems Review Group for feedback

during the development of this review and Cochrane statisticians

for their advice



R E F E R E N C E S

References to studies included in this review

Barthelemy 1989 published data onlylowast Barthelemy C Bruneau N Jouve J Martineau J Muh JP Lelord

G Urinary dopamine metabolites as indicators of the responsiveness

of fenfluramine treatment in children with autistic behavior

Journal of Autism and Developmental Disorders 198919(2)241ndash54

Buchsbaum 2001 published data onlylowast Buchsbaum M Hollander E Haznedar M Tong C Spiegal-

Cohen J Wei T et alEffect of fluoxetine on regional cerebral

metabolism in autistic spectrum disorders a pilot study

International Journal of Neuropsychopharmacology 20014119ndash25

Hollander 2005 published data onlylowast Hollander E Phillips A Chaplin W Zagursky K Novotny S A

placebo controlled crossover trial of liquid fluoxetine on repetitive

behaviours in childhood and adolescent autism

Neuropsychopharmacology 200530582ndash9

King 2009 published data only

King BH Hollander E Sikich L McCracken JT Scahill L

Bregman JD et alLack of efficacy of citalopram in children with

autism spectrum disorders and high levels of repetitive behavior

Archives of General Psychiatry 200966(6)583ndash90

Leventhal 1993 published data onlylowast Leventhal B Cook E Morford M Ravitz A Heller W Freedman

D Clinical and neurochemical effects of fenfluramine in children

with autism Journal of Neuropsychiatry 19935(3)307ndash15

McDougle 1996 published data onlylowast McDougle C Naylor S Cohen D Volkmar F Heninger G Price

L A double-blind placebo-controlled study of fluvoxamine in

adults with autistic disorder Archives of General Psychiatry 199653

(11)1001ndash8

Sugie 2005 published data onlylowast Sugie Y Sugie H Kukuda T Ito M Sasada Y Nakabayashi M et

alClinical efficacy of fluvoxamine and functional polymorphism in

a serotonin transporter gene on childhood autism Journal of

Autism and Developmental Disorders 200535(3)377ndash85

References to studies excluded from this review

Doyle 2001 published data only

Doyle J Casciano J Arikan S Tarride J-E Gonzales M Casciano

R A multinational pharmacoeconomic evaluation of acute major

depressive disorder (MDD) a comparison of cost-effectiveness

between venlafaxine SSRIs and TCAs Value in Health 20014(1)

16ndash31

Gordon 1993 published data onlylowast Gordon C State R Nelson J Hamburger S Rapoport J A

double-blind comparison of clomipramine desipramine and of

autistic disorder Archives of General Psychiatry 199350(6)441ndash7

Humble 2001 published data only

Humble M Bejerot S Bergqvist P Bengtsson F Reactivity of

serotonin in while blood relationship with drug response in

obsessive-compulsive disorder Biological Psychiatry 200149360ndash8

McDougle 1998 published data only

McDougle C Brodkin E Naylor S Carlson D Cohen D Price L

Sertraline in adults with pervasive developmental disorders a

prospective open-label investigation Journal of Clinical

Psychopharmacology 199818(1)62ndash6

Peral 1999 published data only

Peral M Alcami M Gilaberte I Fluoxetine in children with autism

Journal of the American Academy of Child and Adolescent Psychiatry

199938(12)1472ndash3

Remington 2001 published data onlylowast Remington G Sloman L Konstantareas M Parker K Gow R

