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Cited by 117Neuroendocrine regulation and behaviorAutism Spectrum Disorder ResearchGenetics and Neurodevelopmental Disorders

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

Open access
Kosaka, H, Okamoto, Y, Munesue, T, Yamasue, H, Inohara, K, Fujioka, T, Anme, T, Orisaka, M +14 more·2016·Translational Psychiatry
DOI 10.1038/tp.2016.152PMC PMC5022092
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Abstract

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 12-week double-blind phase of a pilot randomized trial in young adults with high-functioning ASD, oxytocin did not improve outcomes in the intention-to-treat population, but high-dose oxytocin improved CGI-I in male participants. Efficacy in males depended on estimated daily dosage (>21 IU/day) and an OXTR SNP (rs6791619) at lower doses.

Key findings

  • In the intention-to-treat population (n=60), no outcomes improved after oxytocin administration.
  • In male participants with good adherence, high-dose oxytocin (32 IU/day) significantly improved CGI-I versus placebo (t(24)=3.714, P=0.001, Cohen’s d=1.52; post hoc power 0.944), whereas low-dose oxytocin (16 IU/day) did not (P=0.08).
  • CGI-I at week 12 correlated with estimated daily oxytocin dosage (n=43, r=−0.512, P<0.001); >21 IU/day was more effective than ≤21 IU/day.
  • The OXTR SNP rs6791619 predicted CGI-I scores for ≤21 IU/day oxytocin, with T-allele carriers showing stronger improvement; no severe adverse events occurred.

Methods

  • Single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group trial; 12-week double-blind phase, 12-week open-label phase, and 8-week follow-up. Sixty participants were randomized 1:1:1 to high-dose oxytocin (32 IU/day), low-dose oxytocin (16 IU/day), or placebo intranasal spray.
  • Primary outcomes were CGI and IRSA; secondary outcomes included depression, anxiety, alexithymia, and Aberrant Behavior Checklist measures. Analyses used intention-to-treat and a male subgroup with good adherence (>50%), with gatekeeping t-tests/ANOVA and random forest regression with conditional inference trees.
  • Twenty-four OXTR SNPs were selected and genotyped; after exclusions, 19 SNPs were analyzed alongside estimated daily oxytocin dosage as predictors of CGI-I.

Limitations

  • The paper states three limitations: higher dosages and time dependency were not confirmed in the double-blind phase; the small sample limited examination of OXTR polymorphisms or sex effects; and plasma oxytocin showed no significant changes, possibly because the non-extracted assay was inappropriate.
  • Evident from the text: the trial was single-center, the main positive findings came from a male-only subgroup rather than the ITT population, and female participants were too few (13 of 60) to support sex-specific efficacy conclusions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/tp.2016.152

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Oxytocin administration for 12 weeks causes no severe adverse events in the trial participants.

    “In the present trial, we did not observe any severe adverse events during a 12-week period of oxytocin administration.”
    Quote in the paperSubstantial claim
  • Findingown data

    Other single-nucleotide polymorphisms were not significantly predictive of Clinical Global Impression-Improvement score improvement.

    “Other SNPs were not significantly predictive of CGI-I score improvement.”
    Quote in the paperSubstantial claim
  • Findingown data

    High-dose (32 IU) oxytocin administration for 12 weeks alleviates comprehensive symptoms in male young adults with ASD.

    “we confirmed that high-dose oxytocin administration for 12 weeks alleviates symptoms in male young adults with ASD with no severe adverse event”
    • Also stated in: § Efficacy of long-term oxytocin administration · plain
      “Overall, our results show that comprehensive symptoms of males with ASD improved after administration of 32 IU oxytocin for 12 weeks.”
    Quote in the paperSubstantial claim
  • Findingown data

    Estimated daily oxytocin dosages were 28.8±4.5 (18.9-32.0) and 13.5±1.4 IU (10.4-15.2) for the high-dose and low-dose groups, respectively.

    “Estimated daily oxytocin dosages were 28.8±4.5 (18.9–32.0) and 13.5±1.4 IU (10.4–15.2) for the high-dose and low-dose groups, respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated daily oxytocin dosage calculated from the residual quantity of the spray bottle accurately reflects the actual daily oxytocin dose received by each participant.
  • Findingown data

    In male participants, Clinical Global Impression-Improvement scores in the high-dose oxytocin group were significantly higher than in the placebo group.

