Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome

May combine two claims.

Oxytocin had no effect on heart rate, respiratory sinus arrhythmia, or heart rate variability.

“There was no effect of OTon heart rate, RSA or HRV”

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

Individual plots of heart rate data suggested that oxytocin increased heart rate in some participants and decreased heart rate in others.

“individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others.”

May combine two claims.

Oxytocin can be safely administered intranasally and is well tolerated by adolescent and adult male patients with fragile X syndrome.

“Safety data also showed that OT can be safely administered intranasally and is well tolerated by adolescent and adult male patients with FXS.”

May combine two claims.

For some participants (P1, P2, P5, P7), administration of either the 24 IU or 48 IU oxytocin dose appeared to result in decreased heart rates, whereas for other participants (P3, P6, P8), oxytocin administration appeared to result in increased heart rates.

“For some participants (e.g., P1, P2, P5 and P7), administration of either the 24 IU or 48 IU OT dose appeared to result in decreased heart rates, whereas for other participants (e.g., P3, P6 and P8), OT administration appeared to result in increased heart rates.”

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

The effect of oxytocin on participant heart rate levels was somewhat variable across participants.

“Visual inspection of the data suggests that the effect of OT on participant heart rate levels was somewhat variable across participants.”

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

Participant P7 developed Bell's Palsy on one side of his face a few days following his first visit to the lab.

“However, participant P7 developed Bell’s Palsy on one side of his face a few days following his first visit to the lab”

May combine two claims.

Salivary cortisol levels decreased in response to the 48 IU oxytocin dose, but not in response to the 24 IU dose.

“Conversely, salivary cortisol levels decreased in response to the 48 IU dose, but not in response to the 24 IU dose.”

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

Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X syndrome but not in their unaffected siblings.

“Increased cortisol was significantly associated with behavior problems in boys and girls with FXS but not in their unaffected siblings (Hessl et al., 2002).”

• cites Hessl et al., 2002 sourceNot checked yet

  Not checked in the free run.

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

FMRP expression is linked to social withdrawal, anxiety and depression in fragile X syndrome.

“FMRP expression (as quantified by immunocytochemistry) has been linked to many of these phenotypic characteristics of FXS, including social withdrawal, anxiety and depression”

• cites Lightbody and Reiss, 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Oxytocin is a hormone with prosocial, antistress, and anxiolytic effects.

“oxytocin (OT), a hormone with prosocial and anxiolytic effects”

• Also stated in: § 1. Introduction · plain

  “the neuropeptide oxytocin (OT), which has a variety of prosocial, antistress, and anxiolytic properties”

May combine two claims.

Boys with fragile X syndrome have increased heart rate and lower parasympathetic activity during experimental challenge.

“Other investigators studying spectral analysis of heart beat intervals have found that boys with FXS have increased heart rate and lower parasympathetic activity during experimental challenge (Boccia and Roberts, 2000; Hall et al., 2009a).”

• cites Boccia and Roberts, 2000Not checked yet

  Not checked in the free run.

• cites Hall et al., 2009aNot checked yet

  Not checked in the free run.

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

In males with fragile X syndrome, problematic behaviors often take the form of social deficits with peers, social avoidance, gaze aversion, qualitative abnormalities in communication, unusual responses to sensory stimuli, stereotypic behavior, inattention, impulsivity and hyperactivity.

“In males, problematic behaviors often take the form of social deficits with peers, social avoidance, gaze aversion, qualitative abnormalities in communication, unusual responses to sensory stimuli, stereotypic behavior, inattention, impulsivity and hyperactivity.”

May combine two claims.

Miller et al. (1999) found increased electrodermal response to stimulation and lower rates of habituation to stimulation in fragile X syndrome compared to age and gender matched control subjects.

“In this study, increased electrodermal response (EDR) to stimulation and lower rates of habituation to stimulation were found in FXS as compared to age and gender matched control subjects.”

• cites Miller et al. (1999) sourceNot checked yet

  Not checked in the free run.

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

FMRP is involved in regulating the glucocorticoid receptor in the hippocampus.

“the discovery that FMRP is involved in regulating the glucocorticoid receptor in the hippocampus (Brown et al., 2001).”