Clomipramine versus haloperidol in the treatment of autistic

disorder a double-blind placebo-controlled cross-over study

Journal of Clinical Psychopharmacology 200121(4)440ndash4

Sanchez 1996 published data only

Sanchez L Campbell M Small A Cueva J Armenteros J Adams P

A pilot study of clomipramine in young autistic children Journal of

the American Academy of Child and Adolescent Psychiatry 199635

(4)537ndash44

Additional references

Aman 2005

Aman MG Lam KSL Van Bourgondien ME Medication patterns

in patients with autism temporal regional and demographic

influences Journal of Child amp Adolescent Psychopharmacology 2005

15(1)116ndash26

APA 1980

Diagnostic and Statistical Manual of Mental Disorders Third

Edition American Psychiatric Association 1980

APA 1987

Diagnostic and Statistical Manual of Mental Disorders Revised third

American Psychiatric Association 1987

APA 1994

Diagnostic and Statistical Manual of Mental Disorders Fourth


APA 2000

Diagnostic and Statistical Manual of Mental Disorders Text revision

- fourth American Psychiatric Association 2000

Atladottir 2007

Atladottir HO Parner ET Schendel D Dalsgaard S Thomsen PH

Thorsen P Time trends in reported diagnoses of childhood

neuropsychiatric disorders A Danish cohort study Archives of

Pediatric amp Adolescent Medicine 2007161(2)193ndash8

Baird 2006

Baird G Simonoff E Pickles A Chandler S Loucas T Meldrum

D et alPrevalence of disorders of the autism spectrum in a

population cohort of children in South Thames the Special Needs

and Autism Project (SNAP) Lancet 2006368(9531)210ndash5

Billstedt 2005

Billstedt E Gillberg IC Gillberg C Autism after adolescence

population-based 13- to 22-year follow-up study of 120 individuals

with autism diagnosed in childhood Journal of Autism amp

Developmental Disorders 200535351ndash60



Bodfish 1999

Bodfish JW Symons FW Lewis MH The Repetitive Behavior Scale

Morganton NC Western Carolina Center Research Reports 1999

Branford 1998

Branford D Bhaumik S Naik B Selective serotonin re-uptake

inhibitors for the treatment of perseverative and maladaptive

behaviours of people with intellectual disability Journal of

Intellectual Disability Research 199842(4)301ndash6

Chen 2007

Chen C-Y Liu C-Y Su W-C Huang S-L Lin K-M Factors

associated with the diagnosis of neurodevelopmental disorders A

population-based longitudinal study Pediatrics 2007119(7)

