Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder

Sikich, Linmarie; Kolevzon, Alexander; King, Bryan H.; McDougle, Christopher J.; Sanders, Kevin; Kim, Soo-Jeong; Spanos, Marina; Chandrasekhar, Tara; Trelles, Maria del Pilar; Rockhill, Carol; Palumbo, Michelle; Cundiff, Allyson Witters; Montgomery, Alicia; Siper, Paige M.; Minjarez, Mendy; Nowinski, Lisa A.; Marler, Sarah; Shuffrey, Lauren C.; Alderman, Cheryl; Weissman, Jordana; Zappone, Brooke; Mullett, Jennifer; Crosson, Hope; Hong, Natalie; Siecinski, Stephen K; Giamberardino, Stephanie N; Luo, Sheng; She, Lilin; Bhapkar, Manjushri; Dean, Russell; Scheer, Abby; Johnson, Jacqueline L.; Gregory, Simon; Veenstra‐VanderWeele, Jeremy

doi:10.1056/nejmoa2103583

Cited by 167 publications

(139 citation statements)

References 36 publications

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“…Although several studies have demonstrated intranasal delivery to the brain like the animal models, it appears that a relatively small fraction of the dose is reaching the CNS [ 7 , 8 ]. Recent studies, such as intranasal oxytocin for autism, have failed to replicate the effects in humans [ 9 ]. Many of these studies were simply using a saline solution to administer the drug to the nasal cavity, just like in the animal models.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System

Crowe

Hsu

2022

Pharmaceutics

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Neurological diseases continue to increase in prevalence worldwide. Combined with the lack of modifiable risk factors or strongly efficacious therapies, these disorders pose a significant and growing burden on healthcare systems and societies. The development of neuroprotective or curative therapies is limited by a variety of factors, but none more than the highly selective blood-brain barrier. Intranasal administration can bypass this barrier completely and allow direct access to brain tissues, enabling a large number of potential new therapies ranging from bioactive peptides to stem cells. Current research indicates that merely administering simple solutions is inefficient and may limit therapeutic success. While many therapies can be delivered to some degree without carrier molecules or significant modification, a growing body of research has indicated several methods of improving the safety and efficacy of this administration route, such as nasal permeability enhancers, gelling agents, or nanocarrier formulations. This review shall discuss promising delivery systems and their role in expanding the clinical efficacy of this novel administration route. Optimization of intranasal administration will be crucial as novel therapies continue to be studied in clinical trials and approved to meet the growing demand for the treatment of patients with neurological diseases.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System

Crowe

Hsu

2022

Pharmaceutics

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“…Oxytocin and balovaptan (vasopressin-V 1A receptor antagonist) were not efficacious in children/adolescents, based on substantial evidence from large trials, e.g., ( n = 290–339) [ 80 , 81 ]. In adults, however, oxytocin improved repetitive behaviors with small-to-medium effect-sizes and moderate-quality evidence.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

et al. 2022

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Background There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. Methods We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. Results We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. Limitations Most of the studies were inadequately powered (sample sizes of 20–80 participants), with short duration (8–13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. Conclusions Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

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“…However, it is clear that OXT peptides do have some effect on modulating social behaviors in mouse offspring. On the other hand, recent placebo-controlled trial using intranasal OXT therapy showed no significant effect on ASD children and adolescents, which can be explained because intranasal OXT administration may not reach sufficient OXT concentrations in OXT-responsive areas of the central nervous system ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

et al. 2022

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Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor β (ERβ) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERβ expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

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Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder

Cited by 167 publications

References 36 publications

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

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