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Cochrane Database of Systematic Reviews

Tricyclic antidepressants for autism spectrum disorders (ASD)


in children and adolescents (Review)

Hurwitz R, Blackmore R, Hazell P, Williams K, Woolfenden S

Hurwitz R, Blackmore R, Hazell P, Williams K, Woolfenden S.


Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents.
Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD008372.
DOI: 10.1002/14651858.CD008372.pub2.

www.cochranelibrary.com

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 31
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) i
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Tricyclic antidepressants for autism spectrum disorders


(ASD) in children and adolescents

Romy Hurwitz1 , Roger Blackmore1 , Philip Hazell2 , Katrina Williams3 , Susan Woolfenden4

1 Department of Community Paediatrics, Sydney South West Local Health District, Liverpool Hospital, Liverpool BC, Australia.
2 Disciplineof Psychiatry, Sydney Medical School, Concord West, Australia. 3 Department of Developmental Medicine, Royal Chil-
dren’s Hospital, Parkville, Australia. 4 Sydney Children’s Hospitals Network, Sydney Children’s Community Health Centre, Randwick,
Australia

Contact address: Romy Hurwitz, Department of Community Paediatrics, Sydney South West Local Health District, Liverpool Hospital,
Hugh Jardine Building, Locked Bag 7017, Liverpool BC, NSW, 1871, Australia. hurwie@hotmail.com.

Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.


Publication status and date: New, published in Issue 3, 2012.
Review content assessed as up-to-date: 23 November 2011.

Citation: Hurwitz R, Blackmore R, Hazell P, Williams K, Woolfenden S. Tricyclic antidepressants for autism spectrum dis-
orders (ASD) in children and adolescents. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD008372. DOI:
10.1002/14651858.CD008372.pub2.

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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.

Objectives

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.

Search 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.
Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 1
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selection criteria

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.

Data collection and analysis

Two review authors independently selected and appraised the studies for inclusion and risk of bias. All data were continuous.

Main 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.

Authors’ 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.

PLAIN LANGUAGE SUMMARY

Tricyclic antidepressant medication for treating children and adolescents with an autism spectrum disorder

Autism spectrum disorders (ASD) are characterised by problems with social interaction and verbal and non-verbal communication,
as well as restricted and repetitive interests and behaviours. Tricyclic antidepressants (TCAs) are medications that alter the level of
the neurotransmitter serotonin and have been used in the treatment of autistic symptoms, anxiety and obsessive-compulsive type
behaviours. We found three trials that studied two different TCAs - clomipramine and tianeptine. One of the clomipramine studies
involved children and young adults; the other two studies enrolled only children. All three trials were small, with between 12 and 32
participants. There is only limited evidence to support the use of clomipramine or tianeptine in the treatment of individuals with ASD,
and some evidence of side effects that would limit their usefulness. Clinicians considering the use of TCAs in ASD need to be aware of
the limited and conflicting evidence of effect and the side effect profile of TCAs when discussing this treatment option with patients
with ASD and their carers. More research is required before TCAs can be recommended for use in ASD.

BACKGROUND Autism spectrum disorders refer to a continuum of heterogeneous


disorders that display varied severity of deficits, ranging from mild
to very severe, of which autism is the prototype (Caronna 2008).
Description of the condition Autism is a complex neurodevelopmental disorder characterised

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 2
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
by the early onset of patterns of delay and deviance in the develop- are more selective for serotonin transport and the secondary amines
ment of social interaction, verbal and non-verbal communication are relatively more selective for noradrenaline transport.
and other skills, and is associated with restricted and/or stereotyp-
ical patterns of interest or behaviour. The autism spectrum dis-
orders (ASD), which include Childhood Autism or Autistic Dis-
order, Pervasive Developmental Disorder - Not Otherwise Spec- How the intervention might work
ified (PDD-NOS), Atypical Autism and Asperger Syndrome, are
In people with ASD there have been reports of high levels of whole
usually diagnosed using either the DSM-IV (APA 2000) or ICD-
blood and platelet serotonin, an inhibitory neurotransmitter in
10 (WHO 1993) classification systems. Intellectual disability is
the central nervous system that is involved in the regulation of
the most commonly associated condition in people with ASD,
multiple functions including mood and emotions (Cook 1996;
with approximately 50% having a comorbid intellectual disability
Hranilovic 2007). Pharmacological interventions are not curative
(Nishiyama 2009). However, ASD can include individuals with
in ASD, but may provide assistance with problematic symptoms or
intellectual functioning ranging from the disability to superior
comorbidities. Pharmacological interventions that target the sero-
range, and autistic symptoms can be equally severe in those with
tonin system may provide assistance with problematic symptoms
average and above-average IQ (Joseph 2002).
such as repetitive behaviours similar to those seen in obsessive-
Difficulties resulting from ASD are usually lifelong and present a
compulsive disorders, stereotyped mannerisms and difficulty with
significant burden on the families of autistic individuals and on
change, or with comorbidities such as affective lability, depression
society, with estimates indicating that only 3% to 10% are able to
and anxiety (Volkmar 2004).
live independently (Howlin 2004; Billstedt 2007).
It has been suggested that TCAs may be useful in the manage-
Estimates of the prevalence of autism vary between 1 and 40 per
ment of patients with ASD through their impact on serotonin.
10,000 and for any ASD between 3 and 82 out of 10,000 (from
Serotonin is involved in multiple neurobiological pathways that
published literature up to April 2004; Williams 2006). Publica-
may be altered in people with ASD, including those that mediate
tions from 2006 have estimated the prevalence of any ASD at be-
mood, social interaction, sleep, obsessive-compulsive behaviours
tween 22 and 116 out of 10,000 (Chakrabarti 2005; Fombonne
and aggression. TCAs are usually used for the relief of symptoms
2005; Baird 2006; Guillem 2006). ASD are three to four times
of depression and are effective in the treatment of panic and obses-
more common in boys than in girls (WHO 1993; Fombonne
sive-compulsive disorders (particularly the serotoninergic TCAs).
1999). It is unclear whether recent suggestions of increasing rates
Through their effects on serotonin in the central nervous system,
are due to a real increase in the occurrence of the disorder or merely
it is plausible that tricyclic antidepressants may have an impact
reflect changing study methods, a broadening of the criteria used
on autistic symptoms and the comorbid disorders that these pa-
for diagnosis and increased awareness of ASD.
tients experience, improving their quality of life and that of their
carers and families. However, the use of tricyclic antidepressants
in children and adolescents has been limited by concerns about
Description of the intervention a narrow therapeutic index and a high toxicity profile. TCAs ex-
Treatment of ASD is aimed at improving the overall functioning ert effects on cholinergic, histaminergic and adrenergic receptors,
of the child. Behavioural and educational interventions are the resulting in physical and cognitive adverse effects. Side effects in-
main focus of treatment, with pharmacological treatments used as clude dry mouth, constipation, urinary retention, blurred vision,
adjuncts (Posey 2001). Pharmacological treatment in ASD may sinus tachycardia, impaired cognition, sedation, impaired motor
focus on a variety of issues, including core symptoms, associated function, weight gain, hypotension, balance problems, impaired
challenging behaviours and comorbid conditions. For example, co-ordination and orthostatic hypotension (Peretti 2000). The se-
people with high levels of repetitive, obsessive-compulsive type dating effects of TCAs can be useful in treating anxiety and insom-
behaviours and mood disorders may experience some relief of nia, but some patients find these medications oversedating. Even
their symptoms through the use of pharmacological interventions at therapeutic doses, tricyclic antidepressants have a potent mem-
(Posey 2001). brane stabilising property, which can lead to cardiac conduction
Tricyclic antidepressants consist of tertiary (amitriptyline, abnormalities, including prolonged PR, QRS and QT intervals,
imipramine) and secondary amines (desipramine, nortriptyline) raising the concern of potential cardiotoxicity and sudden death, as
(Sadock 2005). Tricyclic antidepressants block noradrenaline and well as lowering seizure thresholds (Findling 1999; Peretti 2000).
serotonin reuptake at presynaptic neurons, resulting in increased In overdose, tricyclic antidepressants cause cardiac dysrhythmias,
availability of these neurotransmitters in the central nervous sys- central nervous system depression and seizures (Findling 1999).
tem. After long-term administration they also impact upon recep- The side effects of tricyclic antidepressants tend not to decrease in
tor sensitivity, and the number and function of adrenergic and severity with long-term therapy, and may result in reduced com-
serotonergic receptors, including up-regulating postsynaptic sero- pliance and early termination of therapy (Peretti 2000). In addi-
tonin receptors (Potter 1998; Sadock 2005). The tertiary amines tion, due to the effect on central nervous system amine neuro-

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 3
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
transmitters, tricyclic antidepressant usage may result in mania or Types of interventions
aggravation of psychotic symptoms. Any oral tricyclic antidepressants, regardless of dosage used, dura-
tion of use or frequency of administration, compared with placebo.
Tricyclic antidepressants include amitriptyline (amitriptyline
hydrochloride), amoxapine, clomipramine (clomipramine hy-
Why it is important to do this review drochloride), dothiepin (dosulepin hydrochloride or dothiepin
A systematic review of tricyclic antidepressants for the treatment hydrochloride), doxepin, imipramine (imipramine hydrochlo-
of ASD is required to evaluate their potential benefits and safety. ride), iofepramine, nortriptyline, trimipramine, desipramine, flor-
piramine, dibenzepin, iprindole, protriptyline and modified tri-
cyclic antidepressants such as tianeptine.

Types of outcome measures


OBJECTIVES

To evaluate the use of tricyclic antidepressants in people with Primary outcomes


autism spectrum disorders. The objectives are to determine if treat- • Core symptoms of autism, for example, impairments in
ment with tricyclic antidepressants: communication, reciprocal social interaction and behavioural
problems, such as repetitive behaviours and rituals, obsessional
1. improves the core features of autism, including restricted behaviour and stereotypy.
social interaction, restricted communication and stereotypical • Non-core symptoms, including challenging behaviours,
and repetitive behaviours; sleep disturbance and aggression.
• Comorbidities, including depression and anxiety.
2. improves non-core features such as challenging behaviours; • Adverse effects.

