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

Authors


Abstract

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.

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.

Authors' 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.

Plain Language Summary

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.

Background

Description of the condition

Autism spectrum disorders (ASD) are characterised by qualitative 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 Infantile 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), 'other pervasive developmental disorders', 'pervasive developmental disorder, unspecified', Asperger 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 10,000 and for any ASD between 3 and 82 per 10,000 (Williams 2006). Publications from 2006 have estimated the prevalence of any ASD between 22 and 116 per 10,000 (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 throughout life. Autism places a considerable burden of care on the family and society. Follow-up studies have found that only 3-10% of people 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 individuals 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 and/or 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 disorder, poor attention/concentration 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 reuptake will result in improvement of ASD symptoms.

Why it is important to do this review

Several studies have reported improvements following administration of SSRIs. However, the subject numbers are small, especially for paediatric patients, and serious side effects including increases 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 'off-label' or is directed to an associated indicated disorder such as obsessive compulsive disorder (OCD) or depression.

Regarding indications and prescribing for children, there are between-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 escitalopram 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 antidepressants other than fluoxetine for the treatment of depression in children 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.

Objectives

To determine if treatment with SSRIs:

1. improves the core features of ASD (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 adults or children and their carers;

4. has short and long term effects on outcome;

5. causes harms.

Methods

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 defined using DSM-IV or ICD-10 or equivalent as a Pervasive Developmental Disorder, excluding Rett syndrome and Childhood Disintegrative Disorder. Diagnosis must have been made using a standardised 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 administration. The control group must be a placebo group.

Types of outcome measures

Types of outcomes
  • 1.Core features of ASD, i.e. 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 insufficient information at present to prioritise these outcomes. We intended 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 Trials (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 science and education databases: Sociological Abstracts (December 2009) and ERIC (December 2009).

Search terms were modified to meet the requirements of individual databases. The optimally sensitive search strategy for randomised controlled trials, developed for the Cochrane Collaboration (Clarke 2003), was combined with medical subject headings and text words specific for autism and pervasive development disorders, as developed by the Cochrane Developmental, Psychosocial and Learning Problems Group. Search terms were modified to meet the requirements of individual databases regarding differences 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.

Data collection and analysis

Selection of studies

Titles and abstracts from the searches were screened by two authors, 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 methods, participant details, dose and frequency of SSRI administration, and outcomes. Data were extracted by two independent reviewers (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 ratings of 'Yes' (low risk of bias); 'No' (high risk of bias) and 'Unclear' (uncertain risk of bias):

1.      Sequence generation

Was the allocation sequence adequately generated?

“Yes” (computer generated random numbers, table of random numbers, coin-tossing or similar), “No” (day of week, even/odd clinic record number, clinician judgment, participant preference, laboratory test result such as haemoglobin value, or similar), or “Unclear” (insufficient information about the sequence generation process to permit judgment).

2.      Allocation concealment

Was allocation adequately concealed?

“Yes” (central independent unit, sequentially numbered drug containers or sealed envelopes of identical appearance, or similar), “No” (alternation or rotation, date of birth, non-opaque envelopes, open table of random numbers or similar), or “Unclear” (randomisation stated but no information on method used is available).

3.      Blinding

Was knowledge of the allocated intervention adequately prevented during the study?

“Yes” (identical placebo medication or similar), “No” (tablets versus liquid or similar), or “Unclear” (blinding stated but no information on method used is available).

4.      Incomplete outcome data

Were incomplete data dealt with adequately by the researchers?

“Yes” (no missing outcome data, missing outcome data balanced in numbers across intervention groups and reasons for dropouts and withdrawals described or similar), “No” (reason for missing outcome data likely to be related to true outcome or similar), or “Unclear” (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?

“Yes” (study protocol is available, published reports include all expected outcomes or similar), “No” (not all of the study's pre-specified primary outcomes have been reported, one or more reported primary outcomes were not pre-specified or similar), or “Unclear” (insufficient information to permit judgement of 'adequate' or 'inadequate').