    “However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group.”
    • Also stated in: § Outcomes and safety · plain
      “t-test revealed significant improvement in CGI-I score in the high-dose oxytocin group over the placebo group (t(24)=3.714, P=0.001, two-sided; Cohen's d=1.52) with high post hoc power (0.944).”
    Quote in the paperSubstantial claim
  • May combine two claims. 14
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    Female participants did not complain about menstrual disorders and galactorrhea, and a gynecologist confirmed no abnormality in sex hormone levels, menstrual cycle and uterine peristaltic activity.

    “Female participants did not complain about menstrual disorders and galactorrhea, and a gynecologist confirmed that there was no abnormality in sex hormone levels, menstrual cycle and uterine peristaltic activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two-way ANOVA on plasma oxytocin level revealed no main effects of group and time or interaction between group and time (P>0.05).

    “Two-way ANOVA on plasma oxytocin level revealed no main effects of group and time or interaction between group and time (P>0.05; Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No severe adverse events or abnormal physiological changes were observed across the clinical trial.

    “No severe adverse events occurred.”
    • Also stated in: § Outcomes and safety · plain
      “Across the clinical trial, no severe adverse events or abnormal physiological changes were observed (Table 3).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In male participants, Clinical Global Impression-Improvement scores in the low-dose oxytocin group were not significantly higher than in the placebo group.

    “In the second step of analysis (low-dose vs placebo group), t-test did not reveal a significant difference in CGI-I score between the two groups (P=0.08, two-sided).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    The association between efficacy of long-term oxytocin administration and single-nucleotide polymorphisms in OXTR among individuals with autism spectrum disorder remains unclear.

    “Nonetheless, the association between efficacy of long-term oxytocin administration and SNPs in OXTR among individuals with ASD remains unclear.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The randomization schedule was generated by an unmasked statistician not involved in conducting the trial and data analysis.

    “The randomization schedule was generated by an unmasked statistician not involved in conducting the trial and data analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants were randomly assigned (1:1:1) to high-dose oxytocin, low-dose oxytocin, and placebo groups during the double-blind phase.

    “Participants were randomly assigned (1:1:1) to high-dose oxytocin, low-dose oxytocin and placebo groups during the double-blind phase.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The trial was a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group clinical trial.

    “We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD”
    • Also stated in: § Procedure · plain
      “we conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial at the Department of Neuropsychiatry of University of Fukui Hospital, Japan (UMIN000005211).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    The efficacy of oxytocin administration depends on dosage.

    “it has been proposed that the efficacy of oxytocin administration depends on dosage.10, 12, 13”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Macdonald K, Feifel D . Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Front Neurosci 2013; 7: 35. source

      Not checked in the free run.

    • cites [12] Feifel D, Macdonald K, Nguyen A, Cobb P, Warlan H, Galangue B et al. Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry 2010; 68: 678–680. source

      Not checked in the free run.

    • cites [13] MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ . A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 2011; 36: 1114–1126. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In patients with schizophrenia, 20 IU oxytocin, but not 10 IU oxytocin, ameliorated emotion recognition deficits in a polydipsic group.

    “A clinical study with divergent single-dose oxytocin administration in patients with schizophrenia showed that 20 IU oxytocin, but not 10 IU oxytocin, ameliorated emotion recognition deficits in a polydipsic group.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Goldman MB, Gomes AM, Carter CS, Lee R . Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. Psychopharmacology (Berl) 2011; 216: 101–110. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Intranasal oxytocin administration may be effective for autism spectrum disorder.

    “recent studies have proposed that intranasal oxytocin administration may be effective.2, 3”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Yamasue H, Yee JR, Hurlemann R, Rilling JK, Chen FS, Meyer-Lindenberg A et al. Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction. J Neurosci 2012; 32: 14109–14117. source

      Not checked in the free run.

    • cites [3] Okamoto Y, Ishitobi M, Wada Y, Kosaka H . The potential of nasal oxytocin administration for remediation of autism spectrum disorders. CNS Neurol Disord Drug Targets 15: 564–577. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Dose-dependent oxytocin efficacy has been shown in animal and human studies on diseases other than autism spectrum disorder.