3. improves comorbid states, such as depression and anxiety;


and Secondary outcomes
• Parental, child or family quality of life.
4. causes adverse effects. • Parental or family stress.
We planned to examine short-term (up to three months), medium-
term (three to 12 months) and long-term (greater than 12 months)
METHODS outcomes if the data were available.
We used the primary and secondary outcomes to populate the
’Summary of findings’ tables.
Types of measures:
Criteria for considering studies for this review 1. Standardised diagnostic assessment instruments
(Childhood Autism Rating Scale, Autism Diagnostic Interview-
Revised, Autism Diagnostic Observation Schedule, Diagnostic
Interview for Social and Communication Disorders).
Types of studies 2. Standardised communication assessments.
3. Quality of life questionnaires.
Randomised controlled trials (RCTs).
4. Rating scales of emotions and behaviour, including
depression, anxiety, aggression, obsessive-compulsive behaviour
and social reciprocity.
Types of participants 5. Global Clinical Impression Rating Scales.
Inclusion was limited to children and adolescents (birth to 18 years 6. Other Health Outcome Rating Scale.
of age) with a diagnosis of an autism spectrum disorder (ASD),
using a standardised diagnostic instrument (for example, ADOS,
ADI-R, DISCO, CARS) or using established diagnostic criteria as Search methods for identification of studies
defined by DSM-IV or ICD-10, that is Pervasive Developmental
Disorder, excluding Rett Syndrome and Childhood Disintegrative
Disorder. Electronic searches

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 4
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We identified relevant trials through electronic searches of the bias against the following criteria: random sequence generation,
following databases. Searches were first run in July 2009 with no allocation concealment, blinding of participants, personnel and
date or language limits. They were updated on 23 May 2011, using outcome assessors, incomplete outcome data, selective outcome
date limits to restrict the search to the period since the previous reporting and other sources of bias. Regarding selective reporting,
searches. we had a high index of suspicion of selective reporting if the pri-
• Cochrane Central Register of Controlled Trials mary outcomes to be assessed in this review were not presented in
(CENTRAL), part of the Cochrane Library, 2011 Issue 2. included trials. We assigned each selected study a judgement re-
• MEDLINE (1948 to May Week 2, 2011) lating to the risk of bias for that study by answering a prespecified
• EMBASE (1980 to 2011 Week 2) question about the study’s adequacy in relation to each of the key
• PsycINFO (1887 to current) criteria. Judgements were low risk of bias, high risk of bias and un-
• CINAHL (1937 to current) clear risk of bias, which was used if the risk of bias was unknown.
• Dissertation Abstracts International There were no disagreements about risk of bias assessments. We
• metaRegister of Controlled Trials also explored any other potential sources of bias, such as stopping
a study early or baseline imbalance.
The search strategies are in Appendix 1.

Measures of treatment effect


Searching other resources
If two or more studies had been identified that were suitable for
We also searched bibliographies of articles identified through the
inclusion, measured the same outcomes and were considered to
search strategy and contacted known experts in the field.
be sufficiently homogeneous, we would have performed a meta-
analysis of the results. Meta-analyses were not completed in this
review. If possible in updates we will use odds ratio (OR) in prefer-
Data collection and analysis ence to risk ratio (RR) and Mantel-Haenszel Chi2 statistic (MH)
to best handle small sample size.

Selection of studies
Two authors (RH, RB) independently screened titles and abstracts Dichotomous data
from the search in 2009 and the search in 2011. Those that did Where outcomes from either standardised instruments or diag-
not fulfil the inclusion criteria were discarded. Potentially relevant nostic evaluations were expressed as proportions, we would have
articles were retrieved for full-text assessment, assessment of eli- calculated the risk ratio (RR) with 95% confidence interval (CI)
gibility and data extraction, which the same authors again con- from meta-analysis. We would have calculated number needed to
ducted independently. Disagreements were arbitrated by a third treat if a positive effect for tricyclic antidepressant therapy were
author (SW). The review authors were not blinded to the name(s) found, using the risk ratio estimate and the control risk from the
of the study author(s), their institution(s) or publication sources placebo group.
at any stage of the review.
Continuous data
Data extraction and management Where standardised assessment tools generated a score as the out-
Data extraction forms were developed a priori and these included come measure, we made comparisons between the means of these
information regarding methods, participant details, dose and fre- scores. It was felt that it would be ideal to present data from AN-
quency of tricyclic antidepressant administration, and outcomes. COVA analysis, to take account of potential baseline differences,
Two authors (RH, RB) extracted data independently using this but that is not always possible. Where only endpoint scores or
form. Disagreements were resolved by negotiation with SW. These change scores were available these were used. Where possible, we
data were organised using Review Manager 5 (RevMan 2008). would have calculated the mean difference as the summary statis-
We contacted authors for clarification or additional information tic by meta-analyses. When standard deviations (SDs) or standard
as necessary. One non-English language article was identified, and errors (SEs) were not available, we extracted P value, t value and
translation was arranged. CI data so that SDs and SEs could be imputed. Where the same
clinical constructs are measured using different scales, we planned
to use the standardised mean difference (SMD). The use of a final
Assessment of risk of bias in included studies value or change score did not arise in this review as there was not
In accordance with the Cochrane Handbook for Systematic Reviews a situation where both were available. In future reviews if change
of Interventions (Higgins 2008), two authors (RH, RB) indepen- score or ANOVA analyses that take baseline into account are avail-
dently evaluated studies for methodological quality and risk of able, these will be used in preference to final value scores.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 5
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Unit of analysis issues effects analyses as part of a sensitivity analysis, but this was not
We assessed all included trials to determine the unit of randomi- relevant to this review as no meta-analysis was possible.
sation and whether or not this unit of randomisation was consis- For the ’Summary of findings’ tables we assessed quality of evidence
tent with the unit of analysis. Where cross-over trials were used, using the GRADE system (Higgins 2008). The assumed risk for
we extracted mean and standard error of paired t-tests. No unit the ’Summary of findings’ tables came from the placebo group
of analysis errors were identified. In all included studies randomi- summary estimate.
sation, reporting and analysis were conducted as per individual
participant.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were not possible due to a lack of data for meta-
Dealing with missing data analysis. Anticipated clinical differences had included:
• age of participants, i.e. adult versus paediatric;
Where possible, missing data and drop-outs were assessed and re-
• levels of intellectual disability, i.e. none, mild, moderate,
ported for each included study. We intended to report the number
severe;
of participants included in the final analysis as a proportion of all
• diagnostic classification - Autistic Disorder/Classical
participants in each study. We reported reasons for missing data
Autism versus Asperger’s Disorder versus Pervasive
where they were provided in the published trials. Where data could
Developmental Disorder-NOS; and
not be included in a meta-analysis, as was the case in this review,
• medication, i.e. different types of tricyclic antidepressants
we included a qualitative summary in the text of the review.
used for treatment, dose.

Assessment of heterogeneity
Sensitivity analysis
We assessed consistency of results by visually inspecting the for-
Sensitivity analysis was planned to assess the impact of study risk
est plots, by performing the Chi2 test for heterogeneity to as-
of bias on the results of meta-analyses. However, it was not possible
sess whether observed differences in results were compatible with
to do this as the data were not adequate for meta-analysis.
chance alone (where a significance level less than 0.10 was in-
terpreted as evidence of heterogeneity) and by examining the I2
statistic (Higgins 2008), a quantity that describes approximately
the proportion of variation in point estimates that is due to het-
erogeneity rather than sampling error. We assessed heterogeneity RESULTS
using the I2 statistic using the current recommendations in the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2008): 0% to 40% might not be important; 30% to 60% may rep- Description of studies
resent moderate heterogeneity; 50% to 90% may represent sub-
stantial heterogeneity, and 75% to 100% represents considerable
heterogeneity. Results of the search
Electronic literature searches were conducted in July 2009 and
yielded 114 titles. The search was updated in May 2011, yielding
Assessment of reporting biases
an additional 47 titles. We excluded 140 articles because they were
Insufficient studies were found to use funnel plots to investigate not randomised controlled trials or were not about participants
any relationship between effect size and study precision (closely with ASD. Following full paper review of the remaining 21 articles,
related to sample size). three randomised controlled trials, all of which were cross-over
trials, met the inclusion criteria for full data extraction. A further
14 review articles identified in the original literature reviews were
Data synthesis
searched, but no additional references were identified.
Insufficient studies measured the same outcome construct, so
meta-analysis was not possible.The intention was that, had two
or more studies been suitable for inclusion and had measured the Included studies
same outcome construct, that we would have performed a meta-
analysis of the results, initially of all tricyclic antidepressants to-
gether and if high heterogeneity had been found we would then Characteristics of participants
have conducted relevant subgroup analysis and meta-analysis as re- Two studies used clomipramine. One of these studies was con-
quired. We would have performed both fixed-effect and random- ducted in children aged four to 15 years in Chicago, USA (Gordon