• cites Brown et al., 2001 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Individuals with fragile X syndrome, particularly males, often have abnormally strong physiological and behavioral responses to social stimuli, associated with increased levels of arousal and stress reactivity.

“Individuals with FXS, particularly males, often have abnormally strong physiological and behavioral responses to social stimuli, associated with increased levels of arousal and stress reactivity.”

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

Ten low-functioning males with fragile X syndrome aged 13-28 years were enrolled, and eight completed the study.

“Ten low-functioning males with FXS (aged 13–28 years) traveled to Stanford for the initial visit: 8 completed the study.”

• Also stated in: § 2.1. Subjects · plain

  “Eight subjects were therefore included in the present study.”

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

The most common problem behaviors observed in fragile X syndrome consist of hyperarousal, disturbance in language/communication, and social anxiety.

“Studies from our laboratory and others indicate that the most common problem behaviors observed in FXS consist of hyperarousal, disturbance in language/communication, and social anxiety (Reiss and Hall, 2007).”

• cites Reiss and Hall, 2007Not checked yet

  Not checked in the free run.

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

Centrally administered oxytocin facilitates contact-seeking, attachment bond formation, and social memory in rodents.

“Centrally administered OT facilitates contact-seeking, attachment bond formation, and social memory in rodents (Ferguson et al., 2000; Williams et al., 1992; Witt et al., 1992).”

• cites Ferguson et al., 2000 sourceNot checked yet

  Not checked in the free run.

• cites Williams et al., 1992 sourceNot checked yet

  Not checked in the free run.

• cites Witt et al., 1992 sourceNot checked yet

  Not checked in the free run.

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

Individuals with fragile X syndrome, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations.

“Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations.”

Classified as probably not a substantial claim.

Subjects received all of the treatments in random order over the three visits.

“Subjects received all of the treatments in random order over the 3 visits.”

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

Sample collection and handling procedures were developed in consultation with the fourth author to minimize the potential impact of contaminants, and confounding dietary and physiological factors on the assessment.

“All sample collection and handling procedures were developed in consultation with the fourth author (KJP) to minimize the potential impact of contaminants, and confounding dietary and physiological factors on the assessment (Hessl et al., 2002).”

• cites Hessl et al., 2002 sourceNot checked yet

  Not checked in the free run.

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

Intra- and inter-assay coefficients of variation were under 10%, and assay sensitivity was 0.215 nmol/L.

“Intra- and inter-assay coefficients of variation were under 10%, and assay sensitivity was 0.215 nmol/L (0.008 μg/dl).”

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

Age was included as a covariate in the cortisol and cardiac activity analyses.

“we included age as a covariate in the cortisol and cardiac activity analyses.”

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

Oxytocin administration has been shown to promote visual scanning of faces in patients with autism.

“promote visual scanning of faces (Andari et al., 2010)”

• cites Andari et al., 2010 sourceNot checked yet

  Not checked in the free run.

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

A similar social challenge procedure has been conducted in previous studies with individuals with fragile X syndrome.

“A similar social challenge procedure has been conducted in previous studies with individuals with FXS (Hall et al., 2006, 2009a).”

• cites Hall et al., 2006, 2009aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Similar doses of oxytocin have been administered to subjects in previous studies of social functioning.

“Similar doses of OT have been administered to subjects in previous studies of social functioning (Andari et al., 2010; Feifel et al., 2010; Guastella et al., 2008; Hollander et al., 2007; Ditzen et al., 2009).”

• cites Andari et al., 2010 sourceNot checked yet

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• cites Feifel et al., 2010 sourceNot checked yet

  Not checked in the free run.

• cites Guastella et al., 2008 sourceNot checked yet

  Not checked in the free run.

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

Female mice lacking the oxytocin gene exhibit enhanced corticosteroid responses to psychogenic stressors and enhanced anxiety on the elevated plus-maze compared to wildtype controls.

“Similarly, female mice lacking the oxytocin gene exhibit enhanced corticosteroid responses to psychogenic stressors and enhanced anxiety on the elevated plus-maze compared to wildtype controls (Amico et al., 2004; Mantella et al., 2003).”

• cites Amico et al., 2004 sourceNot checked yet

  Not checked in the free run.

• cites Mantella et al., 2003 sourceNot checked yet

  Not checked in the free run.

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

Oxytocin administration has been shown to increase emotion recognition in patients with autism.