e435ndash43

Clarke 2003

Clarke M Oxman AD (editors) Cochrane Handbook for Systematic

Reviews of Interventions Oxford Update Software 2003

Cook 1996

Cook EH Leventhal BL The serotonin system in autism Current

Opinion in Pediatrics 19968348ndash54

Fombonne 2006

Fombonne E Zakarian R Bennett A Meng L McLean-Heywood

D Pervasive developmental disorders in Montreal Quebec

Canada Prevalence and links with immunizations Pediatrics 2006

118e139ndash50

Gillberg 2006

Gillberg C Cederlund M Lamberg K Zeijlon L Brief report The

ldquoAutism Epidemicrdquo The registered prevalence of autism in a

Swedish urban area Journal of Autism and Developmental Disorders

200626(3)429ndash35

Goodman 1989

Goodman WK Price LH Rasmussen SA Mazure C Delgado P

Heninger GR Charney DS The Yale-Brown Obsessive

Compulsive Scale II Validity Archives of General Psychiatry 1989

46(11)1012ndash16

Goodman 1989b

Goodman WK Price LH Rasmussen SA Mazure C Fleischman

RL Hill CL Heninger GR Charney DS The Yale-Brown

Obsessive Compuslive Scale I Development Use and Reliability

Archives of General Psychiatry 1989461006ndash11

Greenhill 2004

Greenhill LL Vitiello B Fisher P Levine J Davies M Abikoff H et

alComparison of increasingly detailed elicitation methods for the

assessment of adverse events in pediatric psychopharmacology


200443(12)1488ndash96

Gringras 2000

Gringras P Practical paediatric psychopharmacological prescribing

in autism Autism 20004(3)229ndash47

Guillem 2006

Guillem P Cans C Guinchat V Ratel M Jouk P-S Trends

perinatal characteristics and medical conditions in pervasive

developmental disorders Developmental Medicine amp Child

Neurology 200648(11)896ndash900

Guy 1976

Guy W ECDEU Assessment Manual for Psychopharmacology Vol

NIMH Publication DHEW Publ No 76-388 Bethesda MD

National Institute of Mental Health 1976

Higgins 2002

Higgins JPT Thompson SG Quantifying heterogeneity in a meta-

analysis Statistics in Medicine 2002211539ndash58

Higgins 2008

Higgins JPT Green S (editors) Cochrane Handbook for

Systematic Reviews of Interventions Version 502 [updated

September 2009] The Cochrane Collaboration 2009 Available

from wwwcochrane-handbookorg

Howlin 2004

Howlin P Goode S Hutton J Rutter M Adult outcome for

children with autism Journal of Child Psychology amp Psychiatry amp

Allied Disciplines 200445212ndash29

Jesner 2007

Jesner OS Aref-Adib M Coren E Risperidone for autism spectrum

disorder Cochrane Database of Systematic Reviews 2007 Issue 1

McCracken 2002

McCracken JT McGough J Shah B Cronin P Hong D Aman

MG et alRisperidone in children with autism and serious

behavioral problems New England Journal of Medicine 2002347

(5)314ndash21

McKay 2003

McKay D Piacentinib J Greisberga S Graaec F Jafferc M Millerc

J Neziroglud F Yaryura-Tobiasd JA The Childrenrsquos Yale-Brown

Obsessive-Compulsive Scale Item Structure in an Outpatient

Setting Psychological Assessment 200315(4)578ndash81

Murray 2005

Murray ML Wong ICK Thompson M Do selective serotonin

reuptake inhibitors cause suicide Antidepressant prescribing to

children and adolescents by GPs has fallen since CSM advice

(Letter) BMJ 2005330(7500)1151

Nemeroff 2007

Nemeroff CB Kalali A Keller MB Charney DS Lenderts SE

Cascade EF et alImpact of publicity concerning pediatric

suicidality data on physician practice patterns in the United States


Saxena 1995

Saxena PR Serotonin receptors subtypes functional responses and

therapeutic relevance Pharmacology and Therapeutics 199566(2)

339ndash68

Scahill 2006

Scahill L McDougle CJ Williams SK Dimitropoulos A Aman

MG McCracken JT et alThe Childrenrsquos Yale-Brown Obsessive

Compulsive Scales modified for pervasive developmental disorders


200645(9)1114ndash23

Sinha 2004

Sinha Y Silove N Wheeler D Williams K Auditory integration

training and other sound therapies for autism spectrum disorders

Cochrane Database of Systematic Reviews 2004 Issue 1



WHO 1993

World Health Organisation International Classification of

Diseases International Classification of Diseases (ICD-10) World

Health Organisation 1993

Williams 2005

Williams KJ Wray JJ Wheeler DM Intravenous secretin for

autism spectrum disorder Cochrane Database of Systematic Reviews

2005 Issue 3

Williams 2006

Williams JG Higgins JPT Brayne CEG Systematic review of

prevalence studies of autism spectrum disorders Archives of Diseases

in Childhood 2006918ndash15 [DOI 101136adc2004062083]

Williams 2008

Williams K Macdermott S Ridley G Glasson EJ Wray JA The

prevalence of autism in Australia Can it be established from

existing data Journal of Paediatrics and Child Health 200844(9)

504ndash10lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Barthelemy 1989

Methods Cross-over

Participants blind

Treating physicians blind

Blinding of outcome assessors unclear

No loss to follow-up

Participants N = 13

8 males 5 females

Age range 3-10 yrs mean age 6 yrs 4 months Children only

Diagnosis DSM-III autism

IQ range 30-75 Obsessive-compulsive behaviours not required

Interventions Treatment Fenfluramine twice daily divided dose at total 15 mgkg

Reduced to 08 mgkg in 2 children due to adverse effects

Duration 3 months

Placebo identical placebo phase duration 1 month

Outcomes Weight

Behavior Summarised Evaluation

Urinary dopamine metabolites

Notes

Risk of bias

Item Authorsrsquo judgement Description

Blinding Unclear Unclear if there was blinding of outcome

assessors

Incomplete outcome data addressed

All outcomes

Yes No loss to follow-up

Buchsbaum 2001

Methods Cross-over

Participants blind

Blinding of treating physicians unclear





Buchsbaum 2001 (Continued)

Participants N = 6

5 male 1 female

Mean age 305 plusmn 86 yrs Adults only

Diagnosis DSM-IV ADI

5 autism 1 Asperger disorder

IQ scores ranged from 53 to 119 and all participants were verbal Obsessive-compulsive

behaviours were not a requirement

Interventions Treatment fluoxetine starting dose 10 mgday up to maximum dose 40 mgday for 8

weeks

Placebo not described Duration of placebo phase = 8 weeks

Outcomes Yale-Brown Obsessive Compulsive Scale

Hamilton Rating Scale for Anxiety

Clinical Global Impression Scale

Positron Emission Tomography

Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over

Outcome assessors blind

Randomisation method not stated

44 children randomised of 62 consented 5 lost to follow-up

Participants N = 44 39 completed

30 males 9 females

mean age 818 plusmn 30 range 5-16 Children only

Diagnosis DSM-IV-TR of Autism PDD-NOS or Asperger Syndrome

IQ range 30-132 No required threshold for obsessive compulsive behaviours

Interventions Treatment fluoxetine 8 weeks treatment 4 weeks washout 8 weeks cross-over