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 6
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1993). The other study, conducted in Toronto, Ontario, Canada, ranging from 12 (Niederhofer 2003) to 36 (Remington 2001).
involved 23 children and adolescents as well as eight adults and Two of the studies involved a third drug comparator. Gordon
five patients on the border of the adolescent age group (18 and 1993 included desipramine, a predominantly noradrenergic TCA,
19 years of age), with participants ranging in age from 10 years to in the third arm and Remington 2001 included haloperidol in
36 years (Remington 2001). The mean age in this study was 16.3 their third arm. Data were only extracted from the TCA versus
years, and as the majority of participants were within the child placebo branches of each of these studies. Although desipramine is
and adolescent age bracket, the authors felt that the results were a TCA, the data from this branch of Gordon’s study could not be
relevant to this review. included in the review as the effects of desipramine were compared
One randomised controlled trial was conducted in children to clomipramine and not placebo.
aged four to 15 years in Innsbruck, Austria, using tianeptine Treatment durations were short, with the clomipramine studies
(Niederhofer 2003). being conducted over five weeks (Gordon 1993) and seven weeks
Niederhofer 2003 used ICD-10 diagnostic criteria for Childhood (Remington 2001), and the tianeptine study being conducted over
Autism, requiring two independent Child and Adolescent Psy- six weeks (Niederhofer 2003).
chologists to agree on the diagnosis. Gordon 1993 used DSM-
IIIR and Autism Diagnostic Interview (ADI) criteria for Autis-
tic Disorder and Remington used DSM-IV criteria for Autistic Types of outcomes
Disorder, requiring independent confirmation of this diagnosis by
two investigators.
In two studies, participant IQ varied from 30 to 107 (mean 57)
Behaviour
(Gordon 1993) and 35 to 84 (mean 65) (Niederhofer 2003), re-
spectively. The authors of the third study did not report partici- Seven different standardised outcome measures were used in the
pant IQ or give any other indication of the participants’ level of three included trials (Table 1). Only the Aberrant Behaviour
functioning (Remington 2001). Checklist (ABC) was used in more than one study (Remington
One trial required that all participants be free of any medical or 2001; Niederhofer 2003). Niederhofer reported only parent and
neurological illnesses (Niederhofer 2003). Another required that teacher rating results for the ABC, whereas Remington used clin-
participants be free of medical illness and have no neurological or ician ratings of the ABC. It was felt that parent/teacher and clin-
genetic causes identified for their diagnosis of Autistic Disorder ician observations to assess for treatment effect would be suffi-
(Gordon 1993). ciently different such that these ratings should not be compared
Two studies required that their participants be medication-free for directly. Two studies used only clinician ratings but these two stud-
one month (Niederhofer 2003) or three months before the trial was ies did not have any common outcome measures (Gordon 1993;
started (Gordon 1993). The third required that the participants Remington 2001; see Table 1).
had not previously been prescribed clomipramine or haloperidol
or, if they had, that an adequate therapeutic trial had not been
completed (Remington 2001). The investigators in this study did, Side effects
however, allow participants to continue taking other psychoac- In addition, four scales and checklists were used for recognition
tive medications during the trial, with 13 of their 35 participants of adverse side effects in the three studies. Standardised checklists
taking additional medications. In all three trials, the participants were used in two studies, namely the Dosage Treatment Emergent
continued with their behavioural and educational interventions. Symptoms Checklist (DOTES) and the Extrapyramidal Symp-
One study had an additional drug-response specific inclusion cri- tom Rating scale (Remington 2001), and the Subjective Treat-
teria. The participants proceeded to the active phase of the trial ment Emergent Symptom Scale (Gordon 1993). One study group
only if they had a less than 20 percent improvement on behavioural designed their own symptom checklists (Niederhofer 2003).
rating scales after the two week placebo run-in (Gordon 1993).

Excluded studies
Types of study
Eighteen articles were excluded following full paper review. Nine
The three included studies used a double-blind, placebo-con- were found not to be randomised controlled trials or did not
trolled cross-over study design and all were conducted in out- include a placebo comparison arm in the trial (Kurtis 1966;
patient settings. One study included a one week washout phase Campbell 1971; Szekely 1980; Jaselskis 1992; McDougle 1992;
(Remington 2001). The remaining two studies had a one week Brasic 1994; ; Sanchez 1995; Sanchez 1996; Brodkin 1997). One
taper of one medication while the other was gradually increased in did not involve patients with the specific diagnosis of an ASD
the cross-over stage, but did not have a washout period (Gordon (Aman 1986). Six articles were commentaries, scientific theory pa-
1993; Niederhofer 2003). Numbers of participants were small, pers or case studies (Kehrer 1978; Weizman 1987; Magen 1993;

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 7
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Szabo 1994; Brasic 1997; Oesterheld 1997). One was a confer- Risk of bias in included studies
ence presentation that presented data from Remington 2001 com-
paring clomipramine and haloperidol to placebo treatments in
patients with ASD, and it was therefore not included (Sloman
Allocation
1998). For one study there was discussion amongst the researchers
regarding inclusion. This study was excluded because it did not
randomise the participants to a placebo-controlled group in com-
parison with a TCA, but instead all participants completed a two Random sequence generation
week placebo phase and were subsequently randomised to two Sequence generation was found to be adequate in two of the studies
intervention groups of clomipramine and desipramine (Gordon (Gordon 1993; Remington 2001). In the third, participants were
1992). Although desipramine is a tricyclic antidepressant, the data reported to be “randomly assigned” but no information was given
from this study could not be used as there was not a true placebo- about how the randomisation process was carried out (Niederhofer
control phase of the study. 2003). See Figure 1; Figure 2.

Figure 1. Risk of bias graph: review authors’ judgments about each risk of bias item presented as
percentages across all included studies.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 8
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 2. Risk of bias summary: review authors’ judgments about each risk of bias item for each included
study.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 9
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selective reporting
Allocation concealment
Two of the three studies were felt to be free of selective out-
Allocation concealment was adequate in all three studies (Gordon come reporting (Gordon 1993; Remington 2001). However, there
1993; Remington 2001; Niederhofer 2003). were concerns that there had been reporting of only those out-
comes which showed evidence of treatment effect in the third
(Niederhofer 2003). Only selected portions of the total number of
outcome measures were detailed in the report to show evidence of
Blinding
treatment effect, and these were only those completed by parents
In all three studies, participants and their carers, as well as those in- and teachers of the participants. The authors did not give details
volved in medicating the participants, were reported to be blinded regarding the results of clinician’s assessment data or observation
to allocation to placebo or intervention phases of the trial (Gordon ratings, stating only that “none of the clinician ratings showed
1993; Remington 2001; Niederhofer 2003). In one of the studies, significant differences between placebo and treatment”, which is
it was stated that all involved clinicians who assessed the partici- suboptimal. This bias in reporting of results affects the validity of
pants were blind to treatment allocation (Niederhofer 2003). In the results of this study.
the other two studies, it was not clear as to whether the assessors
were adequately blinded (Gordon 1993; Remington 2001). Both
used the term “double-blind”, but did not specifically report blind- Other potential sources of bias
ing of the assessors. Participants were assessed using the same tools
and rating scales during the placebo and treatment phases, but as Two studies had a one week taper of one medication while the other
these were largely observation based measures there is potential for was gradually increased in the cross-over stage, but did not have
the results to be biased if the assessors were not adequately blind a drug-free washout period (Gordon 1993; Niederhofer 2003).
to which phase each patient was in. This did raise concerns that the lack of a washout phase between
the placebo and treatment phases of the study may impact upon
the results. None of the studies reported any conflict of interest
with regard to the funding of the studies.
Incomplete outcome data
In one of the studies there was no loss to follow-up (Niederhofer
Risk of bias in cross-over trials
2003). In one, there was an equal number of participants lost from
the placebo and treatment groups (Gordon 1993). In this study The main concerns over risk of bias in cross-over trials are whether
each group lost one participant because allocation concealment the cross-over design is suitable, whether there is a carry-over,
had to be broken. In the experimental group this was because one whether only first period data are available, and incorrect analysis
patient was given the wrong medication, and in the placebo-con- (Higgins 2008). A cross-over design study can be appropriate in
trolled group at the insistence of his parents following violent out- studying ASD, as the condition is reasonably stable, and diagnosis
bursts. As the numbers were small and the loss of the participants had been made using standardised tools in all three studies. Carry-
was not related to the study outcomes or due to adverse effects, it over effect of treatment effect across treatment periods may impact
was felt that this was unlikely to create bias in the study results. upon the risk of bias in all three studies. All three studies used
In the third study, incomplete data was not addressed, with the a one week washout or cross-over period between trial arms to
investigators randomising 36 participants to the study but only minimise this effect. In addition, Gordon 1993 reported no drug
reporting on 32 of them (Remington 2001). This was a cross-over order effect. All three trials analysed data from both the first and
study, and there were significant rates of participants dropping out second periods of treatment, and where patients did not complete
of both the experimental and placebo-control phases of the study. a particular arm of the trial, intention-to-treat analysis was carried
Twenty of the 32 participants prematurely withdrew from the ex- out. Paired analysis was used, taking advantage of the cross-over
perimental (clomipramine) phase and 11 of 32 prematurely ended study’s ability to compare treatment effects within individuals. In
participation in the placebo-control phase. Reasons for withdrawal Remington 2001 and Gordon 1993, repeated measures univari-
from the clomipramine phase of this study included 12 partici- ate analysis of variance was conducted comparing clomipramine
pants who experienced adverse side effects, eight who experienced with placebo and versus baseline scores, and Niederhofer 2003
significant behavioural problems and one participant who had pre- compared behavioural ratings at baseline, six weeks and 12 weeks
existing ECG changes. This does potentially add bias to the results using paired, two-tailed t-tests. The order of receiving treatments
reported. was randomised in all three studies.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 10
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Effects of interventions clomipramine a statistically significant difference was found be-
tween groups and baseline on the CARS (F(3, 91) = 2.7, P = 0.05),
Due to the level of heterogeneity between study participants, the
but post hoc comparisons did not indicate a difference from base-
TCA medications investigated and the outcome measures used
line between placebo and clomipramine (baseline mean 41.8 (SD
by the researchers, meta-analysis of data could not be performed.
= 7.1), placebo mean = 39.4 (SD = 7.0), clomipramine mean =
Instead a narrative synthesis of the results is presented; see Table
37.8 (SD = 8.7)).
2.
Gordon 1993 used repeated-measures analysis of variance with
Bonferroni post hoc tests comparing baseline, placebo and
Primary outcomes clomipramine treatment. In this study clomipramine was supe-
rior to placebo in reducing abnormal behaviours as rated by the
Autism Relevant Subscale of the CPRS (placebo mean = 47 (SD
Global clinical impression = 8), clomipramine mean = 36 (SD = 8); F = 24.2; df 3,33; P =
0.0001). In addition, the items that measure features of autism
(including withdrawal, rhythmic motion, abnormal object rela-
tionships, unspontaneous relation to examiner, and underproduc-
Tianeptine tive speech) indicated a statistically significant difference between
Clinician ratings based on videotaped interactions between the treatment with placebo and clomipramine (placebo mean = 23
child and their parent (Niederhofer 2003) were undertaken at (SD = 4), clomipramine mean = 18 (SD = 3); F = 22.5, df = 3,33;
baseline, six weeks and 12 weeks using the Children’s Global As- P = 0.0001).
sessment Scale, a National Institute of Mental Health Clinical
Global Impressions Scale, and a modified Child Psychiatric Rat-
ing Scale (CPRS). The authors report that none of the clinician Abnormal eye contact
ratings showed significant differences between placebo and tianep-
tine, after six or after 12 weeks, but no data have been provided.
Tianeptine
Weekly parent and teacher ratings on the ABC were combined by
Clomipramine the trial authors, averaging the scores presented for each subscale,
Gordon 1993 used the Clinical Global Impressions Scale (CGIA) including ‘inadequate eye contact’. Ratings of placebo and tianep-
to rate overall change. The CGIS is a commonly used subjective tine treatment were compared at baseline, and after six weeks and
measure of symptom severity, treatment response and efficacy in 12 weeks of treatment, using paired, two-tailed t-tests. For this
pharmacotherapy studies in patients with mental disorders. There combined parent/teacher score there were improvements in partic-
was a statistically significant difference in the efficacy index of this ipants’ scores at six weeks (placebo 8.1 (SD = 4.9), tianeptine 7.7
scale, which assesses the therapeutic effect of treatments, indicating (SD = 3.8), P = 0.052), but these were not statistically significant.
the superiority of clomipramine to placebo (placebo mean = 11 At 12 weeks, the improvements from baseline in ratings by parent/
(SD = 3), clomipramine mean = 5 (SD = 3); F = 27.4; df = 2,22; teacher reports for inadequate eye contact reached a minimal level
P = 0.0001). of statistical significance (placebo 8.2 (SD = 5.4), tianeptine 7.4
(SD = 3.6), P = 0.041).
The authors report that clinician ratings did not show statistically
Core features significant differences between placebo and tianeptine, after six or
after 12 weeks on any of the ABC subscales.
Inappropriate speech
Autistic symptoms

