title: Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents.
abstract: BACKGROUND
  Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders, ranging in severity and characterised by early onset of delay and deviance in the development of social interaction, and verbal and nonverbal communication. ASD is associated with restricted and/or stereotyped interests or behaviours. Tricyclic antidepressants (TCAs) block noradrenaline and serotonin reuptake, increasing the availability of these neurotransmitters in the central nervous system. Via their impact on serotonin, TCAs have been used in the treatment of autistic symptoms and comorbidities in individuals with ASD.
  
  
  OBJECTIVE
  To determine if treatment with tricyclic antidepressants:1) improves the core features of autism, including restricted social interaction, restricted communication, and stereotypical and repetitive behaviours; 2) improves non-core features such as challenging behaviours; 3) improves comorbid states, such as depression and anxiety; 4) causes adverse effects.
  
  
  METHODS
  We ran the latest searches for this review on 23 May 2011. We searched: Cochrane Central Register of Controlled Trials (CENTRAL), 2011 Issue 2, MEDLINE (1948 to May Week 2, 2011), EMBASE (1980 to 2011 Week 2), PsycINFO (1887 to current), CINAHL (1937 to current). We also searched Dissertation Abstracts International via Dissertation Express, and the metaRegister of Controlled Trials.
  
  
  METHODS
  Randomised controlled trials of any dose, duration and frequency of oral TCAs compared with placebo, in children and adolescents with a diagnosis of ASD, where at least one standardised outcome measure had been used.
  
  
  METHODS
  Two review authors independently selected and appraised the studies for inclusion and risk of bias. All data were continuous.
  
  
  RESULTS
  Three studies met the inclusion criteria for this review. Two studies used clomipramine and one used tianeptine. All three trials were small, with between 12 and 32 participants. One of the clomipramine trials involved children and young adults, while the other two trials enrolled only children. Due to heterogeneity in study participant characteristics, the TCA medications investigated and the outcome measures used, we were not able to perform any meta-analysis.In only one of the three studies was there any indication that giving children tianeptine could be effective in the short term. In this study, parents and teachers reported that it reduced irritability, hyperactivity, inadequate eye contact and inappropriate speech, but clinician ratings found no significant impact on these symptoms. There were also significant adverse effects, including increased drowsiness and reduced activity levels in these individuals while being treated with tianeptine. The evidence of the impact of clomipramine in the two studies is contradictory. There was evidence of improvement in autistic symptoms, irritability and obsessive-compulsive disorder type symptoms, but conflicting evidence in relation to hyperactivity across the two studies, and no significant changes found with inappropriate speech. There were also adverse effects reported with the use of clomipramine. Although side effect ratings were not significantly different to placebo, there were significant dropout rates in the clomipramine arm of one study.
  
  
  CONCLUSIONS
  Clinicians considering the use of TCAs need to be aware of the limited and conflicting evidence of effect and the side effect profile when discussing this treatment option with people who have ASD and their carers. Further research is required before TCAs can be recommended for treatment of individuals with ASD.
authors.affiliation: Department of Community Paediatrics, Sydney South West Local Health District, Liverpool Hospital, Liverpool BC, Australia.hurwie@hotmail.com.
authors.forename: Romy
authors.initials: R
authors.lastname: Hurwitz
authors.forename: Roger
authors.initials: R
authors.lastname: Blackmore
authors.forename: Philip
authors.initials: P
authors.lastname: Hazell
authors.forename: Katrina
authors.initials: K
authors.lastname: Williams
authors.forename: Susan
authors.initials: S
authors.lastname: Woolfenden
mesh_terms: D000293:Adolescent; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000188:drug therapy*; D002997:Clomipramine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D013841:Thiazepines / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000929:Antidepressive Agents, Tricyclic; D013841:Thiazepines; C050504:tianeptine; D002997:Clomipramine