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 standardised instruments or diagnostic evaluations as proportions, the relative 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 outcome 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 Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Where studies did not use sufficiently similar instruments to measure 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 participant.

Dealing with missing data

Where possible, missing data and dropouts were assessed for each included study and reported. Reasons for missing data were provided when reported in trials. Where insufficient data were reported, 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 heterogeneity 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 precision (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.

Results

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 identified. 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 similar outcomes. For example for CGI, the Clinical Global Impression - Severity scale (CGI-S), the Clinical Global Impression - Improvement scale (CGI-I) and the Clinical Global Improvement Scale Adapted to Global Autism (CGI-AD) were used and sometimes the tool used was uncertain (CGI) (Guy 1976). Similarly, to measure Obsessive Compulsive Behaviour, the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders (CY-BOCS-PDD) (Scahill 2006), the Children's Yale-Brown Obsessive Compulsive scale (CY-BOCS) (McKay 2003) and the Yale-Brown Obsessive-Compulsion Scale (Goodman 1989;Goodman 1989b) and a modified version of it were used.

Included studies

Five studies were conducted in children aged 3-17 years, using fenfluramine (Barthelemy 1989; Leventhal 1993), fluoxetine (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 Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive 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 "diagnosed with autism" 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 "moderate" 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 previously 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 received 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, follow-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 2001;Hollander 2005;Sugie 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 washout 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 usingANOVA(Hollander 2005, Barthelemy 1989) and one of these also used mixed regression models for comparative analyses (Barthelemy 1989). Figure 1 provides a summary of the risk of bias of included studies.

Figure 1.

Risk of bias summary: review authors' 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 information about allocation concealment was forthcoming from trial authors.

Blinding

Outcome assessors were reported as being blind to treatment allocation 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 studies 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 "double blind" to refer to all blinding (Leventhal 1993; Sugie 2005). Given that the outcome measures used rely on subjective observation and assessment, 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 measure by more than one study was uncommon, but occurred for the CGI and the Child's Yale-Brown Obsessive Compulsive (CY-BOCS) scales, albeit using different scales and subsections of existing 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 measureBarthelemyKingBuchsbaumHollanderLeventhalMcDougleSugie
 Core features of autism       
1Behavioural Assessment Scale      x
2Behaviour Summarized Evaluation Scalex      
3Repetitive Behavior Scale–Revised x     
 Obsessive/compulsive behaviour       
4Yale-Brown Obsessive Compulsive Scale (Y-BOCS) xxx x 
 Anxiety       
5Hamilton Rating Scale for Anxiety  x    
 Depression       
6Hamilton Rating Scale for Depression  x    
 Behaviour       
7Ritvo-Freeman Real Life Rating Scale    xx 
8Vineland Adaptive Behaviour Scales     x 
9Clinical Global Impression Scale (CGI) xxx xx
10Aberrant Behavior Checklist (ABC) x     
11Connors Abbreviated Parent and Abbreviated Teacher Questionnaires    x  
 Aggression       
12Brown Aggression Scale     x 
 Other standardised outcomes       
13Merrill-Palmer Scale of Mental Tests    x  
14Wechsler Intelligence Scale for Children    x  
15Alpern-Boll Developmental Profile    x  
 Adverse events       
16Fluoxetine Side Effects Checklist   x   
17Suicidality Subscale, Overt Aggression 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 > 0.36 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 symptoms. 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 investigators and provided in the text of the paper. The tool is reported to have a correlation with the CARS (P < 0.0001). However, 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 "responded" 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 improvement 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 "increasing the threshold for positive response...". Comparative analysis showed no difference between treatment groups for the composite score at 12 weeks (20.6% for citalopram versus 13.2% for placebo; P = 0.28).

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 "...a 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 severity...". Results of the mixed regression analysis indicated a trend towards reduction in this global autism composite improvement measure for subjects on fluoxetine as compared to placebo (z = 1.907, SE = 0.703, P = 0.056).