Tianeptine
Clomipramine Combined parent and teacher ratings for the ‘inappropriate speech’
Remington 2001 used the Childhood Autism Rating Scale subscale of the ABC showed there to be a statistically significant
(CARS) to rate autistic symptomatology. Intention-to-treat anal- improvement in participants’ scores at six weeks (placebo 6.0 (SD
ysis, using repeated-measures univariate analyses of variance, was = 2.7), tianeptine 5.2 (SD = 3.5), P = 0.047). At 12 weeks, ratings
used to compare placebo and clomipramine versus baseline scores. showing improvements in inappropriate speech remained statis-
Post hoc comparisons using Scheffe’s F procedure were also used. tically significant (placebo 6.1 (SD = 2.5), tianeptine 4.2 (SD =
On intention-to-treat analysis of the data comparing placebo to 3.8), P = 0.042).

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 11
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The authors report that clinician ratings did not show significant state that clomipramine was also superior to placebo on the Mod-
differences between placebo and tianeptine, after six or after 12 ified NIMH OCD Scale and the Modified NIMH Global OCD
weeks on any of the ABC subscales. and Anxiety Scales, but did not provide data.

Clomipramine Irritability/anger/uncooperativeness

In one study (Remington 2001) the ABC was scored by clini-


cians. Repeated measures univariate analysis of variance was con-
ducted comparing clomipramine with placebo and haloperidol.
In this report only the results for the arm of the study comparing Tianeptine
clomipramine with placebo are considered. The authors first anal- Parent and teacher reports on the ABC were combined by averag-
ysed using an intention-to-treat approach. There was no statisti- ing the scores. For this combined parent/teacher score there were
cally significant difference between baseline and treatment with slight but not statistically significant improvements in participants’
clomipramine for ‘inappropriate speech“. scores for the Irritability subscale at six weeks (placebo 13.8 (SD
Gordon 1993 used an Autism-specific subscale of the Child Psy- = 5.1), tianeptine 12.3 (SD = 6.9), P = 0.051). At 12 weeks, the
chiatric Rating Scale (CPRS) completed by the clinicians, based on improvements in irritability ratings compared to baseline ratings
parental reports and direct observations. For the speech deviance were statistically significant (placebo 14.2 (SD = 5.4), tianeptine
factors of this measurement there was no statistically significant 11.1 (SD = 7.7), P = 0.047). The authors report that clinician
difference between clomipramine and placebo (placebo mean = 4 ratings did not show significant differences between placebo and
(SD = 2), clomipramine mean = 3 (SD = 2); F = 1.4, df = 3,33; P tianeptine, after six or 12 weeks on the ABC subscales.
= 0.27).
Stereotypical behaviours

Clomipramine
Clomipramine Remington 2001 analysed ratings on the ABC scored by clinicians.
Remington 2001 used clinician ratings on the ABC, comparing On the intention-to-treat data analysis, no statistically significant
clomipramine with placebo. Intention-to-treat analysis showed no difference was found between patients’ ratings of irritability at
statistically significant difference between placebo and treatment baseline and following treatment with clomipramine.
groups for stereotypical behaviours. Gordon 1993 found a statistically significant difference in ratings
on the items measuring features of anger and uncooperativeness
on the Autism-relevant subscale of the clinician rated CPRS in
Non-core features/behaviour the clomipramine treatment phase compared to placebo (placebo
mean = 13 (SD = 6), clomipramine mean = 9 (SD = 5); F = 15.9;
df = 3,33; P = 0.0001).
Obsessive-compulsive type behaviours

Hyperactivity

Clomipramine
One study hypothesised that the ritualised, compulsive behaviours
seen as features of autism may respond to TCA medications in
the same way that the obsessions and repetitive motor behaviours Tianeptine
of obsessive-compulsive disorders would (Gordon 1993). This Combined parent and teacher ratings for the hyperactivity sub-
study used the Modified National Institute of Mental Health scale of the ABC indicated a statistically significant improvement
(NIMH) Global Obsessive-Compulsive Disorder (OCD) and in participants’ scores at 6 weeks (placebo 20.2 (SD = 11.3), tianep-
Anxiety Scales, the Modified NIMH OCD Scale and the Modified tine 19.4 (SD = 9.7), P = 0.048). At 12 weeks, there had been
Child Psychiatric Rating Scale (CPSR) OCD Subscale. It found further improvements in hyperactivity ratings (placebo 21.9 (SD
a statistically significant improvement in OCD symptoms with = 10.8), tianeptine 19.2 (SD = 11.3), P = 0.035).
clomipramine as opposed to placebo as measured by the Modified The authors report that clinician ratings did not show significant
CPRS OCD Subscale (placebo mean = 12 (SD = 4), clomipramine differences between placebo and tianeptine, after 6 or 12 weeks
mean = 8 (SD = 4); F = 12.7; df = 3,33; P = 0.001). The authors on the ABC subscales.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 12
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clomipramine for this reason specifically. However, on analysis of the data from
In Remington 2001, the ABC was used by clinicians. On both the Dosage Treatment Emergent Symptom Scale (DOTES) and
the intention-to-treat data analysis and the analysis of data using Extra-pyramidal Symptom Rating Scale (ESRS), which specifi-
only results from participants who completed the clomipramine cally rated side effects, there were no statistically significant dif-
trial, excluding those who dropped out, there was no significant ferences between the placebo group and the group treated with
difference between baseline and treatment with clomipramine for clomipramine. The Parkinsonism score for the ESRS was not sig-
ratings of patient hyperactivity. nificantly different between baseline and any of the experimen-
Gordon 1993 found a statistically significant difference in rat- tal groups (placebo mean = 7.9 (SD = 7.1), clomipramine mean
ings on the items measuring features of hyperactivity on the 10.3 (SD = 7.3), P = 0.35). The behavioural toxicity subscale of
Autism-relevant subscale of the clinician completed CPRS in the DOTES also found no significant difference between groups
the clomipramine treatment phase compared to placebo (placebo (placebo 0.8 (SD = 1.7), clomipramine 2.0 (SD = 2.9), P = 0.07).
mean = 8 (SD = 2), clomipramine mean = 6 (SD = 2); F = 8.1; df This study also conducted cardiac monitoring at baseline and at
= 3,33; P = 0.001). week six of treatment in as many participants as could tolerate
this (14 in the clomipramine arm of trial and 15 in the placebo
arm), and the analysis of variance indicated no significant changes
Lethargy in ECG variables and no clinically significant arrhythmias were
noted.
The second study featuring clomipramine used a Subjective Treat-
ment Emergent Symptoms Subscale to measure adverse side ef-
Clomipramine fects (Gordon 1993). There was no statistical significance between
In Remington 2001, ratings for lethargy on the ABC rating scale clomipramine and placebo in the reporting of adverse effects. The
performed by clinicians showed no statistically significant differ- investigators report that two participants required their dosage of
ence between baseline and treatment with clomipramine on either clomipramine to be reduced for cardiac considerations - one due
intention-to-treat data analysis or analysis of the data from partic- to the development of a prolonged QT interval and one developed
ipants who completed the clomipramine trial. tachycardia, both of which resolved with this dosage reduction.
Reported side effects included insomnia (clomipramine = 7 par-
ticipants, placebo = 1 participant), constipation (6;2), sedation (6;
Adverse effects 0), twitching (5;0), tremor (4;1), flushing (4;1), dry mouth (3;1),
decreased appetite (3;0) and nausea (2;1).