25 mgday up to 08 mgkgday maximum

Outcomes Yale-Brown Obsessive-Compulsion Scale

Clinical Global Improvement Scale Adapted to Global Autism

Suicidality Subscale of Overt Aggression Scale



Hollander 2005 (Continued)

Fluoxetine side effects checklist

Notes

Risk of bias


Blinding Yes Of outcome assessors


All outcomes

No Loss to follow-up of one non-responder

and three who were non-compliant and no

intention to treat analysis possible

King 2009

Methods Multicentre trial (six centres)

Randomisation using permuted blocks with randomly varying block sizes stratified by

site and age

Outcome assessor blind to treatment allocation

Participants 149 children randomised 76 to placebo and 73 to treatment group

13 withdrew from each group

Aged 5-17 Children only

Autistic Disorder Asperger Disorder or PDD-NOS severity of at least moderate on CGI

severity of illness scale

At least moderate compulsive behaviours

61 gt 70 non-verbal IQ

Interventions Liquid citalopram obtained commercially Placebo matched for smell taste and viscosity

Outcomes CGI improvement scale

CYBOCS-PDD (clinician rated)

Composite measure of the CGI improvement scale and CYBOCS-PDD

6 subscales of the Repetitive Behaviour Scale (parent rated)

Aberrant Behavior Checklist-Community version

Notes

Risk of bias


Adequate sequence generation Yes

Allocation concealment Yes

Blinding Yes Outcome assessor ldquomaskedrdquo



King 2009 (Continued)


All outcomes

Yes ITT analyses used

Free of selective reporting Yes Registered trial

Leventhal 1993

Methods Two phase placebo-treatment-placebo followed by randomised cross-over

ldquodouble blindrdquo no details

Participants N = 15

3-125 yrs (mean age 76 plusmn 26yrs) Children only

Diagnosis infantile autism DSM-III

No loss to follow-up Incomplete data for some outcomes


Interventions Fenfluramine

Outcomes Ritvo-Freeman Real Life Rating Scale

Connors Abbreviated Parent and Teacher Questionnaires

Notes Previous use of fenfluramine

Risk of bias


Blinding Unclear Uncertain if outcome assessors blind to

treatment group


All outcomes

Unclear No loss to follow-up but incomplete data

for some outcomes

McDougle 1996

Methods Participants blind




Participants N = 30

27 males 3 females

Mean age 301 plusmn 77 yrs age range 18-53 yrs Adults only

Diagnosis of autism using DSM-III-R and ICD-10 at least ldquomoderaterdquo in severity using

the CGI global severity of illness rating

Obsessive-compulsive behaviours not required



McDougle 1996 (Continued)

Interventions Fluvoxamine to max 300 mgday for 9-12 weeks

Identical placebo 9-12 weeks

Equality of treatment between groups

Compliance measure unclear


Clinical Global Impression Scale global improvement

Brown Aggression Scale

Vineland Maladaptive Behavior

Yale-Brown Obsessive Compulsive Scale

Notes

Risk of bias


Blinding Yes Outcome assessors blind to treatment

group


All outcomes


Sugie 2005

Methods Cross-over

Computer-based randomisation

ldquodouble-blindrdquo parentscarers participants treatment team


15 males 4 females

Mean age 53 yrs range 3-84 yrs Children only

Diagnosis DSM-IV Autism

1 lost to follow-up

Interventions Placebo or fluvoxamine 1 mgkgday for 2 weeks 2 mgkgday for 3 weeks 3 mgkg

day for 6 weeks 15 mgkgday for 2 weeks 2 week washout cross-over

Outcomes Behavioural Assessment Scale


Notes Haematological and molecular genetic analysis

Risk of bias




Sugie 2005 (Continued)

Adequate sequence generation Yes Computer generated randomisation se-

quence


Blinding Unclear Unclear if outcome assessors blind to treat-

ment group


All outcomes

Yes

Free of selective reporting No

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Doyle 2001 Not trial of SSRIs Cost analysis

