A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism

doi:10.1067/mpd.2001.112474

The Journal of Pediatrics

Volume 138, Issue 5, May 2001, Pages 649-655

https://doi.org/10.1067/mpd.2001.112474 Get rights and content

Abstract

Objective: To determine whether a single injection of intravenous secretin results in measurable improvements in socialization and/or communication skills in children with autism. Study design: Sixty subjects with autism were randomly selected and assigned to either treatment or placebo group. Subjects in the treatment group received 2.0 clinical units of secretin per kilogram of body weight as a single intravenous dose. Subjects in the placebo group received normal saline solution. Neurodevelopmental and behavioral assessments were performed for all subjects before injection and at 3 and 6 weeks after injection. Results: Assessment of language skills and parents’ behavioral assessments revealed no significant differences between the treatment and placebo groups. Raters’ assessments of severity of autistic symptoms did not differ for the 2 groups at 6 weeks after injection. A marginally statistically significant improvement in autistic behaviors was seen in the treatment group at 3 weeks after injection (P =.051). Conclusions: A single dose of intravenous secretin does not appear to have significant effects on either parents’ perception of autistic behaviors or language skills at 6 weeks after injection. Transient, marginally significant improvements in autistic behaviors may occur in some children. (J Pediatr 2001;138:649-55)

Section snippets

Selection of Subjects

Subjects were recruited from 2 populations of children with autism: those followed up by clinicians at the Marcus Institute for Development and Learning and those followed up by the Children’s Healthcare of Atlanta at Scottish Rite neurologists. Potential subjects (n = 203 children aged 3 to 10 years with a diagnosis of autism) were identified. A total of 63 children were randomly selected to participate in the study. Three children failed to meet pre-testing criteria for participation in the

Results

Demographic and clinical characteristics for the secretin and placebo groups at baseline are displayed in Table I.

. Demographic and clinical characteristics of secretin and placebo groups

Variable	Secretin group (n = 30)	Placebo group (n = 30)
Age (mo)	84.6 (25.2)	83.5 (28.9)
Height (in)	45.8 (7.2)	46.5 (7.5)
Weight (kg)	27.8 (12.3)	26.6 (11.2)
Sex (%)
Male	73	77
Female	23	27
Race (%)
White	80	77
African American	17	13
Other	3	10
Age at symptom onset (mo)	18.2 (8.5)	20.1 (8.5)
Age at first diagnosis (mo)	33.1 (10.2)	33.7 (10.1)

Discussion

We report the results of a randomized, double-blind, placebo-controlled trial of intravenous secretin as a treatment for autism. No significant differences in autistic behavioral characteristics or overall communication skills were noted between the treatment and the control groups at 3 or 6 weeks after injection. Parents in both groups reported similar, statistically significant improvements in their children’s behaviors at 3 and 6 weeks. Given that the same degree of perceived improvement

Acknowledgements

We thank the parents and study participants and Ms Deborah Cressler-Leithe, RN, Dr Jean MacDonald, and Ms Susan Bryant of Children’s Healthcare of Atlanta for their tireless support and contributions to the study.