Tianeptine Comorbidities of ASD


Parent and teacher weekly ratings on symptom checklists which No study used any standardised measure to indicate impact of
were averaged found a statistically significant increase in drowsi- treatment with TCA on comorbidities of ASD such as depression
ness at six weeks (placebo 1.4 (SD = 2.3), tianeptine 2.9 (SD = or anxiety.
2.4), P = 0.022) and 12 weeks (placebo 1.5 (SD = 2.8), tianeptine
3.1 (SD = 3.2), P = 0.025).
There was a statistically significant increase in ratings for decreased Secondary outcomes - parental, child or family quality of life
activity at 6 weeks (placebo 2.6 (SD = 3.7), tianeptine 3.8 (SD and stress
= 3.5), P = 0.034) and at 12 weeks (placebo 2.4 (SD = 3.3), None of the studies used any standardised measure of quality of
tianeptine 4.0 (SD = 3.7), P = 0.029). life or stress for the child or their carers and families.

Clomipramine
DISCUSSION
In one study, there was significant drop-out of participants due to
adverse side effects of the medication (Remington 2001). Twelve
of 32 participants in the trials were prematurely discontinued with
adverse effects identified (fatigue/lethargy N = 4, tremors N = 2,
Summary of main results
tachycardia N = 1, insomnia N = 1, diaphoresis N = 1, nausea or TCAs are antidepressants that are used in individuals with ASD.
vomiting N = 1, decreased appetite N = 1). In four of these twelve This review details the findings of three randomised, cross-
cases, behavioural problems were also involved in the discontinu- over controlled trials. Two of the studies evaluated the effect of
ation of the trial, and eight more participants were discontinued clomipramine and one study examined tianeptine.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 13
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
This review includes two studies of children (ages four to 15 years) arm of the study (Remington 2001). Of the 20 who discontinued
and one with children and young adults (ages 10 to 36 years), the clomipramine arm of this trial, 12 dropped out due to side
covering a wide range of ages and IQ levels (ranging from 30 to effects and eight due to behavioural problems. Remington 2001
107). The majority of participants in the studies reviewed had was the only study to formally monitor cardiac conduction, do-
levels of intellectual function in the more severe range of disability. ing an ECG at baseline and at six weeks of treatment in as many
The review found that there is limited and inconsistent evidence of participants as could tolerate this (baseline N = 23, clomipramine
the effectiveness of the TCAs studied (clomipramine and tianep- N = 14, placebo N = 15). They found no significant changes in
tine). Using the overall measure of the Clinical Global Impression PR, QRS or corrected QT intervals and no clinically significant
(CGI) Scale, a commonly used subjective measure of symptom cardiac arrhythmias. In Gordon 1993, two patients required dose
severity, treatment response and efficacy in pharmacotherapy stud- reductions of clomipramine due to the cardiac considerations, one
ies in patients with mental disorders, tianeptine did not show a for a tachycardia and one for a prolonged QT interval, but these
statistically significant difference in outcome to placebo, whereas changes resolved with this dose alteration. Tianeptine resulted in a
clomipramine was found to be superior to placebo on CGI ratings significant increase in drowsiness and a reduction in activity levels
(Gordon 1993). The clinical significance of these results is uncer- on parent-completed symptom checklists (Niederhofer 2003).
tain.
The results of the impact of TCAs on the core features of ASD
are inconsistent. Tianeptine was reported to reduce abnormal be- Overall completeness and applicability of
haviours such as inadequate eye contact and speech abnormalities evidence
more than placebo when rated by parents and teachers, but not
It is difficult to compare and synthesise information from the stud-
when rated by clinicians (Niederhofer 2003). One clomipramine
ies included in this review for a number of reasons. The diagnosis
trial reported that clomipramine was superior to placebo in re-
of ASD was made using a variety of diagnostic criteria and assess-
ducing abnormal behaviours as rated by the Autism Relevant Sub-
ment tools, with patients having varying levels of severity of ASD
scale of the CPRS, with specific items that measure features of
and of intellectual ability. Although the researchers included stan-
autism (including withdrawal, rhythmic motion, abnormal ob-
dardised measures of outcome, they used 11 different outcome
ject relationships, spontaneous relation to examiner, and under-
measures, only two of which were used across two studies. Gordon
productive speech) indicating a significant difference between
1993 and Remington 2001 used the ABC but involved different
treatment with placebo and clomipramine (Gordon 1993). The
assessors in rating outcomes, parents and teachers in one and clin-
other study found no significant differences in ratings of autis-
icians in the other. Gordon 1993 and Niederhofer 2003 used the
tic symptoms, speech abnormalities or stereotypical behaviours
Clinical Global Impression Scale but the medications being inves-
(Remington 2001). However, in this study only 37.5% of partic-
tigated were different. Due to an absence of comparable outcome
ipants completed the clomipramine branch of the trials, limiting
measures of the same TCA in the same participant group, meta-
the power of the study to find a difference in outcomes.
analysis was not possible.
There were also inconsistent results in relation to TCA and non-
There were additional limitations of the studies of TCAs in the
core features of ASD. Clomipramine treatment resulted in statis-
treatment of ASD identified in this review. All three studies in-
tically significant improvements in obsessive-compulsive type be-
volved small numbers of participants, ranging from 12 to 32, and
haviours (Gordon 1993). One clomipramine trial showed signifi-
the majority of participants were male. Small sample sizes increase
cant improvements in anger and uncooperativeness ratings and rat-
the risk that no significant change will be found where one ex-
ings of hyperactivity with clomipramine (Gordon 1993), whereas
ists. ASD is commonly associated with additional features such as
the other showed no difference in either of these symptoms, nor
sleep disturbance, feeding and dietary difficulties and sensory pro-
in ratings of lethargy (Remington 2001). Treatment with tianep-
cessing issues, many of which cause significant impairment. The
tine was reported on parent-teacher ratings to significantly im-
studies reviewed did not measure the impact of TCAs on these as-
prove irritability and hyperactivity, but clinician ratings did not
sociated features. In addition, the duration of each trial was short,
show any significant difference between tianeptine and placebo
and although data were provided at the end of each trial period,
(Niederhofer 2003).
the maximum length of follow-up was 12 weeks, and there was
There has been limited use of TCAs in the treatment of individu-
no medium- or long-term follow-up done in any of the studies.
als with ASD, especially in children, due to concerns about possi-
In a chronic condition such as ASD, where treatment durations
ble adverse effects, such as interference with cardiac conduction.
are likely to be continued for significant periods of time, long-
Although none of the studies reviewed found statistically signifi-
term data are required to understand the medium- and long-term
cant differences on side effect rating scales between placebo and
consequences of medication in this patient population, and these
clomipramine treatment ratings, one study had high dropout rates
outcomes were not available in any of the studies reviewed.
(20 out of 32 participants) due to adverse effects, with a large num-
There are a wide variety of TCAs available for treatment of psy-
ber of participants not completing the clomipramine treatment
chiatric conditions, but only clomipramine and tianeptine were

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 14
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
trialled in the included studies. In one study of tianeptine in children and adolescents, parents and
teachers reported perceived reductions in irritability, hyperactiv-
ity, inadequate eye contact and inappropriate speech, but clinician
Quality of the evidence ratings found no significant impact on these features (Niederhofer
2003). There were also significant adverse effects, including in-
The overall quality of each study was felt to be adequate, but there
creased drowsiness and reduced activity levels in these individuals
were some areas of high risk of bias in each study. Gordon 1993
while treated with tianeptine.
and Remington 2001 did not provide details about the blinding of
outcome assessors. The selection of participants in Gordon 1993, In the two studies of clomipramine, the evidence was conflicting.
based on a less than 20% response to placebo, could increase the There are adverse effects reported with the use of clomipramine.
treatment effect size that was identified for the outcomes in which Although the difference in side effect ratings were not statistically
a treatment effect was reported. There were issues with allocation significant compared to placebo, there were high dropout rates in
concealment and random sequence generation in Niederhofer the clomipramine arm of one study (Remington 2001). There was
2003, as well as incomplete reporting of outcomes. All three studies evidence of improvements in ‘autistic symptoms’, irritability and
were cross-over study designs, posing a risk of bias, particularly OCD-like symptoms, but conflicting evidence in relation to hy-
with their short washout periods. peractivity, and no significant changes found with inappropriate
speech. Clomipramine was not found to reduce ’autistic symp-
toms’ on intention-to-treat analyses.
Potential biases in the review process Clinicians considering the use of TCAs in children and adolescents
None known. with ASD need to be aware of the limited and conflicting evidence
of effect and the side effect profile of TCAs when discussing this
treatment option with patients with ASD and their carers.
Agreements and disagreements with other
studies or reviews Implications for research
There are no other reviews of the use of TCAs in children and This review highlights the limited evidence base regarding the use
adolescents with ASD. It is postulated that TCA medications are of TCAs for ASD in children and adolescents.
effective through their serotonin reuptake inhibition activity, and
The evidence base regarding the effectiveness of TCAs for children
a Cochrane Systematic Review of selective serotonin reuptake in-
with ASD needs to be developed by means of adequately powered
hibitors (SSRIs) has been conducted (Williams 2010). The au-
randomised, placebo-controlled trials of commonly prescribed and
thors reviewed seven RCTs, five of which included only children.
newer TCAs, with sufficient numbers of participants to permit
The conclusion of the review was that there is no evidence of ef-
examination of subgroups and their differing responses to these
fect of SSRIs in children, and that there was evidence of potential
medications, especially differences between paediatric, adolescent
harm through side effects.
and adult patients.
The review highlights the need for a consensus regarding standard-
ised outcome measures that are relevant and specific to ASD. The
AUTHORS’ CONCLUSIONS multiplicity of measures currently in use prevents the meaningful
comparison and synthesis of data across trials. Future analytical
Implications for practice strategies need to be considered that appropriately take into ac-
count baseline differences for optimal data analyses, and should
A limited sample of TCAs have shown small positive effects in
present change scores or ANOVA statistics with baseline taken
children and adolescents with ASD, but the strength of this ev-
into account, rather than presenting only final outcome scores.
idence is negatively impacted upon by the inconsistent findings
between studies, the small sample sizes of the studies and their There are no data on the effect of TCAs on the comorbidities that
unclear risk of bias, making clear recommendations impossible at are commonly associated with ASD, such as anxiety and depres-
this time. sion, or on the associated features that may cause significant im-
pairment, such as sleep disturbance, dietary and feeding issues and
Only two of the many TCAs available for use in individuals
sensory processing issues. No studies have examined the impact of
with ASD have been evaluated using randomised controlled trials,
these medications on the patients’ or carers’ quality of life, so this
namely tianeptine and clomipramine. The three studies in this
is highlighted as an area for further investigation.
review, two of which assessed the effects of clomipramine, only
provide data at the end of short time periods studied, with no Although short-term evidence of benefits and adverse effects are
evidence of medium or long-term outcomes and adverse effects. important to our knowledge about the use of TCAs in autism,

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 15
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
this is a chronic and heterogeneous condition, and there is a need
for trials that examine the long-term effects of TCA medication in
ASD, both positive and adverse. In particular, the risk for children
of the membrane stabilising impact on cardiac tissue makes this is
an area that requires further study.