Not RCT no placebo

Gordon 1993 Clomipramine not SSRI

Humble 2001 Participants not ASD

McDougle 1998 Open-label non-randomised no placebo control

Peral 1999 Open-label no randomisation no placebo

Remington 2001 Clomipramine not SSRI

Sanchez 1996 Open-label not RCT



D A T A A N D A N A L Y S E S

This review has no analyses

A P P E N D I C E S

Appendix 1 MEDLINE search strategy

MEDLINE (via OVID) searched December 4th 2009

1 exp Child Development Disorders Pervasive

2 communicat$tw

3 autis$tw

4 PDDtw

5 pervasive developmental disorder$tw

6 (language adj3 delay$)tw

7 (speech adj3 disorder$)tw

8 childhood schizophreniatw

9 kanner$tw

10 asperg$tw

11 or1-10

12 Serotonin Uptake Inhibitors

13 selective serotonin reuptake inhibitor$tw

14 SSRItw

15 5-hydroxytryptaminetw

16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 randomized controlled trialpt

32 controlled clinical trialpt

33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41

Appendix 2 CENTRAL search strategy

Cochrane Central Register of Controlled Trials (The Cochrane Library 2009 Issue 4)

1 MeSH descriptor Child Development Disorders Pervasive explode all trees

2 (communicat)

3 (autis)

4 (PDD)

5 (pervasive next developmental disorder)

6 (language near3 delay)

7 speech near3 disorder

8 childhood next schizophrenia

9 kanner

10 asperg

11 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10)

12 MeSH descriptor Serotonin Uptake Inhibitors this term only

13 (selective serotonin reuptake inhibitors)

14 (SSRI)

15 (5-hydroxytryptamine)

16 (5HT)

17 MeSH descriptor Fluvoxamine explode all trees

18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)

21 MeSH descriptor Fluoxetine explode all trees

22 MeSH descriptor Paroxetine explode all trees

23 paroxetine

24 MeSH descriptor Sertraline explode all trees

25 sertraline

26 MeSH descriptor Citalopram explode all trees

27 citalopram

28 venlafaxine

29 (12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26

OR 27 OR 28)

30 (11 AND 29)

Appendix 3 EMBASE search strategy

EMBASE (via OVID) Searched 2009 Week 49


2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw

37 (doubl$ adj blind$)tw

38 (singl$ adj blind$)tw

39 assign$tw

40 allocat$tw

41 volunteer$tw

42 Crossover Procedure

43 double-blind proceduretw

44 Randomized Controlled Trial

45 Single Blind Procedure

46 or31-45

47 30 and 46

Appendix 4 ERIC search strategy

ERIC (via Dialog Datastar) Searched December 2009

1 Pervasive-Developmental-DisordersDE

2 communicat$

3 autis$

4 PDD unrestricted

5 pervasive ADJ developmental ADJ disorder$

6 language NEAR delay$ unrestricted 690 show titles

7 speech NEAR disorder$

8 childhood ADJ schizophrenia

9 kanner$



10 asperg$

11 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10

12 selective ADJ serotonin ADJ reuptake ADJ inhibitor$

13 SSRI

14 5-hydroxytryptamine

15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine

23 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22

24 11 AND 23

25 random$ OR control$ OR blind$ OR trial$ OR crossover

26 24 and 25

Appendix 5 PsycINFO search strategy

PsycINFO (via OVID) Searched December 2009 Week 2

1 exp Pervasive Developmental Disorders

2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10

12 Serotonin Reuptake Inhibitors


14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



31 Treatment Effectiveness Evaluation

32 exp Treatment Outcomes

33 Psychotherapeutic Outcomes

34 PLACEBO

35 exp Followup Studies

36 placebo$tw

37 random$tw

38 comparative stud$tw

39 randomied controlled trial$tw

40 (clinical adj3 trial$)tw

41 (research adj3 design)tw

42 (evaluat$ adj3 stud$)tw

43 (prospectiv$ adj3 stud$)tw

44 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$))tw

45 control$tw

46 45 or 37 or 35 or 43 or 42 or 38 or 31 or 36 or 32 or 44 or 40 or 34 or 33 or 41 or 39

