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

1. Selective serotonin reuptake inhibitors for autism spectrum disorders: a Cochrane Review Clinical www.cochranejournalclub.com

2. Clinical questions 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. www.cochranejournalclub.com 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? 2

3. Context www.cochranejournalclub.com 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 benefits. 3

4. Methods www.cochranejournalclub.com 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. 4

5. PICO(S) to assess eligible studies www.cochranejournalclub.com 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.

6. Description of eligible studies www.cochranejournalclub.com 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.

7. Results - children www.cochranejournalclub.com 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. 7

8. Results - adults www.cochranejournalclub.com 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. 8

9. Results – adverse effects www.cochranejournalclub.com 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. 9

10. Conclusions - children www.cochranejournalclub.com 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. 10

11. Conclusions - adults www.cochranejournalclub.com The possible risk of bias and small sample size of the existing research makes clear recommendations impossible at this time. 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. 11

12. Future research - 1 www.cochranejournalclub.com Replication of the citalopram study (which recruited 149 children) would confirm or refute the absence of an important effect on core symptoms in children. 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. 12

13. Future research - 2 www.cochranejournalclub.com • 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 13

14. Useful links Cochrane Journal Club discussion points Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) www.cochranejournalclub.com