Composite scores used were different and were presented as categorical data in one study and continuous data in the other, therefore, 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 (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61 to 1.51; P = 0.99) (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 = 0.94), 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 improvement. Continuous outcomes were compared using paired t-tests and reported for 'baseline' and fluoxetine with no significant change (mean difference -1.00; SD 1.26). However, it is uncertain whether 'baseline' represents the control phase so these data were unsuitable for inclusion in a meta-analysis.

Fluvoxamine

One study (McDougle 1996) reported statistically significant improvements 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 improvement, 53% of participants in the treatment arm were reported to have improved on the CGI improvement item, while no participants 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 manifest 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), −2.0 (3.4) points for the citalopram group and −1.9 (2.5) points for the placebo group; P = 0.85) (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 reported no statistically significant difference between groups (effect size changes were mean of -1.3 for phase 1 and -0.6 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 statistically significant improvement in obsessions (P = 0.03) but not compulsions (P = 0.86) and a 4 point difference, favouring treatment groups, that was not statically significant for the overall score (P = 0.06) (Buchsbaum 2001). As reported for the CGI outcome, uncertainty about whether 'baseline' 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 version 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 -8.2, 95% CI -13.92 to -2.48). Sample size was small (N = 30). Statistically significant improvements in both obsession (P < 0.02) and compulsion (P < 0.02) scores were reported at 8 weeks and also at 12 weeks (obsession P < 0.02, compulsion P < 0.001).

Both studies reported improvement in obsessions, as scored using 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–Community version only the irritability scale achieved statistical significance (without any correction for multiple comparisons) from baseline to week 12, and the difference in change scores was small (2.27 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 interpret. 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 0.73, SD 0.11, mean placebo 0.80, SD 0.15). There was a significant 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 treatment (mean difference 4.50, SD 3.51, P = 0.03). Sample size was very small (N = 6).

Depression (adult data only)

Fluoxetine

One study (Buchsbaum 2001) used the Hamilton Rating Scale for Depression. There was no significant benefit seen in the treatment group compared with the control group (mean difference 3.83, SD 3.87, P = 0.06).

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 = 4.57, P < 0.03).

No other non-core behaviour outcomes, such as sleep or self mutilation, were reported.

Adverse effects

Children
Citalopram

Significantly more children in the citalopram-treated group had one or more emergent adverse events compared to placebo (97.3% versus 86.8%, P = 0.03), 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 prolonged 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 treatment at 1.5 mg/kg the dosage had to be reduced due to adverse effects 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 irritability in the second month. Mean weight significantly decreased in the treatment group (P < 0.02) 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 fenfluramine administration. No further assessment of adverse effects was reported.

Fluoxetine

One study (Hollander 2005) used a side effects symptom checklist. 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 "dosage reduction" 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 adverse events, and one reported a serious adverse event and statistically 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 treatment 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 anticholinergic adverse effects, no significant changes in pulse, blood pressure or electrocardiographic changes. No seizures or dyskinesias 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 duration, with the exception of Barthelemy 1989 who monitored weight loss (see adverse effects).

Discussion

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 assessment procedures, and with different severity of problems and intellectual ability. Despite these differences there is consistency of findings for the studies conducted in children and for those conducted 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 fluoxetine), 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 profile of ASD trial participants, such as the age of participants, their IQ, the severity of their problems and whether they have the problems 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 different 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 outcomes 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 monitoring, dose adjustment and time, all but one of these adverse effects were resolved. No significant differences were reported for side effects in children in the treatment or placebo group for fluoxetine (Hollander 2005) and little information was available for side effects in children in the fluvoxamine study (Sugie 2005). The adult studies (fluvoxamine and fluoxetine) both reported that treatment was well tolerated.

