Skip to main content
. 2021 Feb 14;2021(2):CD013457. doi: 10.1002/14651858.CD013457.pub2

Minshawi 2016.

Study characteristics
Methods Study design: randomised, parallel‐group, placebo‐controlled trial
Masking: double‐blind (participant, care provider and investigator)
Study start date: March 2010
Study end date: January 2014
Setting: recruitment from academic autism treatment centres, local schools and community organizations
Country: USA
Study location: Indiana University School of Medicine (n = 52) and Cincinnati Children's Hospital Medical Centre (n = 15)
Participants Number recruited: 68 children (154 participants assessed for eligibility and 86 participants excluded: 35 = not meeting inclusion criteria; 40 = refused to participate; 11 = other reason)
Number randomised: 68 children
Number completed: 67 children
Number dropouts/withdrawals: 1 child with ASD was excluded from the analyses due to early dropout prior to taking study drug
Inclusion criteria

  • Children with ASD aged between 5 and 11 years old, recruited using Autism Diagnostic Observation Schedule, Autism Diagnostic Interview‐Revised, and DSM‐IV‐TR

  • Intelligence quotient (IQ) more than 70 on the Stanford‐Binet Intelligence Scales, 5th Edition, and a standard score of more than 70 on the Communication domain of the Vineland Adaptive Behavioural Scales, 2nd Edition (VABS‐II)

  • Triad Social Skills Assessment (TSSA) score of 70% or less on both the parent questionnaire and child assessment, a T score of 60 or greater on the Social Responsiveness Scale (SRS) and a Clinical Global Impression‐Severity (CGI‐S) scale score of at least 4

  • Stable psychotropic medication dosing targeting symptoms for a minimum of 2 weeks prior to randomisation (with the exception of 4 weeks for fluoxetine)


Exclusion criteria

  • Participants taking more than 2 psychotropic medications

  • Participants currently taking a glutamatergic modulator (e.g. riluzole, memantine, acamprosate, topiramate, amantadine)

  • Group skill training outside of the study


Pretreatment: differences in age, sex and number of participants between the two groups are small
Baseline characteristics

  • D‐cycloserine group: mean age = 8.38 years (SD = 1.93); 82.35% male; full scale IQ = 92.42 (SD = 17.76); mean score on VABS‐II = 87.38 (SD = 13.36); and mean score on CGI‐S = 4.03 (SD = 1.08)

  • Placebo group: mean age = 8.25 years (SD = 1.73); 81.82% male; full scale IQ = 87.30 (SD = 15.74); mean score on VABS‐II = 84.55 (SD = 14.94); and mean score on CGI‐S = 4.06 (SD = 0.24)
Interventions Experimental intervention: D‐cycloserine, 50 mg weekly

  • Duration: 10 weeks

  • Adminstration: 10 doses of D‐cycloserine were given 30 minutes prior to weekly, group social skills training

  • Age group: 5 to 11 years old


Control intervention: placebo

  • Duration: 10 weeks

  • Adminstration: 10 doses of placebo were given 30 minutes prior to weekly, group social skills training

  • Age group: 5 to 11 years old
Outcomes Primary outcomes
Outcome 1: social interaction impairment, measured by:

  • Social Responsiveness Scale (SRS)

    • Outcome type: continuous outcome

    • Reporting: fully reported

    • Scale: 4‐point Likert scale

    • Range: within normal limit to severe range of impairment

    • Unit of measure: 0 to 195

    • Direction: lower is better

    • Data value: endpoint

    • Notes: the 65‐item SRS is a standardised measure of the core symptoms of autism. Each item is scored on a 4‐point Likert scale. The score of each individual item is summed to create a total raw score. Total score results are as follows: 0 to 62 = within normal limit; 63 to 79 = mild range of impairment; 80 to 108 = moderate range of impairment; and 109 to 149 = severe range of impairment.

  • Triad Social Skills Assessment (TSSA)

    • Outcome type: continuous outcome

    • Reporting: fully reported

    • Scale: 4‐point scale

    • Range: not very well to very well

    • Unit of measure: 1 to 4

    • Direction: higher is better

    • Data value: endpoint

    • Notes: the TSSA is a 35‐item, parent‐rated questionnaire with four subscales: (1) ability to understand emotions and perspectives of others (affect) (8 items); (2) ability to initiate interaction (11 items); (3) ability to maintain interaction (11 items); (4) ability to respond to others (5 items). Each item is scored on a 4‐point scale: 1 (not very well) to 4 (very well).