47 30 and 46

Appendix 6 CINAHL search strategy

CINAHL (via EBSCO) Searched December 2009

S46 S29 and S45

S45 S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40

or S41 or S42 or S43 or S44

S44 allocat random

S43 (MH ldquoQuantitative Studiesrdquo)

S42 (MH ldquoPlacebosrdquo)

S41 placebo

S40 random allocat

S39 (MH ldquoRandom Assignmentrdquo)

S38 (Randomied control trial)

S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28


or S23 or S24 or S25 or S26 or S27

S27 Venlafaxine

S26 (MH ldquoVenlafaxinerdquo)

S25 Citalopram

S24 (MH ldquoCitalopramrdquo)

S23 Sertraline

S22 (MH ldquoSertraline Hydrochloriderdquo)

S21 Paroxetine

S20 (MH ldquoParoxetinerdquo)

S19 (MH ldquoFluoxetinerdquo)



S18 fluoxetine

S17 fluvoxamine or fluvocamine

S16 5HT

S14 SSRI

S13 selective serotonin reuptake inhibitor

S12 (MH ldquoSerotonin Uptake Inhibitorsrdquo)

S11 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10

S10 asperg

S9 kanner

S8 childhood schizophrenia

S7 speech N3 disorder

S6 language N3 delay

S5 pervasive developmental disorder

S4 PDD

S3 autis

S2 communicat

S1 (MH ldquoChild Development Disorders Pervasive+rdquo)

Appendix 7 Sociological Abstracts

Sociological Abstracts searched 10 December 2009

(((DE=ldquoautismrdquo) or(communicat) or (autis) or (PDD) or (pervasive developmental disorder) or(language within 3 delay)

or (speech within 3 disorder) or(childhood schizophrenia) or (kanner))

AND

((selective serotonin reuptake inhibitor) or(SSRI) or(5-hydroxytryptamine) or(5HT) or(fluvoxamine) or(fluvocamine)or(fluoxetine)

or(paroxetine) or(sertraline) or(citalopram)or(venlafaxine)))

AND

((random or trial or control) or (blind or crossover))

W H A T rsquo S N E W

Last assessed as up-to-date 30 May 2010

Date Event Description

4 August 2010 Amended Typographical error corrected



H I S T O R Y

Protocol first published Issue 1 2004

Review first published Issue 8 2010


7 November 2008 Amended Converted to new review format

C O N T R I B U T I O N S O F A U T H O R S

Danielle Wheeler and Katrina Williams conducted literature searches extracted data and made decisions about data synthesis All

authors were involved in writing the protocol and review

D E C L A R A T I O N S O F I N T E R E S T

Professor Philip Hazell has worked as a consultant for Eli Lilly and Janssen He has had research contracts with Eli Lilly and Celltech

He is a member of the advisory board of Eli Lilly Australia Janssen Australia Novartis Australia and Shire International Professor

Hazell has given presentations for Eli Lilly Pfizer Janssen and Sanofi He is an investigator on a non-industry funded trial of fluoxetine

for autism spectrum disorders

Dr Natalie Silove is an investigator on a non-industry funded trial of fluoxetine for autism spectrum disorders

S O U R C E S O F S U P P O R T

Internal sources

bull Small Grants Scheme The Childrenrsquos Hospital at Westmead Sydney Australia

External sources

bull Financial Markets Foundation for Children Australia

bull Department of Health and Aging Australia

Cochrane Entities funding

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

No significant changes were made to the protocol



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

6RESULTS

Figure 1 8

15DISCUSSION

16AUTHORSrsquo CONCLUSIONS

16ACKNOWLEDGEMENTS

17REFERENCES

19CHARACTERISTICS OF STUDIES

26DATA AND ANALYSES

26APPENDICES

31WHATrsquoS NEW

31HISTORY

32CONTRIBUTIONS OF AUTHORS

32DECLARATIONS OF INTEREST

32SOURCES OF SUPPORT

32DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iSelective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) (Review)

















A B S T R A C T

Background




Objectives






5 causes harms

Search strategy



restrictions

Selection criteria








Main results






















B A C K G R O U N D



































2005 Howlin 2004)






























































O B J E C T I V E S








5 causes harms

M E T H O D S


Types of studies















were applied





Types of outcomes




activities






5 Adverse events





available

Types of measures


ADI-R ADOS DISCO)