Authors' conclusions

Implications 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 indications 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 controlled trials for ASD. As ASD causes substantial impairment, parents of children with the condition are motivated to try treatments regardless of the evidence. Nevertheless, it is important that prescribing 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 instance 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 owing to its favourable safety profile. We are aware of one such study that reached primary study completion in 2009 (ClinicalTrials.gov 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-puberty 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 adequately 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 minimum we recommend a measure of global functioning (e.g. CGI); a measure of repetitive and stereotyped behaviours (e.g. Repetitive Behavior Scale - Revised); a measure of disruptive behaviour (e.g. Aberrant Behavior Checklist), and a measure of obsessive compulsive symptoms (e.g. 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 conducted over 12-18 months. This is relevant as treatments directed to autism tend to be long term. A relapse prevention trial also affords the opportunity to obtain systematic adverse event data over a longer period.

Acknowledgements

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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barthelemy 1989
MethodsCross-over Participants blind Treating physicians blind Blinding of outcome assessors unclear No loss to follow-up
ParticipantsN = 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.
InterventionsTreatment: Fenfluramine twice daily divided dose at total 1.5 mg/kg. Reduced to 0.8 mg/kg in 2 children due to adverse effects Duration: 3 months Placebo: identical, placebo phase duration 1 month
OutcomesWeight Behavior Summarised Evaluation Urinary dopamine metabolites
Notes 
Risk of bias
ItemAuthors' judgementDescription
Blinding?UnclearUnclear if there was blinding of outcome assessors
Incomplete outcome data addressed? All outcomesYesNo loss to follow-up
Buchsbaum 2001
MethodsCross-over Participants blind Blinding of treating physicians unclear Blinding of outcome assessors unclear No loss to follow-up
ParticipantsN = 6 5 male, 1 female Mean age 30.5 ± 8.6 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.
InterventionsTreatment: fluoxetine starting dose 10 mg/day up to maximum dose 40 mg/day for 8 weeks Placebo not described. Duration of placebo phase = 8 weeks
OutcomesYale-Brown Obsessive Compulsive Scale Hamilton Rating Scale for Anxiety Clinical Global Impression Scale Positron Emission Tomography
Notes 
Risk of bias
ItemAuthors' judgementDescription
Blinding?UnclearUnclear if there was blinding of outcome assessors
Incomplete outcome data addressed? All outcomesYesNo loss to follow-up
Hollander 2005
MethodsCross-over Outcome assessors blind Randomisation method not stated 44 children randomised of 62 consented. 5 lost to follow-up
ParticipantsN = 44, 39 completed 30 males, 9 females mean age 8.18 ± 3.0, 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
InterventionsTreatment: fluoxetine 8 weeks treatment, 4 weeks washout, 8 weeks cross-over 2.5 mg/day up to 0.8 mg/kg/day maximum
OutcomesYale-Brown Obsessive-Compulsion Scale Clinical Global Improvement Scale Adapted to Global Autism Suicidality Subscale of Overt Aggression Scale Fluoxetine side effects checklist
Notes 
Risk of bias
ItemAuthors' judgementDescription
Blinding?YesOf outcome assessors