  • Vineland Adaptive Behaviour Scales 2nd Edition (VABS‐II)

    • Outcome type: continuous outcome

    • Reporting: fully reported

    • Scale: 3‐point scale

    • Range: never performed to habitually performed

    • Unit of measure: 0 to 2

    • Direction: higher is better

    • Data value: endpoint

    • Notes: the Socialisation domain is a 99‐item, parent‐rated questionnaire with 3 subscales: (1) Interpersonal relationships (38 items); (2) play and leisure time (31 items); (3) coping skills (30 items). Each item is scored on a 3‐point scale: 0 (never performed), 1 (sometimes performed), 2 (habitually performed).


Outcome 2: social communication impairment, measured by:

  • Inappropriate Speech subscale (4 items) of the Aberrant Behaviour Checklist (ABC)

    • Each item is scored on a 4‐point scale: 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem).

  • Communication domain (97‐items) of the Vineland Adaptive Behaviour Scales 2nd Edition (VABS‐II)

    • Parent‐rated questionnaire with 3 subscales: (1) Receptive (20 items); (2) Expressive (54 items); (3) Written (23 items). Each item is scored on a 3‐point scale: 0 (never performed), 1 (sometime performed), 2 (habitually performed).


Outcome 3: restricted, repetitive, stereotyped patterns of behaviour and interests, measured by:

  • the Stereotypic Behaviour subscale (7 items) of the Aberrant Behaviour Checklist (ABC)

    • Each item is scored on a 4‐point scale: 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem)


Outcome 4: adverse events

  • Outcome type: dichotomous outcome

  • Reporting: fully reported

  • Range: serious adverse events and non‐serious adverse events


Secondary outcomes
Outcome 1: non‐core symptoms of ASD, measured by Clinical Global Impression‐Improvement (CGI‐I) scale

  • Outcome type: dichotomous outcome

  • Reporting: fully reported

  • Scale: 7‐point scale

  • Range: very much improved to very much worse

  • Unit of measure: 1 to 7

  • Notes: at the end of treatment, participants were assessed with CGI‐I and categorised as either responders to treatment (CGI‐I score of 1 or 2) or non‐responders to treatment (CGI‐I score of 3 or higher)


Outcome 2: tolerability of D‐cycloserine

  • Outcome type: dichotomous outcome

  • Reporting: fully reported
Identification Author's name: Noha F Minshawi (contact author)
Institution: Indiana University School of Medicine, Department of Psychiatry
Email: craig.erickson@cchmc.org
Address: Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229, USA
Notes Sponsorship source: United States Department of Defense, Award Number W81XWH‐09‐1‐0091
Comments: This RCT was approved by the Institutional review board at each site.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Quote: "Children with ASD were randomised to receive 10 weeks (10 doses) of DCS or placebo in a 1:1 ratio."
Judgement comment: it was a randomised, double‐blind, placebo‐controlled trial but did not state the method of randomisation clearly. We asked the authors for clarification, but did not receive a response.
Allocation concealment (selection bias) Unclear risk Judgement comment: the method of allocation concealment was not reported.
Blinding of participants and personnel (performance bias)
All outcomes Low risk Quote: "10‐week, double‐blind, placebo‐controlled trial of low dose (50 mg) DCS given 30 min prior to weekly group social skills training was conducted at two sites, Indiana University School of Medicine and Cincinnati Children’s Hospital Medical Center."
Judgement comment: it is clearly stated that there was blinding of participants and personnel.
Blinding of outcome assessment (detection bias)
All outcomes Low risk Quote: "Outcome assessors were unaware of the treatment allocation until after 12 weeks post‐treatment follow‐up visits and the data set was locked."
Judgement comment: it was stated as triple blind in the trial register. (clinicaltrials.gov/ct2/show/NCT01086475) before full publication.
Incomplete outcome data (attrition bias)
All outcomes Low risk Quote: "One subject with ASD was excluded from the analyses due to early dropout prior to taking the study drug."
Judgement comment: only one participant was excluded.
Selective reporting (reporting bias) Low risk Judgement comment: the trial reported all outcomes listed on the trial registration.
Other bias Low risk Quote: "The authors declare that they have no competing interests."
Judgement comment: the principal investigators are not employed by the organisation sponsoring the study. The study was supported by the United States Department of Defense. The authors declared no conflict of interest.

ASD: autism spectrum disorder
DCS: D‐cycloserine
DSM‐IV‐TR: Diagnostic and Statistical Manual of Mental Disorders‐Fourth Edition‐Text Revision.
IQ: intelligence quotient
min: minute(s)
SD: standard deviation