REFERENCES

References to studies included in this review Gordon 1992 {published data only}
Gordon CT, Rapoport JL, Hamburger SD, State RC,
Gordon 1993 {published data only} Mannheim GB. Differential response of seven subjects
Gordon CT, State RC, Nelson JE, Hamburger SD, with Autistic Disorder to clomipramine and desipramine.
Rapoport JL. A double-blind comparison of clomipramine, American Journal of Psychiatry 1992;149(3):363–6.
desipramine and placebo in the treatment of Autistic
Disorder. Archives of General Psychiatry 1993;50(6):441–7. Jaselskis 1992 {published data only}
Jaselskis CA, Cook EH, Fletcher KE, Leventhal BL.
Niederhofer 2003 {published data only} Clonidine treatment of hyperactive and impulsive
Niederhofer H, Staffen W, Mair A. Tianeptine: A novel children with Autistic Disorder. Journal of Clinical
strategy of psychopharmacological treatment of children Psychopharmacology 1992;12(5):322–7.
with autistic disorder. Human Psychopharmacology 2003;18
(5):389–93. Kehrer 1978 {published data only}
Kehrer HE. Infantile autism and drug therapy [German]
Remington 2001 {published data only}
[Die medikamentose Behandlung des kindlichen Autismus].
Remington G, Sloman L, Konstantareas M, Parker K,
Bibliotheca Psychiatrica 1978;157:91–7.
Gow R. Clomipramine versus haloperidol in the treatment
of autistic disorder: a double-blind, placebo-controlled, Kurtis 1966 {published data only}
crossover study. Journal of Clinical Psychopharmacology Kurtis LB. Clinical study of the response to nortriptyline
2001;21(4):440–4. on autistic children. International Journal of Neuropsychiatry
1966;2(4):298–301.
References to studies excluded from this review
Magen 1993 {published data only}
Aman 1986 {published data only} Magen J. Negative results with clomipramine [comment].
Aman MG, White AJ, Vaithianathan C, Teehan CJ. Journal of the American Academy of Child and Adolescent
Preliminary study of imipramine in profoundly retarded Psychiatry 1993;32(5):1079–80.
residents. Journal of Autism and Developmental Disorders
1986;16(3):263–73. McDougle 1992 {published data only}
McDougle CJ, Price LH, Volkmar FR, Goodman WK,
Brasic 1994 {published data only} Ward-O’Brien D, Nielson J, et al. Clomipramine in autism:
Brasic JR, Barnett JY, Kaplan D, Sheitman BB, Aisemberg P, Preliminary evidence of efficacy. Journal of the American
Lafargue RT, et al. Clomipramine ameliorates adventitious Academy of Child and Adolescent Psychiatry 1992;31(4):
movements and compulsions in prepubertal boys with 746–50.
autistic disorder and severe mental retardation. Neurology
1994;44(7):1309–12. Oesterheld 1997 {published data only}
Oesterheld J, Kallepalli BR. Grapefruit juice and
Brasic 1997 {published data only}
clomipramine: Shifting metabolic ratios. Journal of Clinical
Brasic JR, Barnett JY, Sheitman BB, Tsaltas MO. Adverse
Psychopharmacology 1997;17(1):62–3.
effects of clomipramine. Journal of the Americam Academy of
Child and Adolescent Psychiatry 1997;36(9):1165–6. Sanchez 1995 {published data only}
Brodkin 1997 {published data only} Sanchez LE, Campbell M, Small AM, Adams PB,
Brodkin ES, McDougle CJ, Naylor ST, Cohen DJ, Price Uysal S, Hallin A. A comparison of live and videotaped
LH. Clomipramine in adults with pervasive developmental ratings: Clomipramine and haloperidol in autism.
disorders: A prospective open-label investigation. Journal of Psychopharmacology Bulletin 1995;31(2):371–8.
Child and Adolescent Psychopharmacology 1997;7(2):109–21.
Sanchez 1996 {published data only}
Campbell 1971 {published data only} Sanchez LE, Campbell M, Small AM, Cueva JE, Armenteros
Campbell M, Fish B, Shapiro T, Floyd A. Imipramine in JL, Adams PB. A pilot study of clomipramine in young
preschool autistic and schizophrenic children. Journal of autistic children. Journal of the American Academy of Child
Autism and Childhood Schizophrenia 1971;1(3):267–82. and Adolescent Psychiatry 1996;35(4):537–44.
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Sloman 1998 {published and unpublished data} Fombonne 2005
Sloman L. Haloperidol versus clomipramine in Autistic Fombonne E. Epidemiology of autistic disorder and other
Disorder. 151st Annual Meeting of the American pervasive developmental disorders. Journal of Clinical
Psychiatric Association. 1998 May–June; Vol. 17. Psychiatry 2005;66:3–8.
Szabo 1994 {published data only} Guillem 2006
Szabo CP, Bracken C. Imipramine and Asperger’s. Journal Guillem P, Cans C, Guinchat V, Ratel M, Jouk PS. Trends,
of the American Academy of Child and Adolescent Psychiatry perinatal characteristics and medical conditions in pervasive
1994;33(3):431–2. developmental disorders. Developmental Medicine and Child
Szekely 1980 {published data only} Neurology 2006;48(11):896–900.
Szekely GA, Caplan R, Rotman A. Platelet dopamine
Higgins 2008
uptake in autistic and other psychotic children. Inhibition
Higgins JPT, Green S (editors). Cochrane Handbook for
by imipramine. Progress in Neuro-Psychopharmacology 1980;
Systematic Reviews of Interventions Version 5.0.1 [updated
4(2):215–8.
September 2008]. The Cochrane Collaboration. Available
Weizman 1987 {published data only} from www.cochrane-handbook.org.
Weizman A, Gonen N, Tyano S, Rehavi M. Platelet
[3H] imipramine binding in autism and schizophrenia. Howlin 2004
Psychopharmacology 1987;91(1):101–3. Howlin P, Goode S, Hutton J, Rutter M. Adult outcomes
for children with autism. Journal of Child Psychology and
Additional references Psychiatry 2004;45:212–29.
APA 2000 Hranilovic 2007
American Psychiatric Association. Diagnostic and Statistical Hranilovic D, Busjas-Petkovic Z, Vragovic R, Vuk T, Hock
Manual of Mental Disorders Text Revision (DSM-IV-TR). K, Jernej B. Hyperserotonemia in adults with autistic
4th Edition. Washington DC: American Psychiatric disorder. Journal of Autism and Developmental Disorders
Association, 2000. 2007;37(10):1934–40.
Baird 2006 Joseph 2002
Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Joseph RM, Tager-Flusberg H, Lord C. Cognitive profiles
Meldrum D, et al. Prevalence of disorders of the autism and social-communicative functioning in children with
spectrum in a population cohort of children in South autism spectrum disorder. Journal of Child Psychology and
Thames: the Special Needs and Autism Project (SCAP). Psychiatry 2002;43(6):807–21.
Lancet 2006;368(9531):210–5.
Nishiyama 2009
Billstedt 2007
Nishiyama T, Taniai H, Miyachi T, Ozaki K, Tomita M,
Billstedt E, Gillberg IC, Gillberg C. Autism in adults:
Sumi S. Genetic correlation between autistic traits and IQ
symptom patterns and early childhood predictors. Use
in a population-based sample of twins with autism spectrum
of the DISCO in a community sample followed from
disorders (ASDs). Journal of Human Genetics 2009;54:
childhood. Journal of Child Psychology and Psychiatry 2007;
56–61.
48(11):1102–10.
Caronna 2008 Peretti 2000
Caronna EB, Milunsky JM, Tager-Flusberg H. Autism Peretti S, Judge R, Hindmarch I. Safety and tolerability
spectrum disorders: clinical and research frontiers. Archives considerations: tricyclic antidepressants versus serotonin
of Disease in Childhood 2008;93:518–23. reuptake inhibitors. Review. Acta Psychiatrica Scandinavica.
Supplementum 2000;101(403):17–25.
Chakrabarti 2005
Chakrabarti S, Fombonne E. Pervasive developmental Posey 2001
disorders in preschool children: confirmation of high Posey DJ, McDougle CJ. Pharmacotherapeutic management
prevalence. American Journal of Psychiatry 2005;162: of autism. Expert Opinion of Pharmacotherapy 2001;2(4):
1133–41. 587–685.
Cook 1996 Potter 1998
Cook EH, Leventhal BL. The serotonin system in autism. Potter WZ, Manji HK, Rudorfer MW. Tricyclics and
Current Opinion in Paediatrics 1996;8:348–54. tetracyclics. The American Psychiatric Press Textbook of
Findling 1999 Psychopharmacology. 2nd Edition. Washington, DC:
Findling RL, Reed MD, Blumer JL. Pharmacological American Psychiatric Press, 1998:199–218.
treatment of depression in children and adolescents. RevMan 2008 [Computer program]
Paediatric Drugs 1999;1:161–82. The Nordic Cochrane Centre. The Cochrane
Fombonne 1999 Collaboration. Review Manager (RevMan). Version 5.0.
Fombonne E. The epidemiology of autism: a review. Copenhagen: The Nordic Cochrane Centre. The Cochrane
Psychological Medicine 1999;29(4):769–86. Collaboration, 2008.