    “Previous animal14, 15 and human studies on diseases other than ASD16, 17, 18 have shown dose-dependent oxytocin efficacy.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Bales KL, van Westerhuyzen JA, Lewis-Reese AD, Grotte ND, Lanter JA, Carter CS . Oxytocin has dose-dependent developmental effects on pairbonding and alloparental care in female prairie voles. Horm Behav 2007; 52: 274–279. source

      Not checked in the free run.

    • cites [15] Feifel D, Shilling PD, Hillman J, Maisel M, Winfield J, Melendez G . Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs. Behav Brain Res 2015; 278: 424–428. source

      Not checked in the free run.

    • cites [16] Legros JJ, Chiodera P, Geenen V, Smitz S, von Frenckell R . Dose-response relationship between plasma oxytocin and cortisol and adrenocorticotropin concentrations during oxytocin infusion in normal men. J Clin Endocrinol Metab 1984; 58: 105–109. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Genetic alteration of OXTR is associated with autism spectrum disorder occurrence.

    “Previous studies reported that genetic alteration of OXTR is associated with ASD occurrence;21, 24”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] LoParo D, Waldman ID . The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20: 640–646. source

      Not checked in the free run.

    • cites [24] Di Napoli A, Warrier V, Baron-Cohen S, Chakrabarti B . Genetic variation in the oxytocin receptor (OXTR) gene is associated with Asperger syndrome. Mol Autism 2014; 5: 48. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Intranasally administered oxytocin acts through the oxytocin receptor (OXTR).

    “Intranasally administered oxytocin is considered to act through the oxytocin receptor (OXTR).21, 22”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] LoParo D, Waldman ID . The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20: 640–646. source

      Not checked in the free run.

    • cites [22] Gimpl G, Fahrenholz F . The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001; 81: 629–683. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    We analyzed 60 and 43 participants for the intention-to-treat population and subgroup population (male participants with good adherence), respectively.

    “We analyzed the 60 and 43 participants for ITT population and subgroup population (male participants with good adherence), respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In resting-state functional MRI analysis, activation could not be compared between high-dose and placebo groups because of the small number of participants in the high-dose group (n=1).

    “In resting-state functional MRI analysis, we could not compare activation between high-dose and placebo groups because of the small number of participants in the high-dose group (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Randomization was centralized, using a computer-generated list with random block sizes of six.

    “Randomization was centralized, using a computer-generated list with random block sizes of six.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Participants, their family and staff were masked to treatment, and the allocation sequence was not disclosed until the open-label phase for all participants was completed.

    “Participants, their family and staff were masked to the treatment, and the allocation sequence was not disclosed until the open-label phase for all the participants was completed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    55 of 60 participants (91.7%) continued the intranasal spray administration throughout the trial period.

    “Therefore, 55 of 60 participants (91.7%) continued the intranasal spray administration throughout the trial period.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    We conducted intention-to-treat analyses including all participants, and subgroup analyses in only male participants with good adherence (>50%).

    “We conducted intention-to-treat (ITT) analyses including all participants, and subgroup analyses in only male participants with good adherence (>50%) because sex-based differences in responses to oxytocin administration have been reported (Table 1, Figure 1).2, 38”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Yamasue H, Yee JR, Hurlemann R, Rilling JK, Chen FS, Meyer-Lindenberg A et al. Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction. J Neurosci 2012; 32: 14109–14117. source

      Not checked in the free run.

    • cites [38] Macdonald KS . Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Front Neurosci 2013; 6: 194. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Two psychiatrists confirmed the diagnosis using the Diagnostic Interview for Social and Communication Disorders.

    “Two psychiatrists (HK and TM) confirmed the diagnosis using the Diagnostic Interview for Social and Communication Disorders.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Wing L, Leekam S, Libby S, Gould J, Larcombe M . The Diagnostic Interview for Social and Communication Disorders: background, inter-rater reliability and clinical use. J Child Psychol Psychiatry 2002; 43: 307–325. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The clinical trial was approved by the institutional review board of the University of Fukui, Japan, and conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labour and Welfare of Japan.

    “This clinical trial was approved by the institutional review board of the University of Fukui, Japan, and was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labour and Welfare of Japan.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    A two-step analysis with a gatekeeping strategy was used to control the family-wise type 1 error rate.

