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. 2021 Feb 14;2(2):CD013457.
doi: 10.1002/14651858.CD013457.pub2.

The effectiveness and adverse effects of D-cycloserine compared with placebo on social and communication skills in individuals with autism spectrum disorder

Swe Zin Aye  1 , Han Ni  2 , Htwe H Sein  1 , San T Mon  3 , Qishi Zheng  4 , Yoko Kin Yoke Wong  5
Affiliations

The effectiveness and adverse effects of D-cycloserine compared with placebo on social and communication skills in individuals with autism spectrum disorder

Swe Zin Aye et al. Cochrane Database Syst Rev. .

Abstract

Background: Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted.

Objectives: To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD.

Search methods: In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events. SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD.

Data collection and analysis: Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review.

Main results: We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted at two sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out 1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment. The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reported low certainty evidence of little to no difference between the two groups for all outcomes measured at one week post-treatment: social interaction impairment (mean difference (MD) 3.61 (assessed with the Social Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment (MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD (RR 0.97 (measured by the Clinical Global Impression-Improvement scale), 95% CI 0.49 to 1.93); and tolerability of D-cycloserine (RR 0.32 (assessed by the number of dropouts), 95% CI 0.01 to 7.68). AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.

Trial registration: ClinicalTrials.gov NCT01086475 NCT00198120.

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Conflict of interest statement

Swe Zin Aye: none known.

Han Ni: none known.

Htwe Htwe Sein: none known.

San Thidar Mon: none known.

Qishi Zheng: none known.

Yoko Kin Yoke Wong: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 1: Social interaction impairment measured by Social Responsiveness Scale (SRS) parent total score at one week post‐treatment
1.2
1.2. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 2: Social interaction impairment measured by Social Responsiveness Scale (SRS) parent total score at 12 weeks post‐treatment
1.3
1.3. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 3: Social interaction impairment measured by Vineland Adaptive Behaviour Scales 2nd Edition (VABS‐II) parent scores for socialization subscale
1.4
1.4. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 4: Social interaction impairment measured by Triad Social Skills Assessment (TSSA) parent score
1.5
1.5. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 5: Social communication impairment measured by Aberrant Behaviour Checklist (ABC) parent score ‐ inappropriate speech subscale
1.6
1.6. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 6: Social communication impairment measured by Vineland Adaptive Behaviour Scales 2nd Edition (VABS‐II) parent scores for communication subscale
1.7
1.7. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 7: Stereotype patterns of behaviour and interests measured by Aberrant Behaviour Checklist (ABC) parent score ‐ stereotypy subscale
1.8
1.8. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 8: Total adverse events measured by reports of adverse events
1.9
1.9. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 9: Responders to treatment assessed with Clinical Global Impression‐Improvement (CGI‐I) scale
1.10
1.10. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 10: Tolerability of D‐cycloserine assessed with numbers of dropouts at one week post‐treatment
1.11
1.11. Analysis
Comparison 1: D‐cycloserine versus placebo, Outcome 11: Tolerability of D‐cycloserine assessed with numbers of dropouts at 12 weeks post‐treatment
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013457

References

References to studies included in this review

Minshawi 2016 {published data only}
    1. Minshawi NF, Wink LK, Shaffer R, Plawecki MH, Posey DJ, Liu H, et al. A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders. Molecular Autism 2016;7:2. [DOI: 10.1186/s13229-015-0062-8] [PMC4712595] [PMID: ] - DOI - PMC - PubMed
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References to studies excluded from this review

NCT00198107 {published data only}
    1. NCT00198107. Evaluating the effectiveness of Aripiprazole and D-cycloserine to treat symptoms associated with autism [Novel pharmacological strategies in autism]. clinicaltrials.gov/ct2/show/results/NCT00198107 (first received 12 September 2005).
Posey 2004 {published data only}
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Urbano 2014 {published data only}
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References to ongoing studies

NCT00198120 {published data only (unpublished sought but not used)}
    1. NCT00198120. Safety and effectiveness of D-Cycloserine in children with autism [A randomized controlled trial of D-Cycloserine in autism]. clinicaltrials.gov/ct2/show/study/NCT00198120 (first received 12 September 2005).

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