Electronic searches



















database











extraction

































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources























A B S T R A C T

Background




Objectives






5 causes harms

Search strategy



restrictions

Selection criteria








Main results






















B A C K G R O U N D



































2005 Howlin 2004)






























































O B J E C T I V E S








5 causes harms

M E T H O D S


Types of studies















were applied





Types of outcomes




activities






5 Adverse events





available

Types of measures


ADI-R ADOS DISCO)








Electronic searches



















database











extraction

































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources











Main results






















B A C K G R O U N D



































2005 Howlin 2004)






























































O B J E C T I V E S








5 causes harms

M E T H O D S


Types of studies















were applied





Types of outcomes




activities






5 Adverse events





available

Types of measures


ADI-R ADOS DISCO)








Electronic searches



















database











extraction

































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources















2005 Howlin 2004)






























































O B J E C T I V E S








5 causes harms

M E T H O D S


Types of studies















were applied





Types of outcomes




activities






5 Adverse events





available

Types of measures


ADI-R ADOS DISCO)








Electronic searches



















database











extraction

































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources




















were applied





Types of outcomes




activities






5 Adverse events





available

Types of measures


ADI-R ADOS DISCO)








Electronic searches



















database











extraction

































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources
































3 Blinding


during the study











described)



reporting






adequatersquo)




Binary data







Continuous data









mean difference




ipant


















Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








Data synthesis








school age








R E S U L T S



studies



































were used

Included studies






(McDougle 1996)
















1993) and 30-75 (Barthelemy 1989)








(McDougle 1996)
















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources

















Excluded studies










Study design























study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









study



Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








Sequence generation



Allocation






authors

Blinding




































Selective reporting













included studies











Outcome

measure


Core features

of autism




1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









1 Behavioural

Assessment

Scale

x

2 Be-

haviour Sum-

marized Eval-

uation Scale

x

3 Repet-

itive Behavior

Scale-Revised

x

Obsessive

compulsive

behaviour

4 Yale-Brown

Obses-

sive Compul-

sive Scale (Y-

BOCS)

x x x x

Anxiety

5 Hamilton

Rating Scale

for Anxiety

x

Depression

6 Hamilton

Rating

Scale for De-

pression

x

Behaviour

7 Ritvo-Free-

man Real Life

Rating Scale

x x

8 Vineland

Adaptive Be-

haviour

Scales

x




9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









9 Clinical

Global Im-

pression Scale

(CGI)

x x x x x

10 Aberrant Be-

hav-

ior Checklist

(ABC)

x

11 Connors Ab-

breviated Par-

ent

and Abbrevi-

ated Teacher

Question-

naires

x

Aggression

12 Brown Ag-

gression Scale

x

Other stan-

dardised out-

comes

13 Merrill-

Palmer

Scale of Men-

tal Tests

x

14 Wechsler In-

tel-

ligence Scale

for Children

x

15 Alpern-Boll

Developmen-

tal Profile

x

Adverse

events

16 Fluox-

etine Side Ef-

fects Check-

list

x




17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









17 Suicidal-

ity Subscale

Overt Aggres-

sion Scale -

Modified

x


Citalopram





Fenfluramine








Fluvoxamine

















only)





















placebo (z = 1907 SE = 0703 P = 0056)




Clinical impression

Children

Citalopram













Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










Fluoxetine




Fluvoxamine







children

Adults

Fluoxetine








Fluvoxamine















Children







separately










analyses

Adults

Fluoxetine








analysis

Fluvoxamine

















Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









Citalopram






Fenfluramine













Fluoxetine





very small (N = 6)


Fluoxetine




SD 387 P = 006)