    “we utilized two-step analysis with a gatekeeping strategy40 to control the family-wise type 1 error rate.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Dmitrienko A, Millen BA, Brechenmacher T, Paux G . Development of gatekeeping strategies in confirmatory clinical trials. Biom J 2011; 53: 875–893. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Correction of multiple comparisons was conducted with two-sided α=0.004 (0.05/11, number of primary and secondary outcomes).

    “Correction of multiple comparisons was conducted with two-sided α=0.004 (0.05/11, number of primary and secondary outcomes).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Oxytocin administration improves various psychiatric symptoms such as depression and anxiety, as well as social-communicative dysfunction.

    “Oxytocin administration improves various psychiatric symptoms such as depression and anxiety, as well as social-communicative dysfunction.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Hofmann SG, Fang A, Brager DN . Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies. Psychiatry Res 2015; 228: 708–714. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Written informed consent was obtained from each participant and parents if the participant was under 20 years old.

    “Written informed consent was obtained from each participant and parents if the participant was under 20 years old, after a complete explanation of the trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Random forests are a recursive partitioning method particularly well-suited to small n large p problems.

    “Random forests are a recursive partitioning method particularly well-suited to small n large p problems.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Strobl C, Malley J, Tutz G . An introduction to recursive partitioning: rationale, application, and characteristics of classification and regression trees, bagging, and random forests. Psychol Methods 2009; 14: 323–348. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The dependence of long-term oxytocin efficacy on dosage and oxytocin receptor genetic background in young men with high-functioning autism spectrum disorder contributes to the effectiveness of oxytocin treatment of autism spectrum disorder.

    “which contributes to the effectiveness of oxytocin treatment of ASD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Changes in gaze-behaviors are easier to detect by the person interacting with the participants than by a third person.

    “Such changes in gaze-behaviors are easier to detect by the person interacting with the participants than by a third person.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxytocin administration improves eye contact during naturalistic social interaction.

    “Previous studies have found that oxytocin administration improves eye contact during naturalistic social interaction.5, 45”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N et al. Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 2015; 138 (Pt 11): 3400–3412. source

      Not checked in the free run.

    • cites [45] Auyeung B, Lombardo MV, Heinrichs M, Chakrabarti B, Sule A, Deakin JB et al. Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry 2015; 5: e507. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The inconsistent results between IRSA and other measures might be because of difference in the assessment procedure.

    “The inconsistent results might be because of difference in the assessment procedure.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    rs6791619 is not solely associated with ASD occurrence.

    “a recent meta-analysis revealed that rs6791619 is not solely associated with ASD occurrence,21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] LoParo D, Waldman ID . The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20: 640–646. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    Non-extracted approaches may not have been appropriate as a methodology.

    “Non-extracted approaches may not have been appropriate as a methodology.48, 59”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Leng G, Ludwig M . Intranasal oxytocin: myths and delusions. Biol Psychiatry 2016; 79: 243–250. source

      Not checked in the free run.

    • cites [59] McCullough ME, Churchland PS, Mendez AJ . Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci Biobehav Rev 2013; 37: 1485–1492. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    11 carriers of the T-G-T-T haplotype at rs237851-rs6791619-rs53576-rs237884 have more impairment than 89 noncarriers in social interaction and communication domains of the Autism Diagnostic Interview-Revised in individuals with ASD.

    “Wermter et al.37 found that 11 carriers of the T–G–T–T haplotype at rs237851–rs6791619–rs53576–rs237884 have more impairment than 89 noncarriers in social interaction and communication domains of the Autism Diagnostic Interview-Revised56 in individuals with ASD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Wermter AK, Kamp-Becker I, Hesse P, Schulte-Korne G, Strauch K, Remschmidt H . Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 629–639. source

      Not checked in the free run.

    • cites [56] Le Couteur A, Lord C, Rutter M . Autism Diagnostic Interview-Revised (ADI-R). WPS: Torrance, CA, 2003.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxytocin is known to induce uterine contractions.