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Sadock 2005 Williams 2006
Sadock BJ, Sadock VA. Kaplan and Sadock’s Comprehensive Williams JG, Higgins JPT, Brayne CEG. Systematic review
Textbook of Psychiatry. 8th Edition. Lippincott Williams of prevalence of autism spectrum disorders. Archives of
and Wilkins, 2005. Disease in Childhood 2006;91:8–15.
Volkmar 2004
Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A. Autism Williams 2010
and Pervasive Developmental Disorders. Journal of Child Williams K, Wheeler DM, Silove N, Hazell P. Selective
Psychology and Psychiatry 2004;45(1):135–70. serotonin reuptake inhibitors (SSRIs) for autism
WHO 1993 spectrum disorders (ASD). Cochrane Database of
World Health Organization. The ICD-10 classification Systematic Reviews 2010, Issue 8. [DOI: 10.1002/
of mental and behaviour disorders: diagnostic criteria for 14651858.CD004677.pub2]
research. Geneva: World Health Organization 1993. ∗
Indicates the major publication for the study

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 18
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Gordon 1993

Methods Randomised control trial - double-blind randomised cross-over comparison

Participants 7-15 years of age with DSM-IIIR and Autism Diagnostic Interview criteria for autistic
disorder

Interventions Clomipramine compared to placebo

Outcomes Childhood Psychiatric Rating Scale - Autism relevant Subscale


Modified Childhood Psychiatric Rating SCale - OCD Subscale
Clinical Global Impressions Scale

Notes Unusual inclusion criteria. To be included the participants had to have less than 20%
improvement on rating scales in the 2-week single-blind placebo trial

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk ”random number table“


bias)

Allocation concealment (selection bias) Low risk ”randomisation was performed by the Na-
tional Institute of Health Pharmacy“ - cen-
tral allocation by pharmacy

Blinding (performance bias and detection Low risk ”double-blind randomised crossover com-
bias) parison“. It appears the participants were
Participants blinded in regards to the medication and
they were assessed in the same way in the
treatment and placebo phases. It is likely
that the blinding was not broken and out-
comes not influenced

Blinding (performance bias and detection Low risk Likely adequate. When blinding was bro-
bias) ken for one participant due to violent out-
Personnel bursts and for one who received the wrong
medication, they were removed from the
trial

Blinding (performance bias and detection Unclear risk No information provided


bias)
Outcome assessors

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 19
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Gordon 1993 (Continued)

Incomplete outcome data (attrition bias) Low risk One patient lost in experimental group due
All outcomes to wrong medication being given. One pa-
tient lost in control group due to incorrect
medication being given. Equal number of
patients lost in each group and loss not re-
lated to study outcomes or adverse effects

Selective reporting (reporting bias) Low risk The protocol is well described and all ex-
pected outcomes are reported

Other bias Unclear risk The referral process of self- and clinic-refer-
ral may lead to bias as these are potentially
self-selected participants. Risk of bias from
cross-over trial design is low, with appro-
priate data analysis (repeated measures uni-
variate analysis of variance), and the order
of receiving medication was randomised.
There was felt to be a small risk of carry-
over effect biasing results as there was a
short cross-over period between treatment
arms (one week)

Niederhofer 2003

Methods Randomised control trial - double-blind and placebo-controlled cross-over study

Participants Outpatients, aged 4-15 years, with ICD-10 criteria for Autistic Disorder, with two
independent Child and Adolescent Psychiatrists agreeing on the diagnosis

Interventions Tianeptine compared with placebo

Outcomes Parent and Teacher Ratings on Symptom Checklist and Aberrant Behaviour Checklist
(ABC)
Clinician ratings on Childhood Global Assessment Scale, Modified Childhood Psychi-
atric Rating Scale (CPRS) and Clinical Gllobal Impression scales

Notes Information presented in abstract that is not included in study report

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information on the method of ran-
bias) domisation is given - ”the subjects were ran-
domly assigned by a non-rating clinician to
begin tianeptine or placebo“

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 20
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Niederhofer 2003 (Continued)

Allocation concealment (selection bias) Unclear risk No description given of how patients were
allocated, but does say that ”tianeptine
and identical placebo tablets were admin-
istered“

Blinding (performance bias and detection Low risk Identical medications administered
bias)
Participants

Blinding (performance bias and detection Low risk ”All raters (parents, teachers and clinicians)
bias) were blind to drug order“
Personnel

Blinding (performance bias and detection Low risk ”All raters (parents, teachers and clinicians)
bias) were blind to drug order“
Outcome assessors

Incomplete outcome data (attrition bias) Low risk All participants completed the trial so no
All outcomes loss to follow-up

Selective reporting (reporting bias) High risk Only parents reports were used to report re-
sults, and only selected sections of this were
reported in the study. There is no mention
of what was done with the clinician rat-
ings, except to say ”none of the clinician
ratings showed significant differences be-
tween placebo and tianeptine, after 6 weeks
or after 12 weeks“

Other bias Unclear risk Risk of bias from cross-over trial design is
low, with appropriate data analysis (two-
tailed t-tests), and the order of receiving
medication was randomised. There was felt
to be a small risk of carry-over effect biasing
results as there was a short cross-over period
between treatment arms (one week)

Remington 2001

Methods Randomised control trial

Participants DSM-IV diagnosis of Autistic disorder confirmed by two investigators, aged 10-36 years

Interventions Three arms to trial - used First Phase data comparing clomipramine with placebo

Outcomes Childhood Autism Rating Scales (CARS)


Aberrant Behaviour Checklist (ABC)
Dosage Treatment Emergent Symptom Scales (DOTES)

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 21
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Remington 2001 (Continued)

Extrapyramidal Symptom Ratig Scale (ESRS)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk ”subjects were randomly assigned to one of three treatment
bias) groups using Latin Square design“

Allocation concealment (selection bias) Low risk ”medications and placebo were packaged in similar capsules
to maintain double-blind component“

Blinding (performance bias and detection Low risk ”medications and placebo were packaged in similar capsules
bias) to maintain double-blind component“
Participants

Blinding (performance bias and detection Low risk ”medications and placebo were packaged in similar capsules
bias) to maintain double-blind component“
Personnel

Blinding (performance bias and detection Unclear risk no information provided


bias)
Outcome assessors

Incomplete outcome data (attrition bias) High risk There was a big loss from all arms of the trial, and although
All outcomes 36 patients were randomised only 32 are reported on

Selective reporting (reporting bias) Low risk Reported all that researchers had stated would report.

Other bias Unclear risk Risk of bias from cross-over trial design is low, with appro-
priate data analysis (repeated measures univariate analysis of
variance), and the order of receiving medication was ran-
domised. There was felt to be a small risk of carry-over effect
biasing results as there was a short cross-over period between
treatment arms (one week)

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Aman 1986 Did not meet inclusion criteria. Subjects did not have a diagnosis of ASD/Autistic Disorder or PDD-NOS

Brasic 1994 Not a randomised control trail and no placebo control.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 22
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Brasic 1997 Letter to editor referencing study but is not report of a randomised controlled trial

Brodkin 1997 Not randomised and no placebo control group.

Campbell 1971 Not a randomised controlled trial.

Gordon 1992 Not randomised to control versus tricyclic antidepressant.

Jaselskis 1992 Not a tricyclic antidepressant.

Kehrer 1978 Not a randomised controlled trial. Discussion paper.

Kurtis 1966 Not a randomised control trial, with no placebo control group used and diagnostic status of participants is unclear

Magen 1993 Comment in letter to editor, not report of randomised control trial

McDougle 1992 Case studies, not randomised control trial and no placebo comparison group

Oesterheld 1997 Case study.

Sanchez 1995 Not randomised, no control group - same patients and pre-treatment placebo

Sanchez 1996 Open-label pilot study, not randomised or placebo-controlled. Had one week pre-treatment placebo as baseline
for comparison

Sloman 1998 Contacted author. Data presented from a study which is included among other studies found and excluded

Szabo 1994 Case report, not RCT.

Szekely 1980 Not a randomised control trial of tricyclic antidepressants versus placebo

Weizman 1987 Not randomised, no placebo control

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 23
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES
This review has no analyses.

ADDITIONAL TABLES
Table 1. Outcome measures used in included studies

Outcome measures Gordon Remington Niederhofer

TCA being investigated Clomipramine Clomipramine Tianeptine

Ratings conducted by: Parent-Teacher Ratings Clinician Ratings Clinician Ratings

Aberrant Behaviour Checklist x x


(ABC)

Childhood Autism Rating x


Scales (CARS)

Childhood Global Assessment x


Scale (CGAS)

Children’s Psychiatric Rating x


Scale (CPRS)

CPRS-Autism Relevant Sub- x


scale

CPRS- OCD and Anxiety Rel- x


evant Subscale

Clinical Global Impression x x


Scale

Symptom Checklist x

Subjective Treatment Emergent x


Symptom Scale

Dosage Treatment Emergenct x


Symptom Scale (DOTES)

Extrapyramidal Symptom Rat- x


ing

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 24
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Clinically significant outcomes - tricyclic antidepressants compared to placebo

Outcome measures Gordon Remington Niederhofer

TCA being investigated Clomipramine Clomipramine Tianeptine

Ratings conducted by: Clinician Ratings Clinician Ratings Parent-teacher Ratings Clinician Ratings

Aberrant Behaviour Not significant Eye contact P = 0.041 Not significant


Checklist (ABC) Inappropriate speech P =
0.042
Irritability P = 0.047
Hyperactivity P = 0.035

Childhood Autism Rat- Not significant


ing Scale (CARS)

Childhood Global As- Not significant


sessment Scale (CGAS)

Children’s Psychiatric P = 0.0001 Not significant


Rating Scale (CPRS)

CPRS - Autism Relevant P = 0.0001 Overall - not significant


Subscale Irritability, anger, uncoop-
erativeness P = 0.0001
Hyperactivity P = 0.001