“increase emotion recognition (Guastella et al., 2010)”

• cites Guastella et al., 2010 sourceNot checked yet

  Not checked in the free run.

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

Salivary cortisol was measured in duplicate using a commercially prepared radioimmunoassay.

“Salivary cortisol was measured in duplicate using a commercially prepared radioimmunoassay (Coat-a-Count, Siemens; Los Angeles, CA).”

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

Oxytocin administration has been shown to reduce repetitive behaviors in patients with autism.

“reduce repetitive behaviors (Hollander et al., 2003)”

• cites Hollander et al., 2003 sourceNot checked yet

  Not checked in the free run.

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

All procedures were approved by the local IRB at Stanford University and parental consent and subject assent were obtained in all cases.

“All procedures were approved by the local IRB at Stanford University and parental consent and subject assent were obtained in all cases.”

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

Similar work has not yet been published with intranasally administered oxytocin in humans.

“similar work has not yet been published with intranasally administered OT in humans.”

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

The randomization scheme was generated using an online randomization plan generator with an estimated sample size of 12.

“The randomization scheme was generated using an online randomization plan generator (http://www.randomization.com) with an estimated sample size of 12.”

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

Each dose was administered via two identical spray bottles made up by a Stanford pharmacist who also kept the randomization and blinding scheme.

“Each dose was administered via two identical spray bottles that were made up by a Stanford pharmacist who also kept the randomization and blinding scheme.”

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

Effects of intranasal oxytocin have been demonstrated with functional neuroimaging.

“Effects of intranasal OT have also been demonstrated with functional neuroimaging (Kirsch et al., 2005)”

• cites Kirsch et al., 2005 sourceNot checked yet

  Not checked in the free run.

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

Age and Vineland-II score were included as covariates in the eye gaze analysis.

“Age and Vineland-II score were included as covariates in the eye gaze analysis.”

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

Correlations between duplicate samples within each assay were typically greater than 95%.

“Correlations between duplicate samples within each assay were typically greater than 95%.”

May combine two claims.

Intranasal oxytocin administration in fragile X syndrome may work mechanistically by dampening amygdala reactivity toward socially threatening and anxiety-provoking stimuli, decreasing HPA axis activation, and increasing social motivation.

“Intranasal OT administration in FXS may work mechanistically by dampening amygdala reactivity toward socially threatening and anxiety-provoking stimuli (Kirsch et al., 2005; Petrovic et al., 2008), decreasing HPA axis activation, and increasing social motivation (Witt et al., 1992).”

• cites Kirsch et al., 2005 sourceNot checked yet

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• cites Petrovic et al., 2008 sourceNot checked yet

  Not checked in the free run.

• cites Witt et al., 1992 sourceNot checked yet

  Not checked in the free run.

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

Sample collection occurred between 2 and 4 pm for all subjects to control for circadian variation in cortisol levels.

“Sample collection occurred between 2 and 4 pm for all subjects to control for circadian variation in cortisol levels (Dorn et al., 2007; Ranjit et al., 2005).”

• cites Dorn et al., 2007 sourceNot checked yet

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• cites Ranjit et al., 2005 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The placebo solution contained all inactive ingredients except for the neuropeptide, to avoid subjective substance effects other than those caused by oxytocin.

“In order to avoid any subjective substance effects (e.g., olfactory effects) other than those caused by OT, the placebo solution was compounded by a local pharmacy and contained all inactive ingredients except for the neuropeptide.”

May combine two claims.

In a previous study, heart rate levels in males with fragile X syndrome, aged 8-20 years, averaged approximately 90 bpm at baseline, whereas heart rate levels in their same-gender typically developing siblings averaged approximately 75 bpm.

“In a previous study that included a social challenge, we found that heart rate levels in males with FXS, aged 8–20 years, averaged approximately 90 bpm at baseline, whereas heart rate levels in their same-gender typically developing siblings averaged approximately 75 bpm (Hall et al., 2009a).”

• cites Hall et al., 2009aNot checked yet

  Not checked in the free run.

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

The inter-beat interval data were first inspected to remove artifacts and to correct errors.

“The inter-beat interval (IBI) data were first inspected to remove artifacts and to correct errors.”

May combine two claims.

CNS penetration following intranasal administration occurs within minutes and delivery to the brain is thought to occur via an extracellular pathway.