    “Although oxytocin is known to induce uterine contractions,57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Jovanović A, Jovanović S, Tulić I, Grbović L . Effect of oxytocin as a partial agonist at vasoconstrictor vasopressin receptors on the human isolated uterine artery. Br J Pharmacol 1997; 121: 1468–1474. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    In the present trial, only one participant had the T-G-T-T haplotype at rs237851-rs6791619-rs53576-rs237884, so the trial could not examine whether efficacy differed between carriers and noncarriers.

    “since only one participant had T–G–T–T haplotype at rs237851–rs6791619–rs53576–rs237884 in the present trial, we cannot examine whether the efficacy was different between carriers of T–G–T–T haplotype at rs237851–rs6791619–rs53576–rs237884.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The trial did not confirm the efficacy of higher dosage and time dependency in the double-blind phase.

    “we did not confirm the efficacy of higher dosage and time dependency in the double-blind phase.”
    Quote in the paperSubstantial claim
37 of 37

  • The paper relies on this without support.

    The estimated daily oxytocin dosage calculated from the residual quantity of the spray bottle accurately reflects the actual daily oxytocin dose received by each participant.

    “the estimated daily oxytocin dosage was calculated by averaging the total residual quantity of the entire spray bottle for the 84-day double-blind period for each participant.”

  • The paper relies on this without support.

    No other RCTs have evaluated the hormonal actions of long-term oxytocin administration in female participants.

    “no other RCTs have evaluated the hormonal actions of long-term oxytocin administration in female participants.”

  • The paper relies on this without support.

    This is the longest duration RCT of oxytocin in ASD to date.

    “As this is the longest duration RCT of oxytocin in ASD to date (that is, previous RCTs lasted from 5 to 8 weeks)”
3 of 3

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Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentt(24) = 3.714reported p = .001 · recomputed p = .001

    “t(24)=3.714, p = .001”

1 of 1

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Percentages, sums and reported differences re-computed from the paper’s own numbers.

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Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Le Couteur A, Lord C, Rutter M . Autism Diagnostic Interview-Revised (ADI-R). WPS: Torrance, CA, 2003.

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Authors
Kosaka, H., Okamoto, Y., Munesue, T., Yamasue, H., Inohara, K., Fujioka, T., Anme, T., Orisaka, M., Ishitobi, M., Jung, M., Fujisawa, T. X., Tanaka, S., Arai, S., Asano, M., Saito, D. N., Sadato, N., Tomoda, A., Omori, M., Sato, M., Okazawa, H., Higashida, H., & Wada, Y.
Affiliations
  • Kanazawa University (JP)
  • The University of Tokyo (JP)
  • University of Fukui (JP)
  • University of Tsukuba (JP)
  • Research Center for Child Mental Development, University of Fukui (JP)
  • National Institute for Physiological Sciences (JP)
  • Fukui Prefectural University (JP)
Corresponding author
Kosaka, H
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2016-08-23
Volume
6
Issue
8
Pages
e872-e872
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2016.152
PMC
PMC5022092
OpenAlex
W2514199772
Semantic Scholar
05449293f1770fc83a8b9c791d875bf5a5783d2d
Cited by
117
References
58
Citations by year
2026: 7 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 20 · 2021: 15 · 2020: 14 · 2019: 15 · 2018: 12 · 2017: 16 · 2015: 1
FWCI
22.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (publishedVersion)
  • Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion, cc-by)
Funders
  • Takeda Science Foundation
  • Japan Research Foundation for Clinical Pharmacology
  • Japan Agency for Medical Research and Development
  • Kanazawa University
  • Ministry of Education, Culture, Sports, Science and Technology (21220005, 15H01846)
  • University of Fukui
  • University of Tsukuba
  • SENSHIN Medical Research Foundation
  • Japan Society for the Promotion of Science (15H01846, 21220005, 15K12720, 26250024, 15H03106, 25293248, 15K08093, 21791120)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
oxytocin, high-functioning autism, autism spectrum disorder, oxytocin receptor gene, OXTR polymorphisms, dose dependency, intranasal oxytocin, young adults, sex differences
MeSH terms
Autism Spectrum Disorder, Administration, Intranasal, Adolescent, Adult, Autistic Disorder, Double-Blind Method, Female, Genotype, Humans, Male, Oxytocics, Oxytocin, Sex Factors, Treatment Outcome, Receptors, Oxytocin, Polymorphism, Single Nucleotide, Young Adult

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