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Pharmacotherapy
2008, Clinical Assessment and Intervention for Autism Spectrum Disorders
This chapter is written for parents and other caregivers of persons with pervasive developmental disorders (PDDs) with the intent to help them gain more knowledge of when and how pharmacotherapy can and should be used as an important part of the comprehensive treatment of PDDs. This chapter reviews English-language studies published between 1994 and 2006 and carried out using the Entrez PubMed Database (www.pubmed.gov), which is a service of the US National Library of Medicine and the National Institute of Health. PubMed includes over 16 million citations from MEDLINE and other life science journals for biomedical articles back to the 1950s. The term ASD is used as a synonym of PDDs throughout this chapter. ASD is characterized by deficits in language usage, impairments in social reciprocity, and the presence of behavioral rigidity. ASD also has many coexisting neuropsychiatric disorders. It is quite reasonable to speculate that ASD is related to dysfunctions of certain neurotransmitter systems and that certain medications may be appropriate and effective in improving ASD and coexisting neuropsychiatric disorders.
Partial reversal of phencyclidine-induced impairment of prepulse inhibition by secretin
2005, Biological Psychiatry
Secretin is a “gut-brain” peptide whose neural function is as yet poorly understood. Several clinical studies have reported modestly increased social interaction in autistic children following intravenous secretin administration. Very recently secretin also was administered to schizophrenic patients and found to increase social interaction in some individuals.
In light of this finding, we assessed the ability of secretin to reverse phencyclidine- (PCP) induced impairment in prepulse inhibition (PPI), a leading animal model of sensorimotor gating deficits in schizophrenia.
Similar to atypical antipsychotics, secretin (1, 3, 10, 30, and 100 μg/kg) partially and dose-dependently reversed the PCP-induced deficit in PPI without significantly affecting baseline startle when administered intraperitoneally (IP) 10 minutes following IP administration of PCP (3 mg/kg).
This finding may be relevant to observations of antipsychotic efficacy of secretin in schizophrenic patients as well as our previous report that systemically administered secretin is capable of modulating conditioned fear, even at quite low doses.
Secretin is an ineffective treatment for pervasive developmental disabilities: A review of 15 double-blind randomized controlled trials
2005, Research in Developmental Disabilities
In 1998, Horvath et al. [Horvath, K., Stefanatos, G., Sokolski, K. N., Wachtel, R., Nabors, L., & Tildon, J. T. (1998). Improved social and language skills after secretin administration in patients with autism spectrum disorders. Journal of the Association of the Academy of Minority Physicians, 9, 9–15] reported an uncontrolled trial of secretin with three participants with autism, which apparently resulted in significant behavioral improvement. Subsequently, secretin was widely used. Sandler et al. [Sandler, A. D., Sutton, K. A., SeWeese, J., Girardi, M. A., Sheppard, V., & Bodfish, J. W. (1999). Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive and developmental disorder. The New England Journal of Medicine, 341, 1801–1806] reported the first double-blind trial of secretin with negative results. This article is a review of 15 double-blind trials of secretin. Almost none of the studies reported any significant effects and none concluded that secretin was effective. Transient effects of secretin, including both minor benefits and behavioral deterioration were reported, probably due to multiple statistical tests. Four papers reported data on differential responding in sub-groups of participants, including those with gastrointestinal symptoms. These effects were not replicable. At this time there is no robust evidence that secretin is an effective treatment for pervasive developmental disorders.
Predicted role of secretin and oxytocin in the treatment of behavioral and developmental disorders: implications for autism
2005, International Review of Neurobiology
Citation Excerpt :
The search for even partially ameliorative interventions is a goal for all parents of autistic children. Current pharmacologic treatments, such as anti‐psychotics, mood stabilizers, antidepressants, anticonvulsants, and single peptides treat single symptoms, often with unacceptable side effects and/or limited therapeutic effects (Ansorge et al., 2004; Coniglio et al., 2001; Dunn‐Geier et al., 2000; Kern et al., 2002; Lightdale et al., 2001; Owley et al., 2001; Posey and McDougle, 2000; Roberts et al., 2001; Sandler, 1999). Psychotherapeutic measures have also been attempted with limited success (Diggle et al., 2003; Langworthy‐Lam et al., 2002).
This chapter reviews evidence that two neuropeptides—secretin and oxytocin—are critical in the conditioning of infant adaptive behavioral patterns and that peptidergic mechanisms are abnormal in developmental disorders, such as autism. The clinical observations in the treatment of autism justify the role of peptides in the neurological manifestations of visceral diseases encompassing emotional/visceral brain regions abnormal in autism. The studies have thus demonstrated that (1) visceral inflammation activates visceral/emotional brain regions in areas known to be abnormal in autism, (2) secretin, like oxytocin, activates many of the same visceral/emotional brain regions that are dysregulated in chronic cerebral and visceral disorders, such as autism, (3) a structural basis for the mechanisms of action of secretin and oxytocin was clarified (4) secretin as well as oxytocin is synthesized in the hypothalamus and may act on structures involved in the pathophysiology of autism (5) secretin and oxytocin localize to perivascular and subependymal regions of the paraventricular hypothalamus, suggesting a chemosensory and secretory function.
Effects of secretin on extracellular GABA and other amino acid concentrations in the rat hippocampus
2005, International Review of Neurobiology
Citation Excerpt :
A specific effect that is described in several of the studies concerns the fact that within the secretin and the control groups a certain number of children showed improvements in their autistic behavior, which however did not differ by statistical significance. A possible explanation for this phenomenon could possibly be an effect of habituation of the children to the test situation; as well as a strong expectation effect (Coniglio, 2001; Corbett et al., 2001; Dunn‐Geier et al., 2000; Sandler et al., 1999; Unis et al., 2002). Lightdale et al. (2001) tried to replicate Horvath's results, and treated 20 autistic children with gastrointestinal problems with porcine secretin in an uncontrolled, prospective study.
This chapter examines the effects of secretin on the hippocampus of the rat in the metabolism of amino acids. The chapter focuses on glutamate and gamma-aminobutyric acid (GABA), which are the two most important brain transmitters in mammals. Secretin is applied intracerebroventiculary in three different dosages, to measure the direct neuromodulatory effects of the peptide. The results show an influence of extracellular concentrations of glutamate, aspartate, and GABA in the hippocampus using secretin; the extracellular concentration processes of other measured amino acids, that is, phenylalanine, alanine, methionine, glycine, ornithine, arginine, tyrosine, valine, leucine/ isoleucine, and citrullin are not significantly affected. An unusual aspect of the findings is the simultaneous rise of glutamate and GABA, as both of these brain transmitters are primarily associated with antagonistic effects on the CNS. The chapter presents several different ways in which both the main transmitter systems in the hippocampus can interact with one another and thereby influence one another's release.
Increased Amygdala fMRI Activation After Secretin Administration
2008, Experimental and Clinical Psychopharmacology

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^☆: Supported by Children’s Healthcare of Atlanta Foundation.

^☆☆: Reprint requests: Susan Coniglio, MD, The Marcus Institute at Emory University, 1605 Chantilly Dr, Ste 100, Atlanta, GA 30324.

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Original ArticlesA randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism☆,☆☆

Abstract

Section snippets

Selection of Subjects

Results

Discussion

Acknowledgements

Pharmacol Biochem Behav

Peptides

Improved social and language skills after secretin administration in patients with autistic spectrum disorders

J Assoc Acad Minor Phys

Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorders

N Engl J Med

Secretin update: March 1999

Autism Res Rev Int

Original Articles
A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism☆,☆☆