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					 Selective serotonin reuptake
inhibitors for autism spectrum
 disorders: a Cochrane Review


                    Clinical questions
What are the benefits and harms of serotonin
reuptake inhibiting drugs when prescribed to
children and adults with an autism spectrum
disorder, over the short and longer term?

Source: 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: 10.1002/14651858.CD004677.pub2.

• Autism spectrum disorders (ASD) cause varying levels of
  lifelong disability.
• Individuals affected require specialist health, educational and
  community services.
• Serotonin enhancing drugs are increasingly prescribed to
  individuals with ASD in the hope that these will reduce core or
  associated symptoms.
• In other clinical contexts, these drugs are known to cause
  harm in some young people, which may outweigh their

• The following databases were searched, most
  recently in December 2009, the Cochrane
  Central Register of Controlled Trials, MEDLINE,
  EMBASE, CINAHL, PsycINFO, Sociological
  Abstracts and ERIC.
• The outcomes examined across the eligible
  studies were too varied to allow their findings
  to be combined in meta-analyses.

   PICO(S) to assess eligible studies
• Participants: People of any age with a diagnosis of ASD established with a
  standardized diagnostic interview.
• Intervention: Oral selective serotonin reuptake inhibitors (SSRIs), at any
  dose or frequency of administration.
• Comparison: Placebo.
• Outcomes: Core features of ASD (including social interaction,
  communication, stereotypic or repetitive behaviour, and restricted
  interests or activities), non-core aspects of ASD (such as sleep disturbance,
  self-mutilation, aggression, attention and concentration problems, and
  gastrointestinal function), global assessment of health and function,
  quality of life (for the individual or their family), and adverse events.
• Studies: Randomized trials.

     Description of eligible studies
• Seven trials were included, with a total 271 participants.
• 149 of the participants were in a single trial, testing
  citalopram in children.
• Four other studies recruited children (3-17 years), testing
  fenfluramine, fluoxetine, fluvoxamine.
• Two studies recruited adults (18-53 years), testing fluoxetine
  and fluvoxamine.
• One trial (in children) permitted prior exposure to an SSRI.
• Seventeen different standardised outcome measures were
  used in the seven trials.
• No study assessed quality of life or longer term benefits.
                Results - children
• No improvements were detected for citalopram or
  fenfluramine on composite scores derived by combining
  clinical global impression and obsessive compulsive ratings.
• No improvements were detected for citalopram or fluoxetine
  on clinical global impression scores.
• No improvements were detected for citalopram or fluoxetine
  on obsessive-compulsive symptoms.
• Some statistically significant improvements were found for
  citalopram or fenfluramine on one or two subscales of some
  comprehensive behaviour rating scales.

                Results - adults
• The trial of fluvoxamine reported a statistically
  significant improvement on clinical global impression
  scores, improvements on obsessions and
  compulsions, and a reduction in aggression.
• The trial of fluoxetine reported improvements for
  obsessions and anxiety, but not for depression.

          Results – adverse effects
• Citalopram: 97% of children experienced treatment emergent
  adverse events compared with 87% on placebo, based on a
  semi-structured side effect rating scale. One child who
  received citalopram experienced prolonged seizures.
• Fenfluramine: 4 of 13 children required dose reduction
  because of adverse events. Weight loss was significantly
  greater in the first month of treatment compared to placebo,
  but stabilized thereafter.
• Fluvoxamine was well tolerated in adults, with only minor and
  transient adverse effects reported.

               Conclusions - children
• There is no evidence that SSRIs are an effective treatment for children
  with autism, and emerging evidence that they are not effective and can
  cause harm. Therefore, SSRIs cannot be recommended as a treatment for
  children with autism at this time.
• As ASD causes substantial impairment, parents of children with ASD are
  motivated to try treatments regardless of the evidence. Prescribing
  clinicians should be explicit with them about the limited evidence, discuss
  the potential harms, and discuss other pharmacological and non-
  pharmacological interventions.
• Decisions about the use of SSRIs for established clinical indications that
  may co-occur with autism, such as obsessive-compulsive disorder,
  depression, and anxiety should be made on a case-by-case basis.
• Some SSRIs have not been tested in controlled trials for ASD.
               Conclusions - adults
• The possible risk of bias and small sample size of the existing
  research makes clear recommendations impossible at this
• Small positive effects have been seen, with fewer side effects
  than have been reported among children.
• Decisions about the use of SSRIs for established clinical
  indications that may co-occur with autism, such as obsessive-
  compulsive disorder, depression, and anxiety should be made
  on a case-by-case basis.
• Some SSRIs have not been tested in controlled trials for ASD.

                  Future research - 1
• Replication of the citalopram study (which recruited 149 children) would
  confirm or refute the absence of an important effect on core symptoms in
• Adequately powered randomised trials of at least one other SSRI (such as
  fluoxetine) should be conducted in children.
• Sufficiently large randomised trials would permit assessments of benefits
  and harms in subgroups of children, such as pre-puberty versus puberty,
  and low IQ versus normal IQ.
• Improvements in knowledge about the benefits and harms of SSRIs for
  adult autism require at least one adequately powered randomised trial of
  a commonly used drug, such as fluoxetine.

                    Future research - 2
• If short term benefit for one or more key clinical outcomes is established
  in future trials, sustained benefit could be explored in a relapse prevention
  trial conducted over 12-18 months. This is important because treatments
  directed to autism tend to be long term. Such a trial would also allow the
  collection of adverse event data over a longer period.
• Comparison between trials would be aided by the use of a core battery of
  standard outcome measures. As a minimum, we recommend:
    –   a measure of global functioning
    –   a measure of repetitive and stereotyped behaviours
    –   a measure of disruptive behaviour
    –   a measure of obsessive compulsive symptoms

                Useful links
• Cochrane Journal Club discussion points

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


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