Research ArticleAutism Spectrum Disorder

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaau7356
DOI: 10.1126/scitranslmed.aau7356
  • Fig. 1 The CONSORT flow diagram for the phase 2 clinical trial.

    The CONSORT flow diagram details the progress, from screening through to study completion, of participants in the double-blind randomized placebo-controlled trial testing a 4-week intranasal vasopressin treatment versus placebo in children with ASD. A total of 149 prospective participants were screened. Thirty-eight of the 68 individuals enrolled in the study were not randomized owing to either not meeting eligibility criteria or declining to participate. All 30 participants who were randomized to a treatment condition or placebo completed the study, independent of whether they were in the vasopressin or placebo group.

  • Fig. 2 Improvement scores for participants receiving 4-week intranasal arginine vasopressin (AVP) treatment versus placebo.

    Participants’ improvement scores for the clinical trial’s key primary and secondary outcome measures are provided for each treatment condition. (A) Primary outcome measure: the Social Responsiveness Scale, 2nd Edition (SRS-2) T score. (B to F) Secondary outcome measures: Clinical Global Impression (CGI)-Improvement score (B), Reading the Mind in the Eyes Test (RMET) score (C), Facial Emotion Recognition Test (FERT) score (D), Spence Children’s Anxiety Scale (SCAS) score (E), and Repetitive Behaviors Scale-Revised (RBS-R) total score (F). General linear model F tests were used to evaluate whether participants treated with AVP (orange circles) versus placebo (blue circles) differed as a main effect of treatment (i.e., at the mean pretreatment blood AVP concentration). Data are presented as least-squares means (LSM) ± SEM, with individual data points plotted as residuals from their LSM adjacent to the respective error bar. Thus, all data are plotted corrected for other variables in the analysis. Data depicted in (A) and (C) to (F) are presented as absolute difference scores (between posttreatment and baseline pretreatment) such that positive numbers on the y axis indicate improvement. Data depicted in (B) are presented as clinician improvement ratings where 1 = very much improved since the initiation of treatment, 2 = much improved, 3 = minimally improved, and 4 = no change since the initiation of treatment. AVP-treated participants differed significantly from placebo-treated participants in their improvement scores on nearly all measures except for the RBS-R, in which there was no overall group difference. n = 30 for the SRS, CGI, and SCAS; n = 29 for the RBS-R; n = 17 for the FERT; and n = 16 for the RMET.

  • Table 1 Characteristics of participants in the study.

    Fisher’s exact test was used to test whether the distribution of individuals randomized to the treatment conditions differed by sex and by ethnicity; no significant effects were found. For age, IQ, pretreatment SRS-2 T score, pretreatment CGI-S score, pretreatment blood AVP concentration (in picograms per milliliter), and pretreatment blood AVPR1A:OXTR gene expression, differences between treatment conditions were tested with a simple one-way general linear model; no significant effects were discerned. The values are reported as means ± SE. F, female; M, male; IQ, Intelligence Quotient; SRS-2, Social Responsiveness Scale, 2nd Edition; CGI-S, Clinical Global Impression-Severity; AVP, arginine vasopressin AVPR1A:OXTR, relative gene expression as the ΔΔCt of AVPR1A and OXTR gene expression.

    TreatmentnSexEthnicityAge (years)Full-scale
    IQ score
    SRS-2 T scoreCGI-S scoreBlood AVP
    concentration
    Blood
    AVPR1A:
    OXTR
    FMCaucasianOther
    AVP17314899.14 ± 0.5777.65 ± 5.0378.12 ± 1.664.82 ± 0.151.32 ± 0.252.25 ± 0.31
    Placebo132111129.86 ± 0.6591.85 ± 5.7683.00 ± 1.904.77 ± 0.171.28 ± 0.292.21 ± 0.35
  • Table 2 Change from baseline in the behavioral outcome measures for the 4-week arginine vasopressin (AVP) treatment trial.