Fluvoxamine






Adverse effects

Children

Citalopram










seizures

Fenfluramine















was reported

Fluoxetine








placebo



Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








Fluvoxamine








Adults

Fluoxetine




Fluvoxamine









sias were reported

Quality of life


Long term outcomes




D I S C U S S I O N














































not possible

















of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









of trials in ASD

















was well tolerated











































fluoxetine














a longer period





for their advice



R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








R E F E R E N C E S

























(11)1001ndash8











16ndash31
















199938(12)1472ndash3









(4)537ndash44


Aman 2005




15(1)116ndash26

APA 1980



APA 1987



APA 1994



APA 2000



Atladottir 2007





Baird 2006





Billstedt 2005







Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








Bodfish 1999



Branford 1998





Chen 2007




e435ndash43

Clarke 2003



Cook 1996



Fombonne 2006




118e139ndash50

Gillberg 2006




200626(3)429ndash35

Goodman 1989




46(11)1012ndash16

Goodman 1989b





Greenhill 2004





200443(12)1488ndash96

Gringras 2000



Guillem 2006





Guy 1976




Higgins 2002



Higgins 2008





Howlin 2004




Jesner 2007



McCracken 2002




(5)314ndash21

McKay 2003





Murray 2005




(Letter) BMJ 2005330(7500)1151

Nemeroff 2007





Saxena 1995



339ndash68

Scahill 2006





200645(9)1114ndash23

Sinha 2004






WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








WHO 1993




Williams 2005



2005 Issue 3

Williams 2006




Williams 2008









Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










Barthelemy 1989

Methods Cross-over

Participants blind




Participants N = 13

8 males 5 females






Duration 3 months


Outcomes Weight



Notes

Risk of bias



assessors


All outcomes


Buchsbaum 2001

Methods Cross-over

Participants blind







Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources









Participants N = 6

5 male 1 female







weeks






Notes

Risk of bias



assessors


All outcomes


Hollander 2005

Methods Cross-over





30 males 9 females













Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










Notes

Risk of bias




All outcomes




King 2009



site and age















Notes

Risk of bias









All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










All outcomes



Leventhal 1993



Participants N = 15









Risk of bias



treatment group


All outcomes


for some outcomes

McDougle 1996





Participants N = 30

27 males 3 females

















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources


















Notes

Risk of bias



group


All outcomes


Sugie 2005

Methods Cross-over




15 males 4 females



1 lost to follow-up






Risk of bias






quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










quence



ment group


All outcomes

Yes





Not RCT no placebo











A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources










A P P E N D I C E S




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29



33 randomizedab

34 placeboab

35 drug therapyfs

36 randomlyab

37 trialab

38 groupsab

39 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38

40 humanssh



41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








41 39 and 40

42 30 and 41




2 (communicat)

3 (autis)

4 (PDD)





9 kanner

10 asperg




14 (SSRI)


16 (5HT)


18 fluvoxamine

19 (fluvocamine)

20 (fluoxetine)



23 paroxetine


25 sertraline


27 citalopram

28 venlafaxine


OR 27 OR 28)

30 (11 AND 29)




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw



10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29

31 random$tw

32 factorial$tw

33 crossover$tw

34 cross over$tw

35 cross-over$tw

36 placebo$tw



39 assign$tw

40 allocat$tw

41 volunteer$tw





46 or31-45

47 30 and 46




2 communicat$

3 autis$

4 PDD unrestricted





9 kanner$



10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








10 asperg$



13 SSRI


15 5HT

16 fluvoxamine

17 fluvocamine

18 fluoxetine

19 paroxetine

20 sertraline

21 citalopram

22 venlafaxine


24 11 AND 23


26 24 and 25




2 communicat$tw

3 autis$tw

4 PDDtw





9 kanner$tw

10 asperg$tw

11 or1-10



14 SSRItw


16 5HTtw

17 Fluvoxamine

18 fluvoxaminetw

19 fluvocaminetw

20 Fluoxetine

21 fluoxetinetw

22 Paroxetine

23 paroxetinetw

24 Sertraline

25 sertralinetw

26 Citalopram

27 citalopramtw

28 venlafaxinetw

29 or12-28

30 11 and 29






34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources











34 PLACEBO


36 placebo$tw

37 random$tw








45 control$tw


47 30 and 46



S46 S29 and S45



S44 allocat random



S41 placebo

S40 random allocat



S37 (singl mask )

S36 (doubl mask )

S35 (tripl mask )

S34 (trebl mask )

S33 (trebl blind )

S32 (tripl blind )

S31 (doubl blind )

S30 (singl blind )

S29 S11 and S28



S27 Venlafaxine


S25 Citalopram


S23 Sertraline


S21 Paroxetine





S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








S18 fluoxetine


S16 5HT

S14 SSRI




S10 asperg

S9 kanner





S4 PDD

S3 autis

S2 communicat






AND



AND








H I S T O R Y















Internal sources


External sources








H I S T O R Y















Internal sources


External sources








cochrane review: selective serotonin reuptake inhibitors (ssris) for depressive disorders in...

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