CPRS - OCD and Anx- P = 0.001 Not significant


iety Relevant Subscale

Modified National Insti- Data not provided


tute of Mental Health
Global OCD and Anx-
iety Scale and Modified
OCD Scale

Clinical Global Impres- P = 0.0001 Not significant


sion Scale

Symptom Checklist Not significant Two participants required


dosage modification due
to cardiac changes

Sub- Not significant Increased drowsiness P = 0.


jective Treatment Emer- 025
gent Symptom Scale Reduced activity P = 0.029

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 25
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Clinically significant outcomes - tricyclic antidepressants compared to placebo (Continued)

Dosage Treament Emer- Not significant, but high


gent Symptom Scales drop-out rates
(DOTES)

Extrapyramidal Not significant


Symptom Rating

APPENDICES

Appendix 1. Search strategies


CENTRAL
#1MeSH descriptor Child Development Disorders, Pervasive explode all trees
#2MeSH descriptor Communication, this term only
#3autis* or PDD or PDDs or asd or asds or kanner* or asperger*
#4pervasive developmental disorder*
#5communicat*
#6speech near/3 disorder*
#7language near/3 delay*
#8(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9MeSH descriptor Antidepressive Agents, Tricyclic explode all trees
#10TCA
#11amitriptyline hydrochloride
#12amoxapine
#13clomipramine hydrochloride
#14(dosulepin hydrochloride or dothiepin hydrochloride)
#15doxepin
#16 imipramine hydrochloride
#17lofepramine
#18nortriptyline
#19trimipramine
#20tricyclic*
#21desipramine
#22 florpiramine
#23dibenzepin
#24 iprindole
#25protriptyline
#26MeSH descriptor Amoxapine, this term only
#27Opipramol
#28(#9 OR #10 OR #11 OR #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)
#29(#8 AND #28)
MEDLINE (OVID)
1 exp Child Development Disorders, Pervasive/
2 pervasive developmental disorder$.tw.
Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 26
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3 autis$.tw.
4 kanner$.tw.
5 asperg$.tw.
6 (PDD or PDDs or ASD or ASDs).tw.
7 Communication/
8 communicat$.tw.
9 (speech adj3 disorder$).tw.
10 (language adj3 delay$).tw.
11 childhood schizophrenia.tw.
12 or/1-11
13 adolescent/ or child/
14 (child$ or boy$ or girl$ or teen$ or adolescen$).tw.
15 13 or 14
16 exp Antidepressive Agents, Tricyclic/
17 (tricyclic$ adj3 antidepres$).tw.
18 TCA.tw.
19 Amitriptyline/
20 amitriptyline hydrochloride.tw.
21 Amoxapine/
22 amoxapine.tw.
23 Clomipramine/
24 clomipramine hydrochloride.tw.
25 Dothiepin/
26 (dosulepin hydrochloride or dothiepin hydrochloride).tw.
27 Doxepin/
28 doxepin.tw.
29 Imipramine/
30 imipramine hydrochloride.tw.
31 Lofepramine/
32 lofepramine.tw.
33 Nortriptyline/
34 nortriptyline.tw.
35 Trimipramine/
36 trimipramine.tw.
37 tricyclic$.tw.
38 Desipramine/
39 desipramine.tw.
40 florpiramine.tw.
41 dibenzepin.tw.
42 Iprindole/
43 iprindole.tw.
44 Protriptyline/
45 protriptyline.tw.
46 or/16-45
47 randomized controlled trial.pt.
48 controlled clinical trial.pt.
49 randomi#ed.ab.
50 placebo$.ab.
51 drug therapy.fs.
52 randomly.ab.
53 trial.ab.
54 groups.ab.
55 or/47-54
Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 27
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
56 exp animals/ not humans.sh.
57 55 not 56
58 12 and 15 and 46 and 57
EMBASE (OVID)
1 exp autism/
2 autis$.tw.
3 kanner$.tw.
4 asperg$.tw.
5 childhood schizophrenia.tw.
6 pervasive developmental disorder$.tw.
7 (PDD or PDDs or ASD or ASDs).tw.
8 Communication/
9 (language adj3 delay$).tw.
10 (speech adj3 disorder$).tw.
11 communicat$.tw.
12 or/1-11
13 adolescent/ or child/
14 (child$ or boy$ or girl$ or teen$ or adolescen$).tw.
15 13 or 14
16 exp tricyclic antidepressant agent/
17 TCA.tw.
18 Amitriptyline/
19 amitriptyline hydrochloride.tw.
20 Amoxapine/
21 amoxapine.tw.
22 Clomipramine/
23 clomipramine hydrochloride.tw.
24 Dothiepin/
25 (dosulepin hydrochloride or dothiepin hydrochloride).tw.
26 Doxepin/
27 doxepin.tw.
28 Imipramine/
29 imipramine hydrochloride.tw.
30 Lofepramine/
31 lofepramine.tw.
32 Nortriptyline/
33 nortriptyline.tw.
34 Trimipramine/
35 trimipramine.tw.
36 tricyclic$.tw.
37 Desipramine/
38 desipramine.tw.
39 florpiramine.tw.
40 dibenzepin.tw.
41 Iprindole/
42 iprindole.tw.
43 Protriptyline/
44 protriptyline.tw.
45 or/16-44
46 45 and 12 and 15
47 exp Clinical trial/
48 Randomization/
49 Single blind procedure/
Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 28
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50 Double blind procedure/
51 Crossover procedure/
52 Placebo/
53 Randomi#ed.tw.
54 RCT.tw.
55 (random$ adj3 (allocat$ or assign$)).tw.
56 randomly.ab.
57 groups.ab.
58 trial.ab.
59 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
60 Placebo$.tw.
61 Prospective study/
62 (crossover or cross-over).tw.
63 prospective.tw.
64 or/47-63
65 46 and 64
CINAHL (EBSCOhost)
S34 S12 and S16 and S33
S33 S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or
S27 or S28 or S29 or S30 or S31 or S32
S32 iprindole
S31 protriptyline
S30 dibenzepin
S29 florpiramine
S28 desipramine
S27 tricyclic*
S26 trimipramine
S25 nortriptyline
S24 lofepramine
S23 imipramine hydrochloride
S22 doxepin
S21 dosulepin hydrochloride or dothiepin hydrochloride
S20 clomipramine hydrochloride
S19 amoxapine
S18 amitriptyline hydrochloride
S17 (MH ”Antidepressive Agents, Tricyclic+“)
S16 S13 or S14 or S15
S15 child* or boy* or girl* or teen* or adolescen*
S14 (MH ”Child“)
S13 (MH ”Adolescence“)
S12 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11
S11 communicat*
S10 speech N3 disorder*
S9 language N3 delay*
S8 childhood schizophrenia
S7 PDD or PDDs or ASD or ASDs
S6 pervasive developmental disorder*
S5 kanner*
S4 asperg*
S3 autis*
S2 (MH ”Communication“)
S1 (MH ”Child Development Disorders, Pervasive+“)
PsycINFO (EBSCOhost)
Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 29
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S28 S9 and S27
S27 S10 or S11 or 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
S26 protriptyline
S25 iprindole
S24 dibenzepin
S23 floripramine
S22 desipramine
S21 tricyclic*
S20 trimipramine
S19 nortriptyline
S18 lofepramine
S17 imipramine hydrochloride .
S16 doxepin
S15 dosulepin hydrochloride or dothiepin hydrochloride
S14 clomipramine hydrochloride
S13 amoxapine
S12 amitriptyline hydrochloride
S11 TCA
S10 DE ”Tricyclic Antidepressant Drugs“ OR DE ”Amitriptyline“ OR DE ”Chlorimipramine“ OR DE ”Desipramine“ OR DE
”Doxepin“ OR DE ”Imipramine“ OR DE ”Maprotiline“ OR DE ”Maprotiline“
S9 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8
S8 communicat*
S7 speech N3 disorder*
S6 language N3 delay*
S5 autis* or kanner* or asperg* or childhood schizophrenia*
S4 PDD or PDDs or ASD or ASDs
S3 pervasive developmental disorder*
S2 DE ”Communication“
S1 DE ”Pervasive Developmental Disorders“ OR DE ”Pervasive Developmental Disorders“ OR DE ”Aspergers Syndrome“ OR DE
”Autism“ OR DE ”Rett Syndrome“
Dissertation Abstracts (via Dissertation Express)
tricyclic*
metaRegister of Controlled Trials (mRCT)
tricyclic* AND autis*

CONTRIBUTIONS OF AUTHORS
The protocol was prepared by Romy Hurwitz, with input and supervision from Katrina Williams, Roger Blackmore, Sue Woolfenden,
Phil Hazell and Danielle Wheeler. Romy Hurwitz and Roger Blackmore independently reviewed titles and abstracts and appraised the
quality of papers and extract data. Sue Woolfenden, Katrina Williams and Phil Hazell arbitrated disagreements. All authors contributed
to the writing of the review.

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 30
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST

• Romy Hurwitz - none known.


• Roger Blackmore - none known.
• Philip Hazell - has worked as a consultant for Eli Lilly and Janssen. He has 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. Dr Hazell has
given presentations for Eli Lilly, Pfizer, Janssen and Sanofi. He is an investigator in a trial of fluoxetine for autism spectrum disorders.
• Katrina Williams - I gave a talk about treatments for autism at a symposium organised by Janssen-Cilag Pty Ltd. Janssen-Cilag
had no control over the contents of the talk and the speaker’s fee was paid to the University that employs me. I have no ongoing
relationship with Janssen-Cilag
• Susan Woolfenden - none known.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


In the protocol it was stated that no age limitations would be used in the search criteria. Age limitations were introduced to the search
criteria, limiting the search to participants in the child and adolescent age ranges. As a result the title of the review has been altered to
reflect this.

INDEX TERMS

Medical Subject Headings (MeSH)


Antidepressive Agents, Tricyclic [adverse effects; ∗ therapeutic use]; Child Development Disorders, Pervasive [∗ drug therapy];
Clomipramine [adverse effects; ∗ therapeutic use]; Thiazepines [adverse effects; ∗ therapeutic use]

MeSH check words


Adolescent; Child; Humans; Young Adult

Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents (Review) 31
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.