Incomplete outcome data addressed? All outcomesNoLoss to follow-up of one non-responder and three who were non-compliant and no intention to treat analysis possible
King 2009
MethodsMulticentre trial (six centres) Randomisation using permuted blocks with randomly varying block sizes stratified by site and age Outcome assessor blind to treatment allocation
Participants149 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% > 70 non-verbal IQ
InterventionsLiquid citalopram obtained commercially. Placebo matched for smell, taste and viscosity.
OutcomesCGI 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
ItemAuthors' judgementDescription
Adequate sequence generation?Yes 
Allocation concealment?Yes 
Blinding?YesOutcome assessor "masked"
Incomplete outcome data addressed? All outcomesYesITT analyses used
Free of selective reporting?YesRegistered trial
Leventhal 1993
MethodsTwo phase: placebo-treatment-placebo followed by randomised cross-over "double blind" no details
ParticipantsN = 15 3-12.5 yrs (mean age 7.6 ± 2.6yrs). Children only Diagnosis infantile autism DSM-III No loss to follow-up. Incomplete data for some outcomes IQ range 16-63. Obsessive-compulsive behaviours not required.
InterventionsFenfluramine
OutcomesRitvo-Freeman Real Life Rating Scale Connors Abbreviated Parent and Teacher Questionnaires
NotesPrevious use of fenfluramine
Risk of bias
ItemAuthors' judgementDescription
Blinding?UnclearUncertain if outcome assessors blind to treatment group
Incomplete outcome data addressed? All outcomesUnclearNo loss to follow-up but incomplete data for some outcomes
McDougle 1996
MethodsParticipants blind Treating physicians blind Outcome assessors blind No loss to follow-up
ParticipantsN = 30 27 males, 3 females Mean age 30.1 ± 7.7 yrs, age range 18-53 yrs. Adults only Diagnosis of autism using DSM-III-R and ICD-10 at least "moderate" in severity using the CGI global severity of illness rating Obsessive-compulsive behaviours not required
InterventionsFluvoxamine to max. 300 mg/day for 9-12 weeks Identical placebo, 9-12 weeks Equality of treatment between groups Compliance measure unclear
OutcomesRitvo-Freeman Real Life Rating Scale Clinical Global Impression Scale, global improvement Brown Aggression Scale Vineland Maladaptive Behavior Yale-Brown Obsessive Compulsive Scale
Notes 
Risk of bias
ItemAuthors' judgementDescription
Blinding?YesOutcome assessors blind to treatment group
Incomplete outcome data addressed? All outcomesYesNo loss to follow-up
Sugie 2005
MethodsCross-over Computer-based randomisation "double-blind" parents/carers, participants, treatment team.
ParticipantsN = 19, 18 completed 15 males, 4 females Mean age 5.3 yrs, range 3-8.4 yrs. Children only Diagnosis: DSM-IV Autism 1 lost to follow-up
InterventionsPlacebo or fluvoxamine 1 mg/kg/day for 2 weeks, 2 mg/kg/day for 3 weeks, 3 mg/kg/day for 6 weeks, 1.5 mg/kg/day for 2 weeks, 2 week washout, cross-over.
OutcomesBehavioural Assessment Scale Clinical Global Impression Scale
NotesHaematological and molecular genetic analysis
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputer generated randomisation sequence
Allocation concealment?Yes 
Blinding?UnclearUnclear if outcome assessors blind to treatment group
Incomplete outcome data addressed? All outcomesYes 
Free of selective reporting?No 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Doyle 2001Not trial of SSRIs. Cost analysis Not RCT, no placebo
Gordon 1993Clomipramine: not SSRI
Humble 2001Participants not ASD
McDougle 1998Open-label, non-randomised, no placebo control
Peral 1999Open-label, no randomisation, no placebo
Remington 2001Clomipramine: not SSRI
Sanchez 1996Open-label, not RCT