“CNS penetration following intranasal administration occurs within minutes and delivery to the brain is thought to occur via an extracellular pathway (e.g., patent intercellular clefts in the olfactory epithelium) (Balin et al., 1986)”

• cites Balin et al., 1986 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The extant literature strongly suggests that intranasally administered oxytocin is safe and associated with very few adverse effects.

“The extant literature strongly suggests that intranasally administered OT is safe and associated with very few adverse effects.”

May combine two claims.

Both the subjects and the investigators were blind as to which compound the patient received on a given visit.

“both the subjects and the investigators were therefore blind as to which compound the patient received on a given visit.”

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

The videotapes for each social challenge were reviewed by the third author, who was also blinded.

“The videotapes for each social challenge was transferred to DVD and subsequently reviewed by the third author (BEM) (who was also blinded).”

May combine two claims.

Participants were successfully randomized and counterbalanced to the conditions.

“we confirmed post-study that the participants had been randomized and counterbalanced.”

• Also stated in: § 2.2. Dosing plan · plain

  “Subjects were therefore successfully randomized and counterbalanced to the conditions.”

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

Effects of intranasal oxytocin have been demonstrated with standardized testing, self-report or expert ratings.

“as well as with standardized testing, self-report or expert ratings (Kosfeld et al., 2005).”

• cites Kosfeld et al., 2005 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Oxytocin administration has been shown to improve social decision-making in patients with autism.

“OT administration has been shown to improve social decision-making (Andari et al., 2010; Hollander et al., 2007)”

• cites Andari et al., 2010 sourceNot checked yet

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• cites Hollander et al., 2007 sourceNot checked yet

  Not checked in the free run.

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

All samples from a particular subject were analyzed in the same assay run.

“All samples from a particular subject were analyzed in the same assay run.”

May combine two claims.

Centrally administered oxytocin diminishes stress-induced adrenocorticotropic hormone and corticosterone release, and inhibits corticotropin releasing factor mRNA expression in the hypothalamus during restraint stress in rats.

“Centrally administered OT also diminishes stress-induced adrenocorticotropic hormone (ACTH) and cor-ticosterone release, and inhibits corticotropin releasing factor (CRF) mRNA expression in the hypothalamus during restraint stress in rats (Windle et al., 2004).”

• cites Windle et al., 2004 sourceNot checked yet

  Not checked in the free run.

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

Vasopressin has been detected in cerebrospinal fluid and plasma within 30 min of intranasal administration.

“while vasopressin has been detected in cerebrospinal fluid (CSF) and plasma within 30 min of intranasal administration (Born et al., 1998, 2002)”

• cites Born et al., 1998, 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

When administered intranasally, oxytocin attenuates the neuroendocrine stress response in rodents and monkeys and alters emotion regulation in humans.

“When administered intranasally, OT also attenuates the neuroendocrine stress response in rodents and monkeys and alters emotion regulation in humans (Heinrichs et al., 2003; Parker et al., 2005; Windle et al., 2004).”

• cites Heinrichs et al., 2003 sourceNot checked yet

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• cites Parker et al., 2005 sourceNot checked yet

  Not checked in the free run.

• cites Windle et al., 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Six of the eight participants included in this study were completely medication-free, with one participant remaining on a low dose antidepressant and another taking an antiepileptic medication.

“Six of the eight participants included in this study were completely medication-free with one participant remaining on a low dose antidepressant and another taking an antiepileptic medication.”

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

In a study involving couples engaged in a conflict discussion, salivary cortisol levels were found to decrease following intranasal administration of 40 IU oxytocin.

“Interestingly, in a study involving couples engaged in a conflict discussion, salivary cortisol levels were also found to decrease following intranasal administration of 40 IU OT (Ditzen et al., 2009).”

• cites Ditzen et al., 2009 sourceNot checked yet

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

In a previous study, eye gaze in fragile X syndrome could be significantly improved following the application of behavioral (non-pharmacological) reinforcement techniques conducted over several days.

“In a previous study, we found that eye gaze in FXS could be significantly improved following the application of behavioral (non-pharmacological) reinforcement techniques conducted over several days (Hall et al., 2009b).”

• cites Hall et al., 2009bNot checked yet

  Not checked in the free run.