    Data were analyzed using the same model throughout (which controlled for ethnicity, IQ, pretreatment blood differential receptor gene expression, and baseline behavioral severity for each measure). All analyses tested for a main effect of treatment condition at the mean pretreatment blood AVP concentration. This LSM response takes into account any predictive effect of pretreatment blood AVP concentration on treatment response and gives an overall measure of efficacy in the population of participants as a whole. The ability of pretreatment blood AVP concentration to predict treatment response differentially in the drug-treated group is tested by the treatment condition–by–pretreatment blood AVP concentration interaction. Clinical Global Impression-Improvement (CGI-I) is a single score taken after a 4-week treatment. Otherwise, all other scores are given as a change from baseline, normalized for the direction of the scale, so that symptomatic improvement is reported as a positive change. For all measures, significant overall effects of treatment condition are in the predicted direction (i.e., AVP-treated participants improve more than placebo-treated participants). When a treatment condition–by–pretreatment blood AVP concentration interaction is significant, post hoc tests are reported for AVP-treated and placebo-treated participants: “Greater” indicates that symptomatic improvement increased with higher pretreatment blood concentrations of AVP; “Lesser” indicates that less improvement was observed at higher pretreatment blood concentrations of AVP; “ns” indicates that the scale was not significantly affected by pretreatment blood AVP concentrations. Subscales of an instrument are only tested if the overall score is significant at P < 0.05 and are tested at appropriate Bonferroni-corrected critical α to minimize the risk of false discovery. (Social Behavior Scale, 2nd Edition (SRS-2), critical α < 0.025; Repetitive Behaviors Scale-Revised (RBS-R), critical α < 0.0083). Any post hoc tests of treatment condition–by–pretreatment blood AVP concentration interactions are further Bonferroni-corrected to a critical α half that of the original critical α for the interaction. Effect sizes are given as ηp2. SCI, Social Communication and Interaction; RRB, Restricted Interests and Repetitive Behavior; CGI-S, Clinical Global Impression-Severity; FERT, Facial Emotion Recognition Test; RMET, Reading the Mind in the Eyes Test; NEPSY, Developmental NEuroPSYchological Assessment.