Data and analyses

Download statistical data

This review has no analyses.

Appendices

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     PDD.tw.

5     pervasive developmental disorder$.tw.

6     (language adj3 delay$).tw.

7     (speech adj3 disorder$).tw.

8     childhood schizophrenia.tw.

9     kanner$.tw.

10     asperg$.tw.

11     or/1-10

12     Serotonin Uptake Inhibitors/

13     selective serotonin reuptake inhibitor$.tw.

14     SSRI.tw.

15     5-hydroxytryptamine.tw.

16     5HT.tw.

17     Fluvoxamine/

18     fluvoxamine.tw.

19     fluvocamine.tw.

20     Fluoxetine/

21     fluoxetine.tw.

22     Paroxetine/

23     paroxetine.tw.

24     Sertraline/

25     sertraline.tw.

26     Citalopram/

27     citalopram.tw.

28     venlafaxine.tw.

29     or/12-28

30     11 and 29

31     randomized controlled trial.pt.

32     controlled clinical trial.pt.

33     randomized.ab.

34     placebo.ab.

35     drug therapy.fs.

36     randomly.ab.

37     trial.ab.

38     groups.ab.

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

40     humans.sh.

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 near/3 delay*)

#7 speech near/3 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

1     exp Child Development Disorders, Pervasive/

2     communicat$.tw.

3     autis$.tw.

4     PDD.tw.

5     pervasive developmental disorder$.tw.

6     (language adj3 delay$).tw.

7     (speech adj3 disorder$).tw.

8     childhood schizophrenia.tw.

9     kanner$.tw.

10     asperg$.tw.

11     or/1-10

12     Serotonin Uptake Inhibitors/

13     selective serotonin reuptake inhibitor$.tw.

14     SSRI.tw.

15     5-hydroxytryptamine.tw.

16     5HT.tw.

17     Fluvoxamine/

18     fluvoxamine.tw.

19     fluvocamine.tw.

20     Fluoxetine/

21     fluoxetine.tw.

22     Paroxetine/

23     paroxetine.tw.

24     Sertraline/

25     sertraline.tw.

26     Citalopram/

27     citalopram.tw.

28     venlafaxine.tw.

29     or/12-28

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 procedure.tw.

44     Randomized Controlled Trial/

45     Single Blind Procedure/

46     or/31-45

47     30 and 46

Appendix 4. ERIC search strategy

ERIC (via Dialog Datastar) Searched December 2009

1 Pervasive-Developmental-Disorders#.DE.  

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     PDD.tw.

5     pervasive developmental disorder$.tw.

6     (language adj3 delay$).tw.

7     (speech adj3 disorder$).tw.

8     childhood schizophrenia.tw.

9     kanner$.tw.

10     asperg$.tw.

11     or/1-10

12     Serotonin Reuptake Inhibitors/

13     selective serotonin reuptake inhibitor$.tw.

14     SSRI.tw.

15     5-hydroxytryptamine.tw.

16     5HT.tw.

17     Fluvoxamine/

18     fluvoxamine.tw.

19     fluvocamine.tw.

20     Fluoxetine/

21     fluoxetine.tw.

22     Paroxetine/

23     paroxetine.tw.

24     Sertraline/

25     sertraline.tw.

26     Citalopram/

27     citalopram.tw.

28     venlafaxine.tw.

29     or/12-28

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     randomi#ed 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 "Quantitative Studies")      

S42   (MH "Placebos")     

S41   placebo*      

S40   random* allocat*       

S39   (MH "Random Assignment")       

S38   (Randomi?ed 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    

S28   S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27

S27   Venlafaxine    

S26   (MH "Venlafaxine")       

S25   Citalopram      

S24   (MH "Citalopram")       

S23   Sertraline       

S22   (MH "Sertraline Hydrochloride")    

S21   Paroxetine     

S20   (MH "Paroxetine")    

S19   (MH "Fluoxetine")    

S18   fluoxetine      

S17   fluvoxamine or fluvocamine  

S16   5HT        

S14   SSRI    

S13   selective serotonin reuptake inhibitor*   

S12   (MH "Serotonin Uptake Inhibitors")       

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 "Child Development Disorders, Pervasive+")   

Appendix 7. Sociological Abstracts

Sociological Abstracts searched 10 December 2009

(((DE="autism") 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))

What's new

DateEventDescription
4 August 2010AmendedTypographical error corrected.

History

Protocol first published: Issue 1, 2004

Review first published: Issue 8, 2010

DateEventDescription
7 November 2008AmendedConverted to new review format

Contributions of authors

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.

Declarations of interest

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.

Sources of support

Internal sources

  • Small Grants Scheme, The Children's Hospital at Westmead, Sydney, Australia.

External sources

  • Financial Markets Foundation for Children, Australia.

  • Department of Health and Aging, Australia.

    Cochrane Entities funding

Differences between protocol and review

No significant changes were made to the protocol.

Ancillary