    MeasureTreatment condition
    main effect
    Improvement in
    score LSM ± SE
    *Significant
    after
    correction
    for multiple
    comparisons
    Treatment condition–
    by–pretreatment blood
    AVP concentration
    interaction
    *Significant
    after
    correction
    for multiple
    comparisons
    Improvement in score
    becomes greater or
    lesser with higher
    pretreatment blood
    AVP concentrations
    AVPPlaceboAVPPlacebo
    Primary outcome measure
    SRS-2 T scoreF1,20 = 9.853; P = 0.0052;
    ηp2 = 33.0%
    17.6 ± 1.3710.8 ± 2.11*F1,20 = 50.49; P < 0.0001;
    ηp2 = 71.6%
    *GreaterLesser
      SCIF1,20 = 12.74; P = 0.0019;
    ηp2 = 38.9%
    17.5 ± 1.379.75 ± 2.11*F1,20 = 58.38; P < 0.0001;
    ηp2 = 74.5%
    *GreaterLesser
      RRBF1,20 = 1.045; P = 0.3188;
    ηp2 = 5.0%
    15.6 ± 1.7312.7 ± 2.70nsF1,20 = 7.601; P = 0.0122;
    ηp2 = 27.5%
    *Greaterns
    Secondary outcome measures (clinician-evaluated)
    CGI-S, social and
    communication
    F1,20 = 0.549; P = 0.4674;
    ηp2 = 2.7%
    0.873 ± 0.1260.712 ± 0.202nsF1,20 = 1.519; P = 0.2320;
    ηp2 = 7.1%
    ns
    CGI-I, social and
    communication
    F1,21 = 7.098; P = 0.0145;
    ηp2 = 25.3%
    2.23 ± 0.1492.93 ± 0.244*F1,21 = 9.520; P = 0.0056;
    ηp2 = 31.2%
    *Greaterns
    Secondary outcome measures (parent-rated)
    Spence Children’s
    Anxiety Scale
    F1,20 = 9.014; P = 0.0070;
    ηp2 = 31.1%
    17.9 ± 1.669.14 ± 2.68*F1,20 = 19.48; P = 0.0003;
    ηp2 = 49.3%
    *GreaterLesser
    RBS-R—totalF1,19 = 1.600; P = 0.2213;
    ηp2 = 7.8%
    17.2 ± 1.8321.3 ± 3.18nsF1,19 = 18.57; P = 0.0004;
    ηp2 = 49.4%
    *Greaterns
      StereotypicF1,19 = 0.001; P = 0.9783;
    ηp2 = 0.0%
    2.24 ± 0.3132.23 ± 0.486nsF1,19 = 4.932; P = 0.0381;
    ηp2 = 20.6%
    ns
      Self-injuriousF1,19 = 0.552; P = 0.4666;
    ηp2 = 2.8%
    0.594 ± 0.4671.18 ± 0.828nsF1,19 = 27.54; P < 0.0001;
    ηp2 = 59.2%
    *GreaterLesser
      CompulsiveF1,19 = 2.028; P = 0.1707;
    ηp2 = 9.6%
    3.35 ± 0.5114.59 ± 0.819nsF1,19 = 22.49 ; P = 0.0001;
    ηp2 = 54.2%
    *Greaterns
      RitualisticF1,19 = 3.133; P = 0.0920;
    ηp2 = 14.2%
    3.08 ± 0.5044.63 ± 0.818nsF1,19 = 3.643; P = 0.0708;
    ηp2 = 16.1%
    ns
      SamenessF1,19 = 0.043; P = 0.8375;
    ηp2 = 0.2%
    5.61 ± 0.6615.85 ± 1.03nsF1,19 = 3.071; P = 0.0950;
    ηp2 = 13.9%
    ns
      RestrictedF1,19 = 0.623; P = 0.4392;
    ηp2 = 3.2%
    2.58 ± 0.543.4 ± 1.01nsF1,19 = 4.261; P = 0.0522;
    ηp2 = 18.3%
    ns
    Secondary outcome measures (child performance)
    FERTF1,7 = 10.85; P = 0.0132;
    ηp2 = 60.8%
    3.10 ± 2.42−7.19 ± 1.81*F1,7 = 0.971; P = 0.3573;
    ηp2 = 12.2%
    ns
    RMETF1,6 = 6.2341; P = 0.0467;
    ηp2 = 51.0%
    4.04 ± 1.63−1.28 ± 1.24*F1,6 = 0.068; P = 0.8031;
    ηp2 = 1.1%
    ns
    NEPSY—Theory of
    Mind
    F1,12 = 0.647; P =0.4367;
    ηp2= 5.1%
    2.1 ± 1.410.677 ± 1.20nsF1,12 = 1.162; P =0.3022;
    ηp2= 8.8%
    ns
    NEPSY—Affect
    Recognition
    F1,12 = 0.946; P = 0.3500;
    ηp2 = 7.3%
    0.094 ± 2.20−2.58 ± 1.90nsF1,12 = 0.251; P = 0.6254;
    ηp2 = 2.0%
    ns
  • Table 3 Reported adverse events during the 4-week arginine vasopressin (AVP) treatment trial assessed by the DOTES and OAS scales.

    Adverse events are reported as counts and percentages. Fisher’s exact test was used to test for differences in adverse events between the AVP and placebo treatment conditions. No significant effects were discerned. DOTES, Dosage Record Treatment Emergent Symptom Scale; OAS, Overt Aggression Scale; HEENT, head, ears, eyes, nose, and throat.

    Adverse eventAVP (n = 17)Placebo (n = 13)
    General
      Fever2 (12%)1 (8%)
      Cough1 (6%)0 (0%)
      Body ache1 (6%)0 (0%)
    Neurological/
    psychiatric
      Excitement/agitation4 (24%)1 (8%)
      Insomnia4 (24%)1 (8%)
      Increased motor
    activity
    4 (24%)0 (0%)
      Depressive affect2 (12%)1 (8%)
      Headache2 (12%)0 (0%)
      Drowsiness1 (6%)3 (23%)
      Decreased motor
    activity
    1 (6%)2 (15%)
      Aggression1 (6%)1 (8%)
      Akathisia1 (6%)0 (0%)
      Head banging1 (6%)0 (0%)
      Dizziness0 (0%)1 (8%)
      Lethargy/tiredness0 (0%)1 (8%)
    HEENT
      Nasal congestion3 (18%)4 (31%)
      Dry mouth1 (6%)3 (23%)
      Blurred vision1 (6%)1 (8%)
      Ear infection0 (0%)1 (8%)
      Runny nose0 (0%)1 (8%)
      Sore throat0 (0%)1 (8%)
      Cold sore0 (0%)1 (8%)
    Gastrointestinal
      Decreased appetite4 (24%)5 (38%)
      Nausea/vomiting2 (12%)2 (15%)
      Constipation1 (6%)0 (0%)
      Diarrhea0 (0%)1 (8%)
    Renal
      Increased urination1 (6%)1 (8%)
      Bed-wetting1 (6%)0 (0%)
    Dermatological
      Skin rash1 (6%)1 (8%)
      Bug bite1 (6%)0 (0%)
      Skin burn0 (0%)1 (8%)

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/scitranslmed.aau7356/DC1

    Table S1. Raw data and SAS code for the data and analyses shown in Table 1.

    Table S2. Participants’ stable concomitant medications during the 4-week AVP treatment trial.

    Table S3. Raw data and SAS code testing whether parents could ascertain treatment condition.

    Table S4. Raw data and SAS code testing whether bottle weights differed between treatment conditions.

    Table S5. Raw data and SAS code for Fig. 2A and associated analyses.

    Table S6. Raw data and SAS code testing treatment effects for the SRS-2 using an unweighted analysis.

    Table S7. Raw data and SAS code testing treatment effects for the SCI subscale of the SRS-2.

    Table S8. Raw data and SAS code correlating parent SRS-2 ratings with clinician CGI evaluations.

    Table S9. Raw data and SAS code for Fig. 2B and associated analyses.

    Table S10. Raw data and SAS code for Fig. 2C and associated analyses.

    Table S11. Raw data and SAS code for Fig. 2D and associated analyses.

    Table S12. Raw data and SAS code for Fig. 2E and associated analyses.

    Table S13. Raw data and SAS code for Fig. 2F and associated analyses.

    Table S14. Raw data and SAS code testing treatment effects for the RRB subscale of the SRS-2.

    Table S15. Change from baseline in the safety assessments for the 4-week AVP treatment trial.

    Table S16. Raw data and SAS code for the data and analyses shown in table S15.

  • This PDF file includes:

    • Table S1. Raw data and SAS code for the data and analyses shown in Table 1.
    • Table S2. Participants’ stable concomitant medications during the 4-week AVP treatment trial.
    • Table S3. Raw data and SAS code testing whether parents could ascertain treatment condition.
    • Table S4. Raw data and SAS code testing whether bottle weights differed between treatment conditions.
    • Table S5. Raw data and SAS code for Fig. 2A and associated analyses.
    • Table S6. Raw data and SAS code testing treatment effects for the SRS-2 using an unweighted analysis.
    • Table S7. Raw data and SAS code testing treatment effects for the SCI subscale of the SRS-2.
    • Table S8. Raw data and SAS code correlating parent SRS-2 ratings with clinician CGI evaluations.
    • Table S9. Raw data and SAS code for Fig. 2B and associated analyses.
    • Table S10. Raw data and SAS code for Fig. 2C and associated analyses.
    • Table S11. Raw data and SAS code for Fig. 2D and associated analyses.
    • Table S12. Raw data and SAS code for Fig. 2E and associated analyses.
    • Table S13. Raw data and SAS code for Fig. 2F and associated analyses.
    • Table S14. Raw data and SAS code testing treatment effects for the RRB subscale of the SRS-2.
    • Table S15. Change from baseline in the safety assessments for the 4-week AVP treatment trial.
    • Table S16. Raw data and SAS code for the data and analyses